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Publisher
- Frontiers Media S.A. (364) (remove)
Microglia are the resident immune cells of the central nervous system (CNS) and play a major role in the regulation of brain homeostasis. To maintain their cellular protein homeostasis, microglia express standard proteasomes and immunoproteasomes (IP), a proteasome isoform that preserves protein homeostasis also in non-immune cells under challenging conditions. The impact of IP on microglia function in innate immunity of the CNS is however not well described. Here, we establish that IP impairment leads to proteotoxic stress and triggers the unfolded and integrated stress responses in mouse and human microglia models. Using proteomic analysis, we demonstrate that IP deficiency in microglia results in profound alterations of the ubiquitin-modified proteome among which proteins involved in the regulation of stress and immune responses. In line with this, molecular analysis revealed chronic activation of NF-κB signaling in IP-deficient microglia without further stimulus. In addition, we show that IP impairment alters microglial function based on markers for phagocytosis and motility. At the molecular level IP impairment activates interferon signaling promoted by the activation of the cytosolic stress response protein kinase R. The presented data highlight the importance of IP function for the proteostatic potential as well as for precision proteolysis to control stress and immune signaling in microglia function.
Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets.
Staphylococcus aureus has acquired resistance to antibiotics since their first use. The S. aureus protein NorA, an efflux pump belonging to the major facilitator superfamily (MFS), contributes to resistance to fluoroquinolones (e.g., ciprofloxacin), biocides, dyes, quaternary ammonium compounds, and antiseptics. Different compounds have been identified as potential efflux pump inhibitors (EPIs) of NorA that result in increased intracellular concentration of antibiotics, restoring their antibacterial activity and cell susceptibility. However, none of the currently known EPIs have been approved for clinical use, probably due to their toxicity profiles. In the present study, we screened approved drugs for possible efflux pump inhibition. By screening a compound library of approximately 1200 different drugs, we identified nilotinib, a tyrosine kinase inhibitor, as showing the best efflux pump inhibitory activity, with a fractional inhibitory concentration index of 0.1875, indicating synergism with ciprofloxacin, and a minimum effective concentration as low as 0.195 μM. Moreover, at 0.39 μM, nilotinib, in combination with 8 μg/mL of ciprofloxacin, led to a significant reduction in biofilm formation and preformed mature biofilms. This is the first description of an approved drug that can be used as an efflux pump inhibitor and to reduce biofilms formation at clinically achievable concentrations.
Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.
Polyethylene terephthalate (PET) is a mass-produced petroleum-based non-biodegradable plastic that contributes to the global plastic pollution. Recently, biocatalytic degradation has emerged as a viable recycling approach for PET waste, especially with thermophilic polyester hydrolases such as a cutinase (LCC) isolated from a leaf-branch compost metagenome and its variants. To improve the enzymatic PET hydrolysis performance, we fused a chitin-binding domain (ChBD) from Chitinolyticbacter meiyuanensis SYBC-H1 to the C-terminus of the previously reported LCCICCG variant, demonstrating higher adsorption to PET substrates and, as a result, improved degradation performance by up to 19.6% compared to with its precursor enzyme without the binding module. For compare hydrolysis with different binding module, the catalytic activity of LCCICCG-ChBD, LCCICCG-CBM, LCCICCG-PBM and LCCICCG-HFB4 were further investigated with PET substrates of various crystallinity and it showed measurable activity on high crystalline PET with 40% crystallinity. These results indicated that fusing a polymer-binding module to LCCICCG is a promising method stimulating the enzymatic hydrolysis of PET.
Sturgeons are among the most ancient linages of actinopterygians. At present, many sturgeon species are critically endangered. Surrogate production could be used as an affordable and a time-efficient method for endangered sturgeons. Our study established a method for identifying and isolating type A spermatogonia from different developmental stages of testes using flow cytometric cell sorting (FCM). Flow cytometric analysis of a whole testicular cell suspension showed several well-distinguished cell populations formed according to different values of light scatter parameters. FCM of these different cell populations was performed directly on glass slides for further immunocytochemistry to identify germ cells. Results showed that the cell population in gate P1 on a flow cytometry plot (with high forward scatter and high side scatter parameter values) contains the highest amount of type A spermatogonia. The sorted cell populations were characterized by expression profiles of 10 germ cell specific genes. The result confirmed that setting up for the P1 gate could precisely sort type A spermatogonia in all tested testicular developmental stages. The P2 gate, which was with lower forward scatter and side scatter values mostly, contained type B spermatogonia at a later maturing stage. Moreover, expressions of plzf, dnd, boule, and kitr were significantly higher in type A spermatogonia than in later developed germ cells. In addition, plzf was firstly found as a reliable marker to identify type A spermatogonia, which filled the gap of identification of spermatogonial stem cells in sterlet. It is expected to increase the efficiency of germ stem cell culture and transplantation with plzf identification. Our study thus first addressed a phenotypic characterization of a pure type A spermatogonia population in sterlet. FCM strategy can improve the production of sturgeons with surrogate broodstock and further the analysis of the cellular and molecular mechanisms of sturgeon germ cell development.
Body-size variability results from a variety of extrinsic and intrinsic factors (environmental and biological influences) underpinned by phylogeny. In ostracodes it is assumed that body size is predominantly controlled by ecological conditions, but investigations have mostly focused on local or regional study areas. In this study, we investigate the geographical size variability (length, height, and width) of Holocene and Recent valves of the salinity-tolerant ostracode species Cyprideis torosa within a large geographical area (31°–51° latitude, and 12°–96° longitude). It is shown that distant local size clusters of Cyprideis torosa are framed within two large-scale geographical patterns. One pattern describes the separation of two different size classes (i.e., morphotypes) at around ∼42° N. The co-occurrence of both size morphotypes in the same habitats excludes an environmental control on the distribution of the morphotypes but rather could point to the existence of two differentiated lineages. Generally, correlations between valve size and environmental parameters (salinity, geographical positions) strongly depend on the taxonomic resolution. While latitude explains the overall size variability of C. torosa sensu lato (i.e., undifferentiated for morphotypes), salinity-size correlations are restricted to the morphotype scale. Another large-scale pattern represents a continuous increase in valve size of C. torosa with latitude according to the macroecological pattern referred as Bergmann trend. Existing explanations for Bergmann trends insufficiently clarify the size cline of C. torosa which might be because these models are restricted to intraspecific levels. The observed size-latitude relationship of C. torosa may, therefore, result from interspecific divergence (i.e., size ordered spatially may result from interspecific divergence sorting) while environmental influence is of minor importance. Our results imply that geographical body-size patterns of ostracodes are not straightforward and are probably not caused by universal mechanisms. Consideration of phylogenetic relationships of ostracodes is therefore necessary before attempting to identify the role of environmental controls on body size variability.
Inflammasome activation and formation of ASC specks in patients with juvenile idiopathic arthritis
(2023)
Objective
The formation of large intracellular protein aggregates of the inflammasome adaptor ASC is a hallmark of inflammasome activation and characteristic of autoinflammation. Inflammasome activated cells release the highly proinflammatory cytokine IL-1β in addition to ASC specks into the extracellular space. Autoinflammatory activity has been demonstrated in systemic JIA, however minimal data exist on the role of inflammasomes in other JIA subtypes. We therefore investigated, if pyroptotic cells are present in the circulation of oligo- and poly-articular JIA.
Methods
Peripheral blood of JIA patients (n = 46) was investigated for ASC speck formation, a key step in inflammasome activation, by flow cytometry and immunofluorescence. Free ASC and proinflammatory cytokine levels were determined by ELISA and multiplex assay.
Results
Oligo-articular JIA patients showed a significantly increased proportion of ASC speck+ monocytes compared to poly-articular JIA patients. In serum free ASC alone is not sufficient to assess inflammasome activity and does not correlate with ASC speck+ monocytes. Compared to control several cytokines were significantly elevated in samples of JIA patients. JIA serum containing antinuclear antibodies, incubated with ASC specks boosts a secondary inflammation by IL-1β production in macrophages.
Conclusion
For the first time, we detect ex vivo inflammasome activation by ASC speck formation in oligo- and poly-articular JIA patients. Most notably, inflammasome activation was significantly higher in oligo- compared to poly-articular JIA patients. This data suggests that inflammasome derived autoinflammation may have a greater influence in the previously thought autoimmune oligo-articular JIA patients.
Objectives: Several clinical disease activity indices (DAIs) have been developed to noninvasively assess mucosal healing in pediatric Crohn’s disease (CD). However, their clinical application can be complex. Therefore, we present a new way to identify the most informative biomarkers for mucosal inflammation from current markers in use and, based on this, how to obtain an easy-to-use DAI for clinical practice. A further aim of our proof-of-concept study is to demonstrate how the performance of such a new DAI can be compared to that of existing DAIs.
Methods: The data of two independent study cohorts, with 167 visits from 109 children and adolescents with CD, were evaluated retrospectively. A variable selection based on a Bayesian ordinal regression model was applied to select clinical or standard laboratory parameters as predictors, using an endoscopic outcome. The predictive performance of the resulting model was compared to that of existing pediatric DAIs.
Results: With our proof-of-concept dataset, the resulting model included C-reactive protein (CRP) and fecal calprotectin (FC) as predictors. In general, our model performed better than the existing DAIs. To show how our Bayesian approach can be applied in practice, we developed a web application for predicting disease activity for a new CD patient or visit.
Conclusions: Our work serves as a proof-of-concept, showing that the statistical methods used here can identify biomarkers relevant for the prediction of a clinical outcome. In our case, a small number of biomarkers is sufficient, which, together with the web interface, facilitates the clinical application. However, the retrospective nature of our study, the rather small amount of data, and the lack of an external validation cohort do not allow us to consider our results as the establishment of a novel DAI for pediatric CD. This needs to be done with the help of a prospective study with more data and an external validation cohort in the future.
The Immunomodulator 1-Methyltryptophan Drives Tryptophan Catabolism Toward the Kynurenic Acid Branch
(2020)
Background: Animal model studies revealed that the application of 1-methyltryptophan (1-MT), a tryptophan (TRP) analog, surprisingly increased plasma levels of the TRP metabolite, kynurenic acid (KYNA). Under inflammatory conditions, KYNA has been shown to mediate various immunomodulatory effects. Therefore, the present study aims to confirm and clarify the effects of 1-MT on TRP metabolism in mice as well as in humans.
Methods: Splenocytes from Balb/C or indoleamine 2,3-dioxygenase knockout (IDO1−/−) mice or whole human blood were stimulated with 1-MT for 6, 24, or 36 h. C57BL/6 mice received 1-MT in drinking water for 5 days. Cell-free supernatants and plasma were analyzed for TRP and its metabolites by tandem mass spectrometry (MS/MS).
Results: 1-MT treatment induced an increase in TRP and its metabolite, KYNA in Balb/C, IDO−/− mice, and in human blood. Concurrently, the intermediate metabolite kynurenine (KYN), as well as the KYN/TRP ratio, were reduced after 1-MT treatment. The effects of 1-MT on TRP metabolites were similar after the in vivo application of 1-MT to C57BL/6 mice.
Conclusions: The data indicate that 1-MT induced an increase of KYNA ex vivo and in vivo confirming previously described results. Furthermore, the results of IDO−/− mice indicate that this effect seems not to be mediated by IDO1. Due to the proven immunomodulatory properties of KYNA, a shift toward this branch of the kynurenine pathway (KP) may be one potential mode of action by 1-MT and should be considered for further applications.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Objective
Acute pancreatitis (AP) is an inflammatory disorder, the severe form of which is burdened with multi-organ dysfunction and high mortality. The pathogenesis of life –threatening organ complications, such as respiratory and renal failure, is unknown.
Design
Organ dysfunction was investigated in a mouse model of AP. The influence of monocytes and neutrophils on multi organ dysfunction syndrome (MODS) was investigated in vivo by antibody depletion. Using real-time-fluorescence and deformability-cytometry (RT-DC) analysis we determined the mechanical properties of neutrophils and monocytes during AP. Furthermore, blood samples of pancreatitis patients were used to characterize severity-dependent chemokine profiles according to the revised Atlanta classification.
Results
Similar to AP in humans, severe disease in the mouse model associates with organ dysfunction mainly of lung and kidney, which is triggered by a mobilisation of Ly6g-/CD11b+/Ly6c hi monocytes, but not of Ly6g+/CD11b+ neutrophils. Monocyte depletion by anti-CCR2 antibody treatment ameliorated lung function (oxygen consumption) without interfering with the systemic immune response. RT-DC analysis of circulation monocytes showed a significant increase in cell size during SAP, but without a compensatory increase in elasticity. Patient chemokine profiles show a correlation of AP severity with monocyte attracting chemokines like MCP-1 or MIG and with leukocyte mobilisation.
Conclusion
In AP, the physical properties of mobilized monocytes, especially their large size, result in an obstruction of the fine capillary systems of the lung and of the kidney glomeruli. A selective depletion of monocytes may represent a treatment strategy for pancreatitis as well as for other inflammation-related disorders.
Background/Aims
Patients with chronic pancreatitis (CP) have an increased risk of malnutrition, a condition linked to reduced muscle mass and physical performance. We have investigated the risk factors, phenotypic presentation, and health implications associated with malnutrition in CP.
Materials and Methods
In a multicenter cross-sectional study we recruited patients with confirmed CP and healthy volunteers as a control group. Malnutrition was diagnosed according to the criteria proposed by the Global Leadership Initiative on Malnutrition. We performed detailed examinations of body composition and physical function as well as testing of routine blood parameters and markers of inflammation.
Results
We included 66 patients [mean (±SD) age: 56.0 (±14.5) years; 51 males] and an equal number of age- and sex-matched controls. Moderate malnutrition was diagnosed in 21% (n = 14) and severe malnutrition in 42% (n = 28) of patients. Besides weight loss malnourished patients showed lower fat and skeletal muscle mass compared to both non-malnourished subjects and healthy controls. Only in severe malnutrition, blood parameters reflected elevated inflammation and reduced muscle reserves. Handgrip strength in patients did not differ by nutritional status but there was a significant correlation (rho = 0.705, p < 0.001) with skeletal muscle mass. Although 20 patients (30%) had pathologically reduced skeletal muscle mass, only two individuals (3%) had sarcopenia with concomitantly reduced handgrip strength.
Conclusion
Malnutrition is a frequent complication of CP characterized by loss of skeletal muscle mass. As this condition becomes evident only at an advanced stage, regular testing for altered body composition is recommended. Suitable biomarkers and the link between loss of muscle mass and physical function require further investigation.
Clinical Trial Registration
[https://clinicaltrials.gov/ct2/show/NCT04474743], identifier [NCT04474743].
Background
The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level.
Research Design and Methods
Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE).
Results
Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated.
Conclusions
Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
We present the first systematic literature review on stress and burnout in K−12 teachers during the COVID-19 pandemic. Based on a systematic literature search, we identified 17 studies that included 9,874 K−12 teachers from around the world. These studies showed some indication that burnout did increase during the COVID-19 pandemic. There were, however, almost no differences in the levels of stress and burnout experienced by K−12 teachers compared to individuals employed in other occupational fields. School principals' leadership styles emerged as an organizational characteristic that is highly relevant for K−12 teachers' levels of stress and burnout. Individual teacher characteristics associated with burnout were K−12 teachers' personality, self-efficacy in online teaching, and perceived vulnerability to COVID-19. In order to reduce stress, there was an indication that stress-management training in combination with training in technology use for teaching may be superior to stress-management training alone. Future research needs to adopt more longitudinal designs and examine the interplay between individual and organizational characteristics in the development of teacher stress and burnout during the COVID-19 pandemic and beyond.
The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the main proteolytic systems involved in cellular homeostasis. Since cardiomyocytes, as terminally differentiated cells, lack the ability to share damaged proteins with their daughter cells, they are especially reliant on these protein degradation systems for their proper function. Alterations of the UPS and ALP have been reported in a wide range of cardiac diseases, including cardiomyopathies. In this study, we determined whether the UPS and ALP are altered in a mouse model of eccentric left ventricular (LV) hypertrophy expressing both cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter (double transgenic; DTG). Compared to wild-type (WT) littermates, DTG mice showed higher end-diastolic (ED) LV wall thicknesses and diameter with preserved ejection fraction (EF). The cardiomyopathic phenotype was further confirmed by an upregulation of the fetal gene program and genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling. Likewise, higher NT-proBNP levels were detected in DTG mice. Investigation of the UPS showed elevated steady-state levels of (poly)ubiquitinated proteins without alterations of all proteasomal activities in DTG mice. Evaluation of ALP key marker revealed a mixed pattern with higher protein levels of microtubule-associated protein 1 light chain 3 beta (LC3)-I and lysosomal-associated membrane protein-2, lower protein levels of beclin-1 and FYVE and coiled-coil domain-containing protein 1 (FYCO1) and unchanged protein levels of p62/SQSTM1 in DTG mice when compared to WT. At transcriptional level, a > 1.2-fold expression was observed for Erbb2, Hdac6, Lamp2, Nrg1, and Sqstm1, while a < 0.8-fold expression was revealed for Fyco1 in DTG mice. The results related to the ALP suggested overall a repression of the ALP during the initiation process, but an induction of the ALP at the level of autophagosome-lysosome fusion and the delivery of ubiquitinated cargo to the ALP for degradation.
Intestinal transporter proteins are known to affect the pharmacokinetics and in turn the efficacy and safety of many orally administered drugs in a clinically relevant manner. This knowledge is especially well-established for intestinal ATP-binding cassette transporters such as P-gp and BCRP. In contrast to this, information about intestinal uptake carriers is much more limited although many hydrophilic or ionic drugs are not expected to undergo passive diffusion but probably require specific uptake transporters. A transporter which is controversially discussed with respect to its expression, localization and function in the human intestine is the organic cation transporter 1 (OCT1). This review article provides an up-to-date summary on the available data from expression analysis as well as functional studies in vitro, animal findings and clinical observations. The current evidence suggests that OCT1 is expressed in the human intestine in small amounts (on gene and protein levels), while its cellular localization in the apical or basolateral membrane of the enterocytes remains to be finally defined, but functional data point to a secretory function of the transporter at the basolateral membrane. Thus, OCT1 should not be considered as a classical uptake transporter in the intestine but rather as an intestinal elimination pathway for cationic compounds from the systemic circulation.
Life-threatening toxic shock syndrome is often caused by the superantigen toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus. A well-known risk factor is the lack of neutralizing antibodies. To identify determinants of the anti-TSST-1 antibody response, we examined 976 participants of the German population-based epidemiological Study of Health in Pomerania (SHIP-TREND-0). We measured anti-TSST-1 antibody levels, analyzed the colonization with TSST-1-encoding S. aureus strains, and performed a genome-wide association analysis of genetic risk factors. TSST-1-specific serum IgG levels varied over a range of 4.2 logs and were elevated by a factor of 12.3 upon nasal colonization with TSST-1-encoding S. aureus. Moreover, the anti-TSST-1 antibody levels were strongly associated with HLA class II gene loci. HLA-DRB1*03:01 and HLA-DQB1*02:01 were positively, and HLA-DRB1*01:01 as well as HLA-DQB1*05:01 negatively associated with the anti-TSST-1 antibody levels. Thus, both toxin exposure and HLA alleles affect the human antibody response to TSST-1.
Inflammation is part of the body's immune response in order to remove harmful stimuli—like pathogens, irritants or damaged cells—and start the healing process. Recurrent or chronic inflammation on the other side seems a predisposing factor for carcinogenesis and has been found associated with cancer development. In chronic pancreatitis mutations of the cationic trypsinogen (PRSS1) gene have been identified as risk factors of the disease. Hereditary pancreatitis (HP) is a rare cause of chronic pancreatic inflammation with an early onset, mostly during childhood. HP often starts with recurrent episodes of acute pancreatitis and the clinical phenotype is not very much different from other etiologies of the disease. The long-lasting inflammation however generates a tumor promoting environment and represents a major risk factor for tumor development This review will reflect our knowledge concerning the specific risk of HP patients to develop pancreatic cancer.
Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.
N6-methyladenosine (m6A) RNA methylation is an emerging epigenetic modification in recent years and epigenetic regulation of the immune response has been demonstrated, but the potential role of m6A modification in GBM tumor microenvironment (TME) cell infiltration and stemness remain unknown. The m6A modification patterns of 310 GBM samples were comprehensively evaluated based on 21 m6A regulators, and we systematically correlated these modification patterns with TME cell infiltration characteristics and stemness characteristics. Construction of m6Ascore to quantify the m6A modification patterns of individual GBM samples using a principal component analysis algorithm. We identified two distinct patterns of m6A modification. The infiltration characteristics of TME cells in these two patterns were highly consistent with the immunophenotype of the GBM, including the immune activation differentiation pattern and the immune desert dedifferentiation pattern. We also identified two modes of regulation of immunity and stemness by m6A methylation. Stromal activation and lack of effective immune infiltration were observed in the high m6Ascore subtype. Pan-cancer analysis results illustrate a significant correlation between m6AScore and tumor clinical outcome, immune infiltration, and stemness. Our work reveals that m6A modifications play an important role in the development of TME and stemness diversity and complexity. Patients with a low m6AScore showed significant therapeutic advantages and clinical benefits. Assessing the m6A modification pattern of individual tumors will help enhance our knowledge of TME infiltration and stemness characteristics, contribute to the development of immunotherapeutic strategies.
Introduction: The environmental bacterium Burkholderia pseudomallei causes the often fatal and massively underreported infectious disease melioidosis. Antigens inducing protective immunity in experimental models have recently been identified and serodiagnostic tools have been improved. However, further elucidation of the antigenic repertoire of B. pseudomallei during human infection for diagnostic and vaccine purposes is required. The adaptation of B. pseudomallei to very different habitats is reflected by a huge genome and a selective transcriptional response to a variety of conditions. We, therefore, hypothesized that exposure of B. pseudomallei to culture conditions mimicking habitats encountered in the human host might unravel novel antigens that are recognized by melioidosis patients.
Methods and results: In this study, B. pseudomallei was exposed to various stress and growth conditions, including anaerobiosis, acid stress, oxidative stress, iron starvation and osmotic stress. Immunogenic proteins were identified by probing two-dimensional Western blots of B. pseudomallei intracellular and extracellular protein extracts with sera from melioidosis patients and controls and subsequent MALDI-TOF MS. Among B. pseudomallei specific immunogenic signals, 90 % (55/61) of extracellular immunogenic proteins were identified by acid, osmotic or oxidative stress. A total of 84 % (44/52) of intracellular antigens originated from the stationary growth phase, acidic, oxidative and anaerobic conditions. The majority of the extracellular and intracellular protein antigens were identified in only one of the various stress conditions. Sixty-three immunoreactive proteins and an additional 38 candidates from a literature screening were heterologously expressed and subjected to dot blot analysis using melioidosis sera and controls. Our experiments confirmed melioidosis-specific signals in 58 of our immunoproteome candidates. These include 15 antigens with average signal ratios (melioidosis:controls) greater than 10 and another 26 with average ratios greater than 5, including new promising serodiagnostic candidates with a very high signal-to-noise ratio.
Conclusion: Our study shows that a comprehensive B. pseudomallei immunoproteomics approach, using conditions which are likely to be encountered during infection, can identify novel antibody targets previously unrecognized in human melioidosis.
Introduction
Proteasome inhibition is first line therapy in multiple myeloma (MM). The immunological potential of cell death triggered by defects of the ubiquitin-proteasome system (UPS) and subsequent perturbations of protein homeostasis is, however, less well defined.
Methods
In this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD).
Results
Our data show that while BTZ treatment triggers sterile type I interferon (IFN) responses, exposure of the cells to ONX0914 or RA190 was mostly immunologically silent. Interestingly, inhibition of protein de-ubiquitination by PR619 was associated with the acquisition of a strong type I IFN gene signature which relied on key components of the unfolded protein and integrated stress responses including inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR) and general control nonderepressible 2 (GCN2). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms.
Conclusion
Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.
Intranasal Vaccination With Lipoproteins Confers Protection Against Pneumococcal Colonisation
(2018)
Streptococcus pneumoniae is endowed with a variety of surface-exposed proteins representing putative vaccine candidates. Lipoproteins are covalently anchored to the cell membrane and highly conserved among pneumococcal serotypes. Here, we evaluated these lipoproteins for their immunogenicity and protective potential against pneumococcal colonisation. A multiplex-based immunoproteomics approach revealed the immunogenicity of selected lipoproteins. High antibody titres were measured in sera from mice immunised with the lipoproteins MetQ, PnrA, PsaA, and DacB. An analysis of convalescent patient sera confirmed the immunogenicity of these lipoproteins. Examining the surface localisation and accessibility of the lipoproteins using flow cytometry indicated that PnrA and DacB were highly abundant on the surface of the bacteria. Mice were immunised intranasally with PnrA, DacB, and MetQ using cholera toxin subunit B (CTB) as an adjuvant, followed by an intranasal challenge with S. pneumoniae D39. PnrA protected the mice from pneumococcal colonisation. For the immunisation with DacB and MetQ, a trend in reducing the bacterial load could be observed, although this effect was not statistically significant. The reduction in bacterial colonisation was correlated with the increased production of antigen-specific IL-17A in the nasal cavity. Immunisation induced high systemic IgG levels with a predominance for the IgG1 isotype, except for DacB, where IgG levels were substantially lower compared to MetQ and PnrA. Our results indicate that lipoproteins are interesting targets for future vaccine strategies as they are highly conserved, abundant, and immunogenic.
Stigma of Mental Illness in Germans and Turkish Immigrants in Germany: The Effect of Causal Beliefs
(2019)
Background: Stigma poses an additional burden for people suffering from mental illness, one that often impairs their social participation and can prevent them from seeking adequate help. It is therefore crucial to understand how stigma develops in order to counteract it by setting up effective evidence-based anti-stigma interventions. The present study examines the effect of causal beliefs on stigmatizing behavioral intentions, namely people's desire to distance themselves from persons with mental illness. In addition, we draw cross-cultural comparisons between native Germans and Turkish immigrants to investigate the influence of culture on stigma and causal beliefs and to broaden knowledge on the biggest immigrant group in Germany and on immigrants in Western countries in general.
Methods: n = 302 native Germans and n = 173 Turkish immigrants were presented either a depression or a schizophrenia vignette. Then, causal beliefs, emotional reaction and desire for social distance were assessed with questionnaires. Path analyses were carried out to investigate the influence of causal beliefs on the desire for social distance and their mediation by emotional reactions for Germans and Turkish immigrants, respectively.
Results: We found an influence of causal beliefs on the desire for social distance. Emotional reactions partly mediated this relationship. Causal attribution patterns as well as the relationship between causal attributions and stigma varied across both subsamples and mental illnesses. In the German subsample, the ascription of unfavorable personal traits resulted in more stigma. In the Turkish immigrant subsample, supernatural causal beliefs increased stigma while attribution to current stress reduced stigma.
Conclusion: Our study has implications for future anti-stigma interventions that intend to reduce stigmatization of mentally ill people. Targeting the ascription of unfavorable personal traits and supernatural causal attributions as well as promoting current stress as the cause for mental illness appears to be of particular importance. Also, the mediating influence of emotional responses to causal beliefs needs to be addressed. Furthermore, differential interventions across cultural groups and specific mental illnesses may be appropriate.
Terrestrial surface waters and submarine ground water discharge (SGD) act as a source of dissolved substances for coastal systems. Solute fluxes of SGD depend on the ground water composition and the water-solid-microbe interactions close to the sediment-water interface. Thus, this study aims to characterize and evaluate the hydrogeochemical gradients developing in the fresh-salt water mixing zone of the Wismar Bay (WB), southern Baltic Sea, Germany. Sampling campaigns covering the WB, the fresh-salt water mixing zone at the beach of the WB shoreline, terrestrial surface and ground waters near the WB as well sediments pore water were carried out. In these different waters, the distribution of dissolved inorganic carbon, nutrients, major ions, trace elements, stable isotopes (H, O, C, S), and radium isotopes have been investigated. Enhanced concentrations of radium isotopes together with dissolved manganese, barium in the surface waters of the eastern WB indicated benthic-pelagic coupling via the exchange between pore water and the water column. Salinity, stable isotopes, and major ions in sediment pore water profiles identified the presence of fresh ground water below about 40 cmbsf in the central part of the bay. Geophysical acoustic techniques revealed the local impact of anthropogenic sediment excavation, which reduced the thickness of a sediment layer between the coastal aquifer and the bottom water, causing, therefore, a ground water upward flow close to the top sediments. The fresh impacted pore water stable isotope composition (δ18O, δ2H) plot close to the regional meteoric water line indicating a relatively modern ground water source. The calculated organic matter mineralization rates and the dissolved inorganic carbon sediment-water fluxes were much higher at the fresh impacted site when compared to other unimpacted sediments. Therefore, this study reveals that different fresh water sources contribute to the water balance of WB including a SGD source.
Inflammatory Joint Disease Is a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice
(2020)
Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) – an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines (Ccl2, Cxcl2), inflammatory cytokines (Tnf, Il6), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling (Rankl) and cartilage integrity (Mmp13). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis.
Analysis of volatile organic compounds (VOCs) is a novel approach to accelerate bacterial culture diagnostics of Mycobacterium avium subsp. paratuberculosis (MAP). In the present study, cultures of fecal and tissue samples from MAP-infected and non-suspect dairy cattle and goats were explored to elucidate the effects of sample matrix and of animal species on VOC emissions during bacterial cultivation and to identify early markers for bacterial growth. The samples were processed following standard laboratory procedures, culture tubes were incubated for different time periods. Headspace volume of the tubes was sampled by needle trap-micro-extraction, and analyzed by gas chromatography-mass spectrometry. Analysis of MAP-specific VOC emissions considered potential characteristic VOC patterns. To address variation of the patterns, a flexible and robust machine learning workflow was set up, based on random forest classifiers, and comprising three steps: variable selection, parameter optimization, and classification. Only a few substances originated either from a certain matrix or could be assigned to one animal species. These additional emissions were not considered informative by the variable selection procedure. Classification accuracy of MAP-positive and negative cultures of bovine feces was 0.98 and of caprine feces 0.88, respectively. Six compounds indicating MAP presence were selected in all four settings (cattle vs. goat, feces vs. tissue): 2-Methyl-1-propanol, 2-methyl-1-butanol, 3-methyl-1-butanol, heptanal, isoprene, and 2-heptanone. Classification accuracies for MAP growth-scores ranged from 0.82 for goat tissue to 0.89 for cattle feces. Misclassification occurred predominantly between related scores. Seventeen compounds indicating MAP growth were selected in all four settings, including the 6 compounds indicating MAP presence. The concentration levels of 2,3,5-trimethylfuran, 2-pentylfuran, 1-propanol, and 1-hexanol were indicative for MAP cultures before visible growth was apparent. Thus, very accurate classification of the VOC samples was achieved and the potential of VOC analysis to detect bacterial growth before colonies become visible was confirmed. These results indicate that diagnosis of paratuberculosis can be optimized by monitoring VOC emissions of bacterial cultures. Further validation studies are needed to increase the robustness of indicative VOC patterns for early MAP growth as a pre-requisite for the development of VOC-based diagnostic analysis systems.
Quality of Life in Young Adults With Cerebral Palsy: A Longitudinal Analysis of the SPARCLE Study
(2021)
Introduction: While most people with cerebral palsy (CP) will have a life expectancy similar to that of the general population, international research has primarily focused on childhood and adolescence; and knowledge about the quality of life (QoL) of young adults with CP, its trajectories, and associated factors remains scarce.
Methods: This longitudinal study included young adults with CP living in five European regions and who had previously participated in the SPARCLE cohort as children and/or adolescents. Their QoL in the psychological well-being and social relationships domains was estimated using age-appropriate validated instruments (KIDSCREEN-52 in childhood/adolescence and WHOQOL-Bref in young adulthood). We used generalized linear mixed-effect models with random intercept to estimate long-term trajectories of QoL in both domains and to investigate whether severity of impairment, pain, and seizure influenced these trajectories. We sought to identify potentially different trajectories of QoL from childhood to adulthood using a shape-based clustering method.
Results: In total, 164 young adults with CP aged 22–27 years participated in the study. Psychological well-being linearly decreased by 0.78 points (scale 0–100) per year (95% confidence interval (CI) −0.99 to −0.56) from childhood to young adulthood, whereas QoL in the social relationships domain increased (β coefficient 1.24, 95% CI 0.92–1.55). Severity of impairment was associated with reduced QoL in all life periods of the study (childhood, adolescence, and young adulthood): motor impairment with social relationships, and more nuancedly intellectual disability with psychological well-being and social relationships. At all periods, frequent pain significantly reduced psychological well-being, and seizures were associated with lower QoL in the social relationships domain. In both domains, we identified a group of individuals with CP who presented a reverse trajectory compared with the general QoL trajectory.
Conclusion: Identification of QoL trajectories and their associated factors yields improved knowledge about the experience of individuals with CP until young adulthood. Further studies are needed to better understand the determinants that have the greatest influence on the different shapes of long-term trajectories of QoL.
Recent research suggests that the P3b may be closely related to the activation of the locus coeruleus-norepinephrine (LC-NE) system. To further study the potential association, we applied a novel technique, the non-invasive transcutaneous vagus nerve stimulation (tVNS), which is speculated to increase noradrenaline levels. Using a within-subject cross-over design, 20 healthy participants received continuous tVNS and sham stimulation on two consecutive days (stimulation counterbalanced across participants) while performing a visual oddball task. During stimulation, oval non-targets (standard), normal-head (easy) and rotated-head (difficult) targets, as well as novel stimuli (scenes) were presented. As an indirect marker of noradrenergic activation we also collected salivary alpha-amylase (sAA) before and after stimulation. Results showed larger P3b amplitudes for target, relative to standard stimuli, irrespective of stimulation condition. Exploratory post hoc analyses, however, revealed that, in comparison to standard stimuli, easy (but not difficult) targets produced larger P3b (but not P3a) amplitudes during active tVNS, compared to sham stimulation. For sAA levels, although main analyses did not show differential effects of stimulation, direct testing revealed that tVNS (but not sham stimulation) increased sAA levels after stimulation. Additionally, larger differences between tVNS and sham stimulation in P3b magnitudes for easy targets were associated with larger increase in sAA levels after tVNS, but not after sham stimulation. Despite preliminary evidence for a modulatory influence of tVNS on the P3b, which may be partly mediated by activation of the noradrenergic system, additional research in this field is clearly warranted. Future studies need to clarify whether tVNS also facilitates other processes, such as learning and memory, and whether tVNS can be used as therapeutic tool.
Aquaporins (AQPs) facilitate the transepithelial water flow involved in epithelial fluid secretion in numerous tissues; however, their function in the pancreas is less characterized. Acute pancreatitis (AP) is a serious disorder in which specific treatment is still not possible. Accumulating evidence indicate that decreased pancreatic ductal fluid secretion plays an essential role in AP; therefore, the aim of this study was to investigate the physiological and pathophysiological role of AQPs in the pancreas. Expression and localization of AQPs were investigated by real-time PCR and immunocytochemistry, whereas osmotic transmembrane water permeability was estimated by the dye dilution technique, in Capan-1 cells. The presence of AQP1 and CFTR in the mice and human pancreas were investigated by immunohistochemistry. Pancreatic ductal HCO3- and fluid secretion were studied on pancreatic ducts isolated from wild-type (WT) and AQP1 knock out (KO) mice using microfluorometry and videomicroscopy, respectively. In vivo pancreatic fluid secretion was estimated by magnetic resonance imaging. AP was induced by intraperitoneal injection of cerulein and disease severity was assessed by measuring biochemical and histological parameters. In the mice, the presence of AQP1 was detected throughout the whole plasma membrane of the ductal cells and its expression highly depends on the presence of CFTR Cl- channel. In contrast, the expression of AQP1 is mainly localized to the apical membrane of ductal cells in the human pancreas. Bile acid treatment dose- and time-dependently decreased mRNA and protein expression of AQP1 and reduced expression of this channel was also demonstrated in patients suffering from acute and chronic pancreatitis. HCO3- and fluid secretion significantly decreased in AQP1 KO versus WT mice and the absence of AQP1 also worsened the severity of pancreatitis. Our results suggest that AQP1 plays an essential role in pancreatic ductal fluid and HCO3- secretion and decreased expression of the channel alters fluid secretion which probably contribute to increased susceptibility of the pancreas to inflammation.
Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.
Significant alterations of cambial activity might be expected due to climate warming, leading to growing season extension and higher growth rates especially in cold-limited forests. However, assessment of climate-change-driven trends in intra-annual wood formation suffers from the lack of direct observations with a timespan exceeding a few years. We used the Vaganov-Shashkin process-based model to: (i) simulate daily resolved numbers of cambial and differentiating cells; and (ii) develop chronologies of the onset and termination of specific phases of cambial phenology during 1961–2017. We also determined the dominant climatic factor limiting cambial activity for each day. To asses intra-annual model validity, we used 8 years of direct xylogenesis monitoring from the treeline region of the Krkonoše Mts. (Czechia). The model exhibits high validity in case of spring phenological phases and a seasonal dynamics of tracheid production, but its precision declines for estimates of autumn phenological phases and growing season duration. The simulations reveal an increasing trend in the number of tracheids produced by cambium each year by 0.42 cells/year. Spring phenological phases (onset of cambial cell growth and tracheid enlargement) show significant shifts toward earlier occurrence in the year (for 0.28–0.34 days/year). In addition, there is a significant increase in simulated growth rates during entire growing season associated with the intra-annual redistribution of the dominant climatic controls over cambial activity. Results suggest that higher growth rates at treeline are driven by (i) temperature-stimulated intensification of spring cambial kinetics, and (ii) decoupling of summer growth rates from the limiting effect of low summer temperature due to higher frequency of climatically optimal days. Our results highlight that the cambial kinetics stimulation by increasing spring and summer temperatures and shifting spring phenology determine the recent growth trends of treeline ecosystems. Redistribution of individual climatic factors controlling cambial activity during the growing season questions the temporal stability of climatic signal of cold forest chronologies under ongoing climate change.
Changes in the environment will alter the growth rate of trees and forests. Different disciplines assess such growth rates differently, for example, with tree-ring width data, forest inventories or with carbon-flux data from eddy covariance towers. Such data is used to quantify forests biomass increment, forest’s carbon sequestration or to reconstruct environmental variables before instrumental records. However, raw measurement data is typically not considered to be representative for the average growth rate of trees or forests. Depending on the research question, the effects of certain environmental variables or effects of tree and forest structure have to be removed first. It can be challenging to define and quantify a growth trend that can answer a specific research question because trees and forests grow and respond to environmental change in multiple ways simultaneously, for example, with altered radial increment, height growth, and stand density. Further challenges pose time-lagged feedback loops, for example, between height and radial increment or between stand density and radial increment. Generally, different environments will lead to different tree and forest structures, but because of tree’s longevity this adaptation to the new environment will take decades or even centuries. Consequently, there can be an offset between the present forest structure and what we term the potential natural forest (PNF): Similar to the potential natural vegetation (PNV), the PNF represents that forest that would develop under the current environmental conditions in the absence of human intervention. Because growth rates are affected by the tree and forest structure, growth-trend estimates will differ between the present and the potential forest. Consequently, if the legacy effects of the past are not of interest, the PNF is the theoretical baseline to correct and estimate growth trends.
A Metabolic Labeling Strategy for Relative Protein Quantification in Clostridioides difficile
(2018)
Introduction: Following behavioral recommendations is key to successful containment of the COVID-19 pandemic. Therefore, it is important to identify causes and patterns of non-compliance in the population to further optimize risk and health communication.
Methods: A total of 157 participants [80% female; mean age = 27.82 years (SD = 11.01)] were surveyed regarding their intention to comply with behavioral recommendations issued by the German government. Latent class analysis examined patterns of compliance, and subsequent multinomial logistic regression models tested sociodemographic (age, gender, country of origin, level of education, region, and number of persons per household) and psychosocial (knowledge about preventive behaviors, risk perception, stigmatizing attitudes) predictors.
Results: Three latent classes were identified: high compliance (25%) with all recommendations; public compliance (51%), with high compliance regarding public but not personal behaviors; and low compliance (24%) with most recommendations. Compared to high compliance, low compliance was associated with male gender [relative risk ratio (RRR) = 0.08 (0.01; 0.85)], younger age [RRR = 0.72 (0.57; 0.93)], and lower public stigma [RRR = 0.21 (0.05; 0.88)]. Low compliers were also younger than public compliers [RRR = 0.76 (0.59; 0.98)].
Discussion: With 25% of the sample reporting full compliance, and 51% differing in terms of public and personal compliance, these findings challenge the sustainability of strict regulatory measures. Moreover, young males were most likely to express low compliance, stressing the need for selective health promotion efforts. Finally, the positive association between public stigma and compliance points to potential othering effects of stigma during a pandemic, but further longitudinal research is required to examine its impact on health and social processes throughout the pandemic.
Introduction
Privacy concerns are an important barrier to adoption and continued use of digital technologies, particularly in the health sector. With the introduction of mobile health applications (mHealth apps), the construct of app information privacy concerns has received increased attention. However, few validated measures exist to capture said concerns in population samples, although they can help to improve public health efforts.
Methods
Using a cross-sectional survey of German adults (mean age = 35.62; 63.5% female), this study examined psychometric properties of the app information privacy concerns scale (AIPC). Analyses comprised confirmatory factor analysis, factorial validity (exploratory factor analysis), internal consistency, convergent validity (i.e., correlations with privacy victimhood, and app privacy concerns), and discriminant validity (i.e., daily app use, adoption intentions, and attitudes toward COVID-19 contact tracing app use).
Results
The analysis did not support the proposed three-factor structure of the AIPC (i.e., anxiety, personal attitude, and requirements). Instead, a four-factor model was preferable that differentiated requirements regarding disclosure policies, and personal control. In addition, factors mirroring anxiety and personal attitude were extracted, but shared a significant overlap. However, these factors showed good reliability, convergent and discriminant validity.
Discussion
The findings underline the role of app information privacy concerns as a significant barrier to mHealth app use. In this context, anxiety and personal attitudes seemed particularly relevant, which has implications for health communication. Moreover, the observed differentiation of external (disclosure) and internal (control) requirements aligns with health behavior change models and thus is a promising area for future research.
Quantitative reconstructions of past vegetation cover commonly require pollen productivity estimates (PPEs). PPEs are calibrated in extensive and rather cumbersome surface-sample studies, and are so far only available for selected regions. Moreover, it may be questioned whether present-day pollen-landcover relationships are valid for palaeo-situations. We here introduce the ROPES approach that simultaneously derives PPEs and mean plant abundances from single pollen records. ROPES requires pollen counts and pollen accumulation rates (PARs, grains cm−2 year−1). Pollen counts are used to reconstruct plant abundances following the REVEALS approach. The principle of ROPES is that changes in plant abundance are linearly represented in observed PAR values. For example, if the PAR of pine doubles, so should the REVEALS reconstructed abundance of pine. Consequently, if a REVEALS reconstruction is “correct” (i.e., “correct” PPEs are used) the ratio “PAR over REVEALS” is constant for each taxon along all samples of a record. With incorrect PPEs, the ratio will instead vary. ROPES starts from random (likely incorrect) PPEs, but then adjusts them using an optimization algorithm with the aim to minimize variation in the “PAR over REVEALS” ratio across the record. ROPES thus simultaneously calculates mean plant abundances and PPEs. We illustrate the approach with test applications on nine synthetic pollen records. The results show that good performance of ROPES requires data sets with high underlying variation, many samples and low noise in the PAR data. ROPES can deliver first landcover reconstructions in regions for which PPEs are not yet available. The PPEs provided by ROPES may then allow for further REVEALS-based reconstructions. Similarly, ROPES can provide insight in pollen productivity during distinct periods of the past such as the Lateglacial. We see a potential to study spatial and temporal variation in pollen productivity for example in relation to site parameters, climate and land use. It may even be possible to detect expansion of non-pollen producing areas in a landscape. Overall, ROPES will help produce more accurate landcover reconstructions and expand reconstructions into new study regions and non-analog situations of the past. ROPES is available within the R package DISQOVER.
Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.
Mendelian randomization (MR) is a framework for assessing causal inference using cross-sectional data in combination with genetic information. This paper summarizes statistical methods commonly applied and strait forward to use for conducting MR analyses including those taking advantage of the rich dataset of SNP-trait associations that were revealed in the last decade through large-scale genome-wide association studies. Using these data, powerful MR studies are possible. However, the causal estimate may be biased in case the assumptions of MR are violated. The source and the type of this bias are described while providing a summary of the mathematical formulas that should help estimating the magnitude and direction of the potential bias depending on the specific research setting. Finally, methods for relaxing the assumptions and for conducting sensitivity analyses are discussed. Future researches in the field of MR include the assessment of non-linear causal effects, and automatic detection of invalid instruments.
Mendelian randomization (MR) is a framework for assessing causal inference using cross-sectional data in combination with genetic information. This paper summarizes statistical methods commonly applied and strait forward to use for conducting MR analyses including those taking advantage of the rich dataset of SNP-trait associations that were revealed in the last decade through large-scale genome-wide association studies. Using these data, powerful MR studies are possible. However, the causal estimate may be biased in case the assumptions of MR are violated. The source and the type of this bias are described while providing a summary of the mathematical formulas that should help estimating the magnitude and direction of the potential bias depending on the specific research setting. Finally, methods for relaxing the assumptions and for conducting sensitivity analyses are discussed. Future researches in the field of MR include the assessment of non-linear causal effects, and automatic detection of invalid instruments.
Staphylococcus aureus (S. aureus) can secrete a broad range of virulence factors, among which staphylococcal serine protease-like proteins (Spls) have been identified as bacterial allergens. The S. aureus allergen serine protease-like protein D (SplD) induces allergic asthma in C57BL/6J mice through the IL-33/ST2 signaling axis. Analysis of C57BL/6J, C57BL/6N, CBA, DBA/2, and BALB/c mice treated with intratracheal applications of SplD allowed us to identify a frameshift mutation in the serine (or cysteine) peptidase inhibitor, clade A, and member 3I (Serpina3i) causing a truncated form of SERPINA3I in BALB/c, CBA, and DBA/2 mice. IL-33 is a key mediator of SplD-induced immunity and can be processed by proteases leading to its activation or degradation. Full-length SERPINA3I inhibits IL-33 degradation in vivo in the lungs of SplD-treated BALB/c mice and in vitro by direct inhibition of mMCP-4. Collectively, our results establish SERPINA3I as a regulator of IL-33 in the lungs following exposure to the bacterial allergen SplD, and that the asthma phenotypes of mouse strains may be strongly influenced by the observed frameshift mutation in Serpina3i. The analysis of this protease-serpin interaction network might help to identify predictive biomarkers for type-2 biased airway disease in individuals colonized by S. aureus.
Background: This randomized controlled trial investigated if uni- and bihemispheric transcranial direct current stimulation (tDCS) of the motor cortex can enhance the effects of visuo-motor grip force tracking task training and transfer to clinical assessments of upper extremity motor function.
Methods: In a randomized, double-blind, sham-controlled trial, 40 chronic stroke patients underwent 5 days of visuo-motor grip force tracking task training of the paretic hand with either unilateral or bilateral (N = 15/group) or placebo tDCS (N = 10). Immediate and long-term (3 months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, and WMFT) were investigated.
Results: Trained task performance significantly improved independently of tDCS in a curvilinear fashion. In the anodal stimulation group UE-FM scores were higher than in the sham group at day 5 (adjusted mean difference: 2.6, 95%CI: 0.6–4.5, p = 0.010) and at 3 months follow up (adjusted mean difference: 2.8, 95%CI: 0.8–4.7, p = 0.006). Neither training alone, nor the combination of training and tDCS improved WMFT performance.
Conclusions: Visuo-motor grip force tracking task training can facilitate recovery of upper extremity function. Only minimal add-on effects of anodal but not dual tDCS were observed.
Clinical Trial Registration: https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=NCT01969097&cntry=&state=&city=&dist=, identifier: NCT01969097, retrospectively registered on 25/10/2013.
Objective: This study was conducted to elucidate prevalence, clinical features, outcomes, and best treatment in patients with late-onset seizures due to autoimmune encephalitis (AE).
Methods: This is a single-institution prospective cohort study (2012–2019) conducted at the Epilepsy Center at the University of Greifswald, Germany. A total of 225 patients aged ≥50 years with epileptic seizures were enrolled and underwent an MRI/CT scan, profiling of neural antibodies (AB) in serum and cerebrospinal fluid (CSF), and neuropsychological testing. On the basis of their work-up, patients were categorized into the following three cohorts: definite, suspected, or no AE. Patients with definite and suspected AE were subsequently treated with immunosuppressive therapy (IT) and/or anti-seizure drug (ASD) therapy and were followed up (FU) regarding clinical and seizure outcome.
Results: Of the 225 patients, 17 (8%) fulfilled the criteria for definite or suspected AE according to their AB profile and MRI results. Compared with patients with no evidence of AE, those with AE were younger (p = 0.028), had mesial temporal neuropsychological deficits (p = 0.001), frequently had an active or known malignancy (p = 0.006) and/or a pleocytosis (p = 0.0002), and/or had oligoclonal bands in CSF (p = 0.001). All patients with follow-up became seizure-free with at least one ASD. The Modified Rankin scale (mRS) at hospital admission was low for patients with AE (71% with mRS ≤2) and further decreased to 60% with mRS ≤2 at last FU.
Significance: AE is an important etiology in late-onset seizures, and seizures may be the first symptom of AE. Outcome in non-paraneoplastic AE was favorable with ASD and IT. AB testing in CSF and sera, cerebral MRI, CSF analysis, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late-onset seizures.
Background: Interpersonal skills deficits and dysfunctional metacognitive beliefs have been implicated in the etiology and maintenance of depression. This study aimed to investigate the association between changes in these skills deficits and change in depressive symptoms over the course of treatment with Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Metacognitive Therapy (MCT).
Methods: In this prospective, parallel group observational study, data was collected at baseline and after 8 weeks of an intensive day clinic psychotherapy program. Based on a shared decision between patients and clinicians, patients received either CBASP or MCT. Ninety patients were included in the analyses (CBASP: age M = 38.7, 40.5% female, MCT: age M = 44.7, 43.3% female). Interpersonal deficits were assessed with the short-form of the Luebeck Questionnaire for Recording Preoperational Thinking (LQPT-SF) and the Impact Message Inventory (IMI-R). Metacognitive beliefs were assessed with the Metacognition Questionnaire-30 (MCQ-30). The Quick Inventory of Depressive Symptomatology (QIDS-SR16) was utilized to assess depressive symptoms. A regression analysis was conducted to assess variables associated with outcome. ANCOVAs were utilized to investigate whether improvement in skills deficits is dependent on type of treatment received.
Results: Improvements in preoperational thinking and increases in friendly-dominant behavior were associated with change in depressive symptoms. There was no association between reductions in dysfunctional metacognitive beliefs and a decrease in depressive symptoms. While both treatment groups showed significant improvements in interpersonal and metacognitive skills, there was no significant between-group difference in the change scores for either of these skills.
Conclusion: Our findings suggest that changes in interpersonal skills seem to be of particular relevance in the treatment of depression. These results have to be replicated in a randomized-controlled design before firm conclusions can be drawn.
Background
In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).
Methods
For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.
Results
Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.
Conclusion
ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.
Platelets transfusion is a safe process, but during or after the process, the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). In this review, we focus on the inflammatory potential of platelet components (PCs) and their involvement in SARs. Recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses. Blood platelets are involved in inflammation and various other aspects of innate immunity through the release of a plethora of immunomodulatory cytokines, chemokines, and associated molecules, collectively termed biological response modifiers that behave like ligands for endothelial and leukocyte receptors and for platelets themselves. The involvement of PCs in SARs—particularly on a critically ill patient’s context—could be related, at least in part, to the inflammatory functions of platelets, acquired during storage lesions. Moreover, we focus on causal link between platelet activation and immune-mediated disorders (transfusion-associated immunomodulation, platelets, polyanions, and bacterial defense and alloimmunization). This is linked to the platelets’ propensity to be activated even in the absence of deliberate stimuli and to the occurrence of time-dependent storage lesions.
Staphylococcus aureus is a human pathogen that can cause a wide range of diseases. Although formerly regarded as extracellular pathogen, it has been shown that S. aureus can also be internalized by host cells and persist within these cells. In the present study, we comparatively analyzed survival and physiological adaptation of S. aureus HG001 after internalization by two human lung epithelial cell lines (S9 and A549), and human embryonic kidney cells (HEK 293). Combining enrichment of bacteria from host-pathogen assays by cell sorting and quantitation of the pathogen's proteome by mass spectrometry we characterized S. aureus adaptation during the initial phase between 2.5 h and 6.5 h post-infection. Starting with about 2 × 106 bacteria, roughly 1450 S. aureus proteins, including virulence factors and metabolic enzymes were identified by spectral comparison and classical database searches. Most of the bacterial adaptation reactions, such as decreased levels of ribosomal proteins and metabolic enzymes or increased amounts of proteins involved in arginine and lysine biosynthesis, enzymes coding for terminal oxidases and stress responsive proteins or activation of the sigma factor SigB were observed after internalization into any of the three cell lines studied. However, differences were noted in central carbon metabolism including regulation of fermentation and threonine degradation. Since these differences coincided with different intracellular growth behavior, complementary profiling of the metabolome of the different non-infected host cell types was performed. This revealed similar levels of intracellular glucose but host cell specific differences in the amounts of amino acids such as glycine, threonine or glutamate. With this comparative study we provide an impression of the common and specific features of the adaptation of S. aureus HG001 to specific host cell environments as a starting point for follow-up studies with different strain isolates and regulatory mutants.
Epithelial cells are an important line of defense within the lung. Disruption of the epithelial barrier by pathogens enables the systemic dissemination of bacteria or viruses within the host leading to severe diseases with fatal outcomes. Thus, the lung epithelium can be damaged by seasonal and pandemic influenza A viruses. Influenza A virus infection induced dysregulation of the immune system is beneficial for the dissemination of bacteria to the lower respiratory tract, causing bacterial and viral co-infection. Host cells regulate protein homeostasis and the response to different perturbances, for instance provoked by infections, by post translational modification of proteins. Aside from protein phosphorylation, ubiquitination of proteins is an essential regulatory tool in virtually every cellular process such as protein homeostasis, host immune response, cell morphology, and in clearing of cytosolic pathogens. Here, we analyzed the proteome and ubiquitinome of A549 alveolar lung epithelial cells in response to infection by either Streptococcus pneumoniae D39Δcps or influenza A virus H1N1 as well as bacterial and viral co-infection. Pneumococcal infection induced alterations in the ubiquitination of proteins involved in the organization of the actin cytoskeleton and Rho GTPases, but had minor effects on the abundance of host proteins. H1N1 infection results in an anti-viral state of A549 cells. Finally, co-infection resembled the imprints of both infecting pathogens with a minor increase in the observed alterations in protein and ubiquitination abundance.
Proteostasis is critical for cells to maintain the balance between protein synthesis, quality control, and degradation. This is particularly important for myeloid cells of the central nervous system as their immunological function relies on proper intracellular protein turnover by the ubiquitin-proteasome system. Accordingly, disruption of proteasome activity due to, e.g., loss-of-function mutations within genes encoding proteasome subunits, results in systemic autoinflammation. On the molecular level, pharmacological inhibition of proteasome results in endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) as well as an induction of type I interferons (IFN). Nevertheless, our understanding as to whether and to which extent UPR signaling regulates type I IFN response is limited. To address this issue, we have tested the effects of proteasome dysfunction upon treatment with proteasome inhibitors in primary murine microglia and microglia-like cell line BV-2. Our data show that proteasome impairment by bortezomib is a stimulus that activates all three intracellular ER-stress transducers activation transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and inositol-requiring protein 1 alpha (IRE1α), causing a full activation of the UPR. We further demonstrate that impaired proteasome activity in microglia cells triggers an induction of IFNβ1 in an IRE1-dependent manner. An inhibition of the IRE1 endoribonuclease activity significantly attenuates TANK-binding kinase 1-mediated activation of type I IFN. Moreover, interfering with TANK-binding kinase 1 activity also compromised the expression of C/EBP homologous protein 10, thereby emphasizing a multilayered interplay between UPR and type IFN response pathway. Interestingly, the induced protein kinase R-like endoplasmic reticulum kinase-activation transcription factor 4-C/EBP homologous protein 10 and IRE1-X-box-binding protein 1 axes caused a significant upregulation of proinflammatory cytokine interleukin 6 expression that exacerbates STAT1/STAT3 signaling in cells with dysfunctional proteasomes. Altogether, these findings indicate that proteasome impairment disrupts ER homeostasis and triggers a complex interchange between ER-stress sensors and type I IFN signaling, thus inducing in myeloid cells a state of chronic inflammation.
Objective: Little is known about the specific psychological features that differentiate persistent depressive disorder (PDD) and episodic depression (ED). Thus, the present study aimed to investigate differences in social cognition and interpersonal problems between these two forms of depression and healthy controls. In addition, we aimed to examine childhood maltreatment (CM) as a possible origin of these alterations.
Methods: In a cross-sectional study, adult patients with a current PDD (n = 34) or in a current episode of ED (n = 38), and healthy controls (n = 39) completed questionnaires about depression severity, empathy, interpersonal problems, and CM, as well as tests of affective theory of mind and facial emotion recognition.
Results: Patients with PDD reported higher empathic distress than patients with ED and healthy controls. Both depressive groups recognized angry faces with higher accuracy and reported more interpersonal problems, with no differences between PDD and ED. Empathic distress and interpersonal problems mediated the link between CM and depression in the combined sample.
Limitations: Patient groups were not drug-naïve and antidepressant intake might have influenced social-cognitive functions. Self-report measures of empathy and interpersonal problems are vulnerable to bias. The cross-sectional design does not allow causal conclusions.
Conclusion: Depressed patients may not show deficits in decoding the affective states of others and in feeling with others. However, depressed individuals—in particular patients with PDD—may feel easily overwhelmed by emotionally tense situations, resulting in empathic distress and avoidant/submissive interpersonal behavior. Exposure to CM might be an origin of alterations in social cognition and interpersonal problems.
Changes in Interhemispheric Motor Connectivity Across the Lifespan: A Combined TMS and DTI Study
(2019)
Age-related decline in interhemispheric connectivity between motor areas has been reported with both transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) measurements. However, not all studies were able to confirm these findings, and previous studies did not apply structural (DTI) and functional (TMS) measurements within each individual appropriately. Here, we investigated age dependency of the ipsilateral silent period (ISP) and integrity of fibers in the corpus callosum as operationalized by fractional anisotrophy (FA), using TMS and DTI, respectively, in 20 participants between 19 and 72 years of age. We found age-dependent increase for ISP, and decrease of FA, both indicating a decrease in interhemispheric inhibition, with a negative association between FA and ISP for the dominant hemisphere (r = −0.39, p = 0.043). Our findings suggest that aging leads to decline of interhemispheric motor connectivity, as evidenced in both structural and functional parameters, which should be taken into account when interpreting disease- or medication-related changes.
In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes. Simultaneously arising and misrepaired DNA double-strand breaks are also the cause of another phenomenon called chromoplexy, which is characterized by the presence of chained translocations and interlinking deletion bridges involving several chromosomes. In this study, we demonstrate the genome-wide identification of chromosomal translocations based on the analysis of translocation-associated changes in spatial proximities of chromosome territories on the example of the cutaneous T-cell lymphoma cell line Se-Ax. We have used alterations of intra- and interchromosomal interaction probabilities as detected by genome-wide chromosome conformation capture (Hi-C) to infer the presence of translocations and to fine-map their breakpoints. The outcome of this analysis was subsequently compared to datasets on DNA copy number alterations and gene expression. The presence of chained translocations within the Se-Ax genome, partly connected by intervening deletion bridges, indicates a role of chromoplexy in the etiology of this cutaneous T-cell lymphoma. Notably, translocation breakpoints were significantly overrepresented in genes, which highlight gene-associated biological processes like transcription or other gene characteristics as a possible cause of the observed complex rearrangements. Given the relevance of chromosomal aberrations for basic and translational research, genome-wide high-resolution analysis of structural chromosomal aberrations will gain increasing importance.
Introduction: At the cellular level, acute temperature changes alter ionic conductances, ion channel kinetics, and the activity of entire neuronal circuits. This can result in severe consequences for neural function, animal behavior and survival. In poikilothermic animals, and particularly in aquatic species whose core temperature equals the surrounding water temperature, neurons experience rather rapid and wide-ranging temperature fluctuations. Recent work on pattern generating neural circuits in the crustacean stomatogastric nervous system have demonstrated that neuronal circuits can exhibit an intrinsic robustness to temperature fluctuations. However, considering the increased warming of the oceans and recurring heatwaves due to climate change, the question arises whether this intrinsic robustness can acclimate to changing environmental conditions, and whether it differs between species and ocean habitats.
Methods: We address these questions using the pyloric pattern generating circuits in the stomatogastric nervous system of two crab species, Hemigrapsus sanguineus and Carcinus maenas that have seen a worldwide expansion in recent decades.
Results and discussion: Consistent with their history as invasive species, we find that pyloric activity showed a broad temperature robustness (>30°C). Moreover, the temperature-robust range was dependent on habitat temperature in both species. Warm-acclimating animals shifted the critical temperature at which circuit activity breaks down to higher temperatures. This came at the cost of robustness against cold stimuli in H. sanguineus, but not in C. maenas. Comparing the temperature responses of C. maenas from a cold latitude (the North Sea) to those from a warm latitude (Spain) demonstrated that similar shifts in robustness occurred in natural environments. Our results thus demonstrate that neuronal temperature robustness correlates with, and responds to, environmental temperature conditions, potentially preparing animals for changing ecological conditions and shifting habitats.
Background: Intensive speech-language therapy (SLT) can promote recovery from chronic post-stroke aphasia, a major consequence of stroke. However, effect sizes of intensive SLT are moderate, potentially reflecting a physiological limit of training-induced progress. Transcranial direct current stimulation (tDCS) is an easy-to-use, well-tolerated and low-cost approach that may enhance effectiveness of intensive SLT. In a recent phase-II randomized controlled trial, 26 individuals with chronic post-stroke aphasia received intensive SLT combined with anodal-tDCS of the left primary motor cortex (M1), resulting in improved naming and proxy-rated communication ability, with medium-to-large effect sizes.
Aims: The proposed protocol seeks to establish the incremental benefit from anodal-tDCS of M1 in a phase-III randomized controlled trial with adequate power, ecologically valid outcomes, and evidence-based SLT.
Methods: The planned study is a prospective randomized placebo-controlled (using sham-tDCS), parallel-group, double-blind, multi-center, phase-III superiority trial. A sample of 130 individuals with aphasia at least 6 months post-stroke will be recruited in more than 18 in- and outpatient rehabilitation centers.
Outcomes: The primary outcome focuses on communication ability in chronic post-stroke aphasia, as revealed by changes on the Amsterdam-Nijmegen Everyday Language Test (A-scale; primary endpoint: 6-month follow-up; secondary endpoints: immediately after treatment, and 12-month follow-up). Secondary outcomes include measures assessing linguistic-executive skills, attention, memory, emotional well-being, quality of life, health economic costs, and adverse events (endpoints: 6-month follow-up, immediately after treatment, and 12-month follow-up).
Discussion: Positive results will increase the quality of life for persons with aphasia and their families while reducing societal costs. After trial completion, a workshop with relevant stakeholders will ensure transfer into best-practice guidelines and successful integration within clinical routine.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03930121.
Objectives: To investigate the co-occurrence of 4 behavioral health risk factors (BHRFs), namely tobacco smoking, alcohol at-risk drinking, physical inactivity and unhealthy diet and their association with sick days prior to hospitalization in general hospital patients.
Methods: Over 10 weeks (11/2020-04/2021), all 18-64-year-old patients admitted to internal medicine, general and trauma surgery, and otorhinolaryngology wards of a tertiary care hospital were systematically approached. Among 355 eligible patients, 278 (78.3%) participated, and 256 (72.1%) were analyzed. Three BHRF sum scores were determined, including current tobacco smoking, alcohol use, physical inactivity and 1 of 3 indicators of unhealthy diet. Associations between BHRF sum scores and sick days in the past 6 months were analyzed using multivariate zero-inflated negative binomial regressions.
Results: Sixty-two percent reported multiple BHRFs (≥2). The BHRF sum score was related to the number of sick days if any (p = 0.009) with insufficient vegetable and fruit intake as diet indicator.
Conclusion: The majority of patients disclosed multiple BHRFs. These were associated with sick days prior to admission. The findings support the need to implement interventions targeting multiple BHRFs in general hospitals.
Introduction: With the increased emergence of SARS-CoV-2 variants, the impact on schools and preschools remains a matter of debate. To ensure that schools and preschools are kept open safely, the identification of factors influencing the extent of outbreaks is of importance.
Aim: To monitor dynamics of COVID-19 infections in schools and preschools and identify factors influencing the extent of outbreaks.
Methods: In this prospective observational study we analyzed routine surveillance data of Mecklenburg-Western Pomerania, Germany, from calendar week (CW) 32, 2020 to CW19, 2021 regarding SARS-CoV-2 infection events in schools and preschools considering changes in infection control measures over time. A multivariate linear regression model was fitted to evaluate factors influencing the number of students, teachers and staff tested positive following index cases in schools and preschools. Due to an existing multicollinearity in the common multivariate regression model between the variables “face mask obligation for children” and “face mask obligation for adults”, two further separate regression models were set up (Multivariate Model Adults and Multivariate Model Children).
Results: We observed a significant increase in secondary cases in preschools in the first quarter of 2021 (CW8 to CW15, 2021), and simultaneously a decrease in secondary cases in schools. In multivariate regression analysis, the strongest predictor of the extent of the outbreaks was the teacher/ caregiver mask obligation (B = −1.9; 95% CI: −2.9 to −1.0; p < 0.001). Furthermore, adult index cases (adult only or child+adult combinations) increased the likelihood of secondary cases (B = 1.3; 95% CI: 0.9 to 1.8; p < 0.001). The face mask obligation for children also showed a significant reduction in the number of secondary cases (B = −0.6; 95% CI: −0.9 to −0.2; p = 0.004.
Conclusion: The present study indicates that outbreak events at schools and preschools are effectively contained by an obligation for adults and children to wear face masks.
Hypoxia is common in marine environments and a major stressor for marine organisms inhabiting benthic and intertidal zones. Several studies have explored the responses of these organisms to hypoxic stress at the whole organism level with a focus on energy metabolism and mitochondrial response, but the instrinsic mitochondrial responses that support the organelle’s function under hypoxia and reoxygenation (H/R) stress are not well understood. We studied the effects of acute H/R stress (10 min anoxia followed by 15 min reoxygenation) on mitochondrial respiration, production of reactive oxygen species (ROS) and posttranslational modifications (PTM) of the proteome in a marine facultative anaerobe, the blue mussel Mytilus edulis. The mussels’ mitochondria showed increased OXPHOS respiration and suppressed proton leak resulting in a higher coupling efficiency after H/R stress. ROS production decreased in both the resting (LEAK) and phosphorylating (OXPHOS) state indicating that M. edulis was able to prevent oxidative stress and mitochondrial damage during reoxygenation. Hypoxia did not lead to rearrangement of the mitochondrial supercomplexes but impacted the mitochondrial phosphoproteome including the proteins involved in OXPHOS, amino acid- and fatty acid catabolism, and protein quality control. This study indicates that mussels’ mitochondria possess intrinsic mechanisms (including regulation via reversible protein phosphorylation) that ensure high respiratory flux and mitigate oxidative damage during H/R stress and contribute to the hypoxia-tolerant mitochondrial phenotype of this metabolically plastic species.
Bioinformatics Algorithms and Predictive Models: The Grand Challenge in Computational Virology
(2021)
Never in the past has the relevance of bioinformatic and predictive tools been more central
in the field of virology as today. SARS-CoV-2 has brought along a huge health burden, but also
a deeper awareness that scientific progress can no longer be effective without extensive systems
for data storage, sharing and analysis, as well as computational tools dedicated to molecular
epidemiology, NGS data analysis, prediction of drug targets, multi-OMIC data integration, and
many other applications.
Objective
Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.
Research Design and Methods
In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K+ (KATP) channels. Additionally, KATP channel-independent targets as Ca2+-activated K+ channels of intermediate conductance (KCa3.1) and L-type Ca2+ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1-/-) mice. The cytosolic Ca2+ concentration ([Ca2+]c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.
Results
The selective KATP channel opener NN414 (5 µM) diminished [Ca2+]c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional KATP channels (SUR1-/-) the drug was without effect. VU0071063 (30 µM), another KATP channel opener considered to be selective, lowered [Ca2+]c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1-/- mice, showing that [Ca2+]c is influenced by additional effects besides KATP channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of KCa3.1 channels, DCEBIO (100 µM), significantly decreased [Ca2+]c in SUR1-/- and human CHI islet cell clusters. To target L-type Ca2+ channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca2+]c in stimulated human CHI islet cell clusters as well as in stimulated SUR1-/- islet cell clusters. Similar effects on [Ca2+]c were observed in experiments with simvastatin (7.2 µM).
Conclusions
NN414 seems to provide a good alternative to the currently used KATP channel opener diazoxide. Targeting KCa3.1 channels by channel openers or L-type Ca2+ channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of KATP channels not sensitive to KATP channel openers.
Clostridioides difficile is an intestinal human pathogen that uses the opportunity of a depleted microbiota to cause an infection. It is known, that the composition of the intestinal bile acid cocktail has a great impact on the susceptibility toward a C. difficile infection. However, the specific response of growing C. difficile cells to diverse bile acids on the molecular level has not been described yet. In this study, we recorded proteome signatures of shock and long-term (LT) stress with the four main bile acids cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). A general overlapping response to all tested bile acids could be determined particularly in shock experiments which appears plausible in the light of their common steroid structure. However, during LT stress several proteins showed an altered abundance in the presence of only a single or a few of the bile acids indicating the existence of specific adaptation mechanisms. Our results point at a differential induction of the groEL and dnaKJgrpE chaperone systems, both belonging to the class I heat shock genes. Additionally, central metabolic pathways involving butyrate fermentation and the reductive Stickland fermentation of leucine were effected, although CA caused a proteome signature different from the other three bile acids. Furthermore, quantitative proteomics revealed a loss of flagellar proteins in LT stress with LCA. The absence of flagella could be substantiated by electron microscopy which also indicated less flagellated cells in the presence of DCA and CDCA and no influence on flagella formation by CA. Our data break down the bile acid stress response of C. difficile into a general and a specific adaptation. The latter cannot simply be divided into a response to primary and secondary bile acids, but rather reflects a complex and variable adaptation process enabling C. difficile to survive and to cause an infection in the intestinal tract.
Clostridioides difficile is an intestinal human pathogen that uses the opportunity of a depleted microbiota to cause an infection. It is known, that the composition of the intestinal bile acid cocktail has a great impact on the susceptibility toward a C. difficile infection. However, the specific response of growing C. difficile cells to diverse bile acids on the molecular level has not been described yet. In this study, we recorded proteome signatures of shock and long-term (LT) stress with the four main bile acids cholic acid
(CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). A general overlapping response to all tested bile acids could be determined particularly in shock experiments which appears plausible in the light of their common steroid structure. However, during LT stress several proteins showed an altered abundance
in the presence of only a single or a few of the bile acids indicating the existence of specific adaptation mechanisms. Our results point at a differential induction of the groEL and dnaKJgrpE chaperone systems, both belonging to the class I heat shock genes. Additionally, central metabolic pathways involving butyrate fermentation and the reductive Stickland fermentation of leucine were effected, although CA caused a
proteome signature different from the other three bile acids. Furthermore, quantitative proteomics revealed a loss of flagellar proteins in LT stress with LCA. The absence of flagella could be substantiated by electron microscopy which also indicated less
flagellated cells in the presence of DCA and CDCA and no influence on flagella formation by CA. Our data break down the bile acid stress response of C. difficile into a general and a specific adaptation. The latter cannot simply be divided into a response to primary and secondary bile acids, but rather reflects a complex and variable adaptation process enabling C. difficile to survive and to cause an infection in the intestinal tract.
Observed recent and expected future increases in frequency and intensity of climatic extremes in central Europe may pose critical challenges for domestic tree species. Continuous dendrometer recordings provide a valuable source of information on tree stem radius variations, offering the possibility to study a tree's response to environmental influences at a high temporal resolution. In this study, we analyze stem radius variations (SRV) of three domestic tree species (beech, oak, and pine) from 2012 to 2014. We use the novel statistical approach of event coincidence analysis (ECA) to investigate the simultaneous occurrence of extreme daily weather conditions and extreme SRVs, where extremes are defined with respect to the common values at a given phase of the annual growth period. Besides defining extreme events based on individual meteorological variables, we additionally introduce conditional and joint ECA as new multivariate extensions of the original methodology and apply them for testing 105 different combinations of variables regarding their impact on SRV extremes. Our results reveal a strong susceptibility of all three species to the extremes of several meteorological variables. Yet, the inter-species differences regarding their response to the meteorological extremes are comparatively low. The obtained results provide a thorough extension of previous correlation-based studies by emphasizing on the timings of climatic extremes only. We suggest that the employed methodological approach should be further promoted in forest research regarding the investigation of tree responses to changing environmental conditions.
Together with endothelial cells and the glomerular basement membrane, podocytes form the size-specific filtration barrier of the glomerulus with their interdigitating foot processes. Since glomerulopathies are associated with so-called foot process effacement—a severe change of well-formed foot processes into flat and broadened processes—visualization of the three-dimensional podocyte morphology is a crucial part for diagnosis of nephrotic diseases. However, interdigitating podocyte foot processes are too narrow to be resolved by classic light microscopy due to Ernst Abbe's law making electron microscopy necessary. Although three dimensional electron microscopy approaches like serial block face and focused ion beam scanning electron microscopy and electron tomography allow volumetric reconstruction of podocytes, these techniques are very time-consuming and too specialized for routine use or screening purposes. During the last few years, different super-resolution microscopic techniques were developed to overcome the optical resolution limit enabling new insights into podocyte morphology. Super-resolution microscopy approaches like three dimensional structured illumination microscopy (3D-SIM), stimulated emission depletion microscopy (STED) and localization microscopy [stochastic optical reconstruction microscopy (STORM), photoactivated localization microscopy (PALM)] reach resolutions down to 80–20 nm and can be used to image and further quantify podocyte foot process morphology. Furthermore, in vivo imaging of podocytes is essential to study the behavior of these cells in situ. Therefore, multiphoton laser microscopy was a breakthrough for in vivo studies of podocytes in transgenic animal models like rodents and zebrafish larvae because it allows imaging structures up to several hundred micrometer in depth within the tissue. Additionally, along with multiphoton microscopy, lightsheet microscopy is currently used to visualize larger tissue volumes and therefore image complete glomeruli in their native tissue context. Alongside plain visualization of cellular structures, atomic force microscopy has been used to study the change of mechanical properties of podocytes in diseased states which has been shown to be a culprit in podocyte maintenance. This review discusses recent advances in the field of microscopic imaging and demonstrates their currently used and other possible applications for podocyte research.
Melioidosis is a seasonal infectious disease in tropical and subtropical areas caused by the soil bacterium Burkholderia pseudomallei. In many parts of the world, including South West India, most cases of human infections are reported during times of heavy rainfall, but the underlying causes of this phenomenon are not fully understood. India is among the countries with the highest predicted melioidosis burden globally, but there is very little information on the environmental distribution of B. pseudomallei and its determining factors. The present study aimed (i) to investigate the prevalence of B. pseudomallei in soil in South West India, (ii) determine geochemical factors associated with B. pseudomallei presence and (iii) look for potential seasonal patterns of B. pseudomallei soil abundance. Environmental samplings were performed in two regions during the monsoon and post-monsoon season and summer from July 2016 to November 2018. We applied direct quantitative real time PCR (qPCR) together with culture protocols to overcome the insufficient sensitivity of solely culture-based B. pseudomallei detection from soil. A total of 1,704 soil samples from 20 different agricultural sites were screened for the presence of B. pseudomallei. Direct qPCR detected B. pseudomallei in all 20 sites and in 30.2% (517/1,704) of all soil samples, whereas only two samples from two sites were culture-positive. B. pseudomallei DNA-positive samples were negatively associated with the concentration of iron, manganese and nitrogen in a binomial logistic regression model. The highest number of B. pseudomallei-positive samples (42.6%, p < 0.0001) and the highest B. pseudomallei loads in positive samples [median 4.45 × 103 genome equivalents (GE)/g, p < 0.0001] were observed during the monsoon season and eventually declined to 18.9% and a median of 1.47 × 103 GE/g in summer. In conclusion, our study from South West India shows a wide environmental distribution of B. pseudomallei, but also considerable differences in the abundance between sites and within single sites. Our results support the hypothesis that nutrient-depleted habitats promote the presence of B. pseudomallei. Most importantly, the highest B. pseudomallei abundance in soil is seen during the rainy season, when melioidosis cases occur.
Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.
Ocean literacies: the promise of regional approaches integrating ocean histories and psychologies
(2023)
The current concept of ocean literacy reflects a prerequisite for achieving ocean sustainability. Existing ocean literacy reflects a fundamentally western view of oceans that works in tension with ocean literacy goals. Although ocean literacy practitioners and researchers are, laudably, starting to incorporate Indigenous knowledges and perspectives from BIPOC communities, attention to historical change continues to be left out of ocean literacy, to the detriment of ocean literacy goals. This article points out that, given the reality that human-ocean relationships have changed over time, and differed among cultural groups in the past as well as in the present, ocean literacy needs to incorporate ocean history at a foundational level. Because there are historical differences in human relationships with oceans, it stands to reason that regional ocean literacies must be more effective than a universal and timeless ocean literacy framework. Following the logical efficacy of a regional approach to ocean literacy, this article further argues that regional ocean literacies should involve the systematic inclusion of emotional elements. Regional ocean literacies should be constructed through knowledge co-production, involving diverse types of expertise, knowledge and actors to produce context-specific knowledge and pathways towards a sustainable future. To fully exploit the potential of ocean literacy, there is a need for the UN Ocean Decade to work towards regional and place-based approaches that incorporate history as well as culture in an iterative and collaborative process involving diverse types of expertise, knowledge and actors.
Background
Sepsis is one of the leading causes of preventable deaths in hospitals. This study presents the evaluation of a quality collaborative, which aimed to decrease sepsis-related hospital mortality.
Methods
The German Quality Network Sepsis (GQNS) offers quality reporting based on claims data, peer reviews, and support for establishing continuous quality management and staff education. This study evaluates the effects of participating in the GQNS during the intervention period (April 2016–June 2018) in comparison to a retrospective baseline (January 2014–March 2016). The primary outcome was all-cause risk-adjusted hospital mortality among cases with sepsis. Sepsis was identified by International Classification of Diseases (ICD) codes in claims data. A controlled time series analysis was conducted to analyze changes from the baseline to the intervention period comparing GQNS hospitals with the population of all German hospitals assessed via the national diagnosis-related groups (DRGs)-statistics. Tests were conducted using piecewise hierarchical models. Implementation processes and barriers were assessed by surveys of local leaders of quality improvement teams.
Results
Seventy-four hospitals participated, of which 17 were university hospitals and 18 were tertiary care facilities. Observed mortality was 43.5% during baseline period and 42.7% during intervention period. Interrupted time-series analyses did not show effects on course or level of risk-adjusted mortality of cases with sepsis compared to the national DRG-statistics after the beginning of the intervention period (p = 0.632 and p = 0.512, respectively). There was no significant mortality decrease in the subgroups of patients with septic shock or ventilation >24 h or predefined subgroups of hospitals. A standardized survey among 49 local quality improvement leaders in autumn of 2018 revealed that most hospitals did not succeed in implementing a continuous quality management program or relevant measures to improve early recognition and treatment of sepsis. Barriers perceived most commonly were lack of time (77.6%), staff shortage (59.2%), and lack of participation of relevant departments (38.8%).
Conclusion
As long as hospital-wide sepsis quality improvement efforts will not become a high priority for the hospital leadership by assuring adequate resources and involvement of all pertinent stakeholders, voluntary initiatives to improve the quality of sepsis care will remain prone to failure.
Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-β) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-β load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-β, as well as regional amyloid-β load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-β load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-β load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-β load in the parietal cortex. Higher levels of worry were associated with higher amyloid-β load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-β burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.
Whether mice are an appropriate model for S. aureus infection and vaccination studies is a matter of debate, because they are not considered as natural hosts of S. aureus. We previously identified a mouse-adapted S. aureus strain, which caused infections in laboratory mice. This raised the question whether laboratory mice are commonly colonized with S. aureus and whether this might impact on infection experiments. Publicly available health reports from commercial vendors revealed that S. aureus colonization is rather frequent, with rates as high as 21% among specific-pathogen-free mice. In animal facilities, S. aureus was readily transmitted from parents to offspring, which became persistently colonized. Among 99 murine S. aureus isolates from Charles River Laboratories half belonged to the lineage CC88 (54.5%), followed by CC15, CC5, CC188, and CC8. A comparison of human and murine S. aureus isolates revealed features of host adaptation. In detail, murine strains lacked hlb-converting phages and superantigen-encoding mobile genetic elements, and were frequently ampicillin-sensitive. Moreover, murine CC88 isolates coagulated mouse plasma faster than human CC88 isolates. Importantly, S. aureus colonization clearly primed the murine immune system, inducing a systemic IgG response specific for numerous S. aureus proteins, including several vaccine candidates. Phospholipase C emerged as a promising test antigen for monitoring S. aureus colonization in laboratory mice. In conclusion, laboratory mice are natural hosts of S. aureus and therefore, could provide better infection models than previously assumed. Pre-exposure to the bacteria is a possible confounder in S. aureus infection and vaccination studies and should be monitored.
Background: Mitochondrial dynamics are important for glucose-stimulated insulin secretion in pancreatic beta cells. The mitochondrial elongation factor MiD51 has been proposed to act as an anchor that recruits Drp1 from the cytosol to the outer mitochondrial membrane. Whether MiD51 promotes mitochondrial fusion by inactivation of Drp1 is a controversial issue. Since both the underlying mechanism and the effects on mitochondrial function remain unknown, this study was conducted to investigate the role of MiD51 in beta cells.
Methods: Overexpression and downregulation of MiD51 in mouse insulinoma 6 (MIN6) and mouse islet cells was achieved using the pcDNA expression vector and specific siRNA, respectively. Expression of genes regulating mitochondrial dynamics and autophagy was analyzed by quantitative Real-Time PCR, glucose-stimulated insulin secretion by ELISA, and cellular oxygen consumption rate by optode sensor technology. Mitochondrial membrane potential and morphology were visualized after TMRE and MitoTracker Green staining, respectively. Immunofluorescence analyses were examined by confocal microscopy.
Results: MiD51 is expressed in insulin-positive mouse and human pancreatic islet and MIN6 cells. Overexpression of MiD51 resulted in mitochondrial fragmentation and cluster formation in MIN6 cells. Mitochondrial membrane potential, glucose-induced oxygen consumption rate and glucose-stimulated insulin secretion were reduced in MIN6 cells with high MiD51 expression. LC3 expression remained unchanged. Downregulation of MiD51 resulted in inhomogeneity of the mitochondrial network in MIN6 cells with hyperelongated and fragmented mitochondria. Mitochondrial membrane potential, maximal and glucose-induced oxygen consumption rate and insulin secretion were diminished in MIN6 cells with low MiD51 expression. Furthermore, reduced Mfn2 and Parkin expression was observed. Based on MiD51 overexpression and downregulation, changes in the mitochondrial network structure similar to those in MIN6 cells were also observed in mouse islet cells.
Conclusion: We have demonstrated that MiD51 plays a pivotal role in regulating mitochondrial function and hence insulin secretion in MIN6 cells. We propose that this anchor protein of Drp1 is important to maintain a homogeneous mitochondrial network and to avoid morphologies such as hyperelongation and clustering which are inaccessible for degradation by autophagy. Assuming that insulin granule degradation frequently suppresses autophagy in beta cells, MiD51 could be a key element maintaining mitochondrial health.
This study evaluated the impact of a defined plasma treated water (PTW) when applied to various stages within fresh-cut endive processing. The quality characteristic responses were investigated to establish the impact of the PTW unit processes and where PTW may be optimally applied in a model process line to retain or improve produce quality. Different stages of application of PTW within the washing process were investigated and compared to tap water and chlorine dioxide. Fresh-cut endive (Cichorium endivia L.) samples were analyzed for retention of food quality characteristics. Measurements included color, texture, and nitrate quantification. Effects on tissue surface and cell organelles were observed through scanning electron and atomic force microscopy. Overall, the endive quality characteristics were retained by incorporating PTW in the washing process. Furthermore, promising results for color and texture characteristics were observed, which were supported by the microscopic assays of the vegetal tissue. While ion chromatography detected high concentrations of nitrite and nitrate in PTW, these did not affect the nitrate concentration of the lettuce tissue post-processing and were below the concentrations within EU regulations. These results provide a pathway to scale up the industrial application of PTW to improve and retain quality characteristic retention of fresh leafy products, whilst also harnessing the plasma functionalized water as a process intervention for reducing microbial load at multiple points, whether on the food surface, within the process water or on food-processing surfaces.
Introduction: The topics of bullying, school anxiety and school absenteeism are of steady interest for the scientific community in recent decades. However, it seems surprising that investigations into the combination of these constructs are rare, especially considering their interconnectedness. Due to the lack of joint investigation of these factors, it is hardly possible to compare results of these related, yet distinct factors across other studies, let alone the predictive power of specific factors. The goal of the current study is to investigate how bullying, school anxiety and school absenteeism are related, considering the variables gender and grade level.
Methods: For this purpose, N = 195 secondary school children in the 7th–9th grades in northern Germany were surveyed via self-report questionnaires and additionally collecting their school records. We present complex descriptive analyses with scales and subscales of bullying, anxiety and absenteeism. Further, a structural equation modelling (SEM) approach is utilized to discover the interconnectedness of the constructs.
Results: On the one hand, the descriptive statistics show significant gender and grade level differences regarding bullying and anxiety. On the other hand, the SEM reveals that high values on the bullying victim scale are accompanied by significantly higher school displeasure (anxiety). School displeasure—as well as high bullying offender values—are associated with significantly more days of absence from school.
Discussion: We discuss how school environment improvement through specific interventions such as the cognitive-behavioral approach, could aid to ameliorate this issue.
Background
In addition to the broad dissemination of pathogenic extended-spectrum beta-lactamase (ESBL)-producing Escherichia (E.) coli in human and veterinary medicine and the community, their occurrence in wildlife and the environment is a growing concern. Wild birds in particular often carry clinically relevant ESBL-producing E. coli.
Objectives
We analyzed ESBL-producing and non-ESBL-producing E. coli obtained from wild birds in Mongolia to identify phylogenetic and functional characteristics that would explain the predominance of a particular E. coli clonal lineage in this area.
Methods
We investigated ESBL-producing E. coli using whole-genome sequencing and phylogenetics to describe the population structure, resistance and virulence features and performed phenotypic experiments like biofilm formation and adhesion to epithelial cells. We compared the phenotypic characteristics to non-ESBL-producing E. coli from the same background (Mongolian wild birds) and genomic results to publicly available genomes.
Results and Conclusion
We found ESBL-producing E. coli sequence type (ST) 1159 among wild birds in Mongolia. This clonal lineage carried virulence features typical for extra-intestinal pathogenic or enterotoxigenic E. coli. Comparative functional experiments suggested no burden of resistance in the ST1159 isolates, which is despite their carriage of ESBL-plasmids. Wild birds will likely disseminate these antibiotic-resistant pathogens further during migration.
In micro-densitometry of wood it is standard procedure to extract resin and other soluble compounds before X-ray analysis to eliminate the influence of these extractives on wood-density. Dendrochemical studies using X-ray fluorescence analysis on the other hand are commonly conducted without previous extraction. However, it is well known that translocation processes of elements during heartwood formation in trees or (temporal) differences in sap content of wood samples can influence dendrochemical element profiles. This might bias environmental signals stored in time series of element concentrations in wood proxies. We hypothesize that metals tightly bound to cell walls show a more robust proxy potential for environmental conditions than easily translocated ones. To eliminate the noise of these soluble substances in wood elemental time series, their extraction prior to analysis might be necessary. In our study we tested the effect of different solvents (water, alcohol, and acetone) and different extraction times on elemental time series of three tree species with differing wood structure (Pinus sylvestris; Quercus robur and Populus tremula). Micro-XRF analysis was conducted on nine replicates per species using an ITRAX-Multiscanner. A set of elements commonly detected in wood (S, Cl, K, Ca, Ti, Mn, Fe, and Ni) was analysed at high resolution before and after several extraction runs. Besides lowering their levels, extraction did not significantly change the temporal trends for most elements. However, for some elements, e.g., Potassium, Chlorine or Manganese, especially the water extraction led to significant decreases in concentrations and altered temporal trends. Apparently the dipole effect of water produced the strongest extraction power of all three solvents. In addition we observed a dependency of extraction intensity from wood density which differed between wood types. Our results help in interpreting and evaluating element profiles and mark a step forward in establishing dendrochemistry as a robust proxy in dendro-environmental research.
Animals experience climatic variation in their natural habitats, which may lead to variation in phenotypic responses among populations through local adaptation or phenotypic plasticity. In ectotherm arthropods, the expression of thermoprotective metabolites such as free amino acids, sugars, and polyols, in response to temperature stress, may facilitate temperature tolerance by regulating cellular homeostasis. If populations experience differences in temperatures, individuals may exhibit population-specific metabolite profiles through differential accumulation of metabolites that facilitate thermal tolerance. Such thermoprotective metabolites may originate from the animals themselves or from their associated microbiome, and hence microbial symbionts may contribute to shape the thermal niche of their host. The social spider Stegodyphus dumicola has extremely low genetic diversity, yet it occupies a relatively broad temperature range occurring across multiple climate zones in Southern Africa. We investigated whether the metabolome, including thermoprotective metabolites, differs between populations, and whether population genetic structure or the spider microbiome may explain potential differences. To address these questions, we assessed metabolite profiles, phylogenetic relationships, and microbiomes in three natural populations along a temperature gradient. The spider microbiomes in three genetically distinct populations of S. dumicola showed no significant population-specific pattern, and none of its dominating genera (Borrelia, Diplorickettsia, and Mycoplasma) are known to facilitate thermal tolerance in hosts. These results do not support a role of the microbiome in shaping the thermal niche of S. dumicola. Metabolite profiles of the three spider populations were significantly different. The variation was driven by multiple metabolites that can be linked to temperature stress (e.g., lactate, succinate, or xanthine) and thermal tolerance (e.g., polyols, trehalose, or glycerol): these metabolites had higher relative abundance in spiders from the hottest geographic region. These distinct metabolite profiles are consistent with a potential role of the metabolome in temperature response.
Background
The role of platelets for mediating closure of the ductus arteriosus in human preterm infants is controversial. Especially, the effect of low platelet counts on pharmacological treatment failure is still unclear.
Methods
In this retrospective study of 471 preterm infants [<1,500 g birth weight (BW)], who were treated for a patent ductus arteriosus (PDA) with indomethacin or ibuprofen, we investigated whether platelet counts before or during pharmacological treatment had an impact on the successful closure of a hemodynamically significant PDA. The effects of other factors, such as sepsis, preeclampsia, gestational age, BW, and gender, were also evaluated.
Results
Platelet counts before initiation of pharmacological PDA treatment did not differ between infants with later treatment success or failure. However, we found significant associations between low platelet counts during pharmacological PDA therapy and treatment failure (p < 0.05). Receiver operating characteristic (ROC) curve analysis showed that platelet counts after the first, and before and after the second cyclooxygenase inhibitor (COXI) cycle were significantly associated with treatment failure (area under the curve of >0.6). However, ROC curve analysis did not reveal a specific platelet cutoff-value that could predict PDA treatment failure. Multivariate logistic regression analysis showed that lower platelet counts, a lower BW, and preeclampsia were independently associated with COXI treatment failure.
Conclusion
We provide further evidence for an association between low platelet counts during pharmacological therapy for symptomatic PDA and treatment failure, while platelet counts before initiation of therapy did not affect treatment outcome.
Introduction
Neurofilament light (NfL) can be detected in blood of healthy individuals and at elevated levels in those with different neurological diseases. We investigated if the choice of biological matrix can affect results when using NfL as biomarker in epidemiological studies.
Method
We obtained paired serum and EDTA-plasma samples of 299 individuals aged 37–67 years (BiDirect study) and serum samples of 373 individuals aged 65–83 years (MEMO study). In BiDirect, Passing–Bablok analyses were performed to assess proportional and systematic differences between biological matrices. Associations between serum or EDTA-plasma NfL and renal function (serum creatinine, serum cystatin C, glomerular filtration rate, and kidney disease) were investigated using linear or logistic regression, respectively. All regression coefficients were estimated (1) per one ng/L increase and (2) per one standard deviation increase (standardization using z-scores). In MEMO, regression coefficients were estimated (1) per one ng/L increase of serum or calculated EDTA-plasma NfL and (2) per one standard deviation increase providing a comparison to the results from BiDirect.
Results
We found proportional and systematic differences between paired NfL measurements in BiDirect, i.e., serum NfL [ng/L] = −0.33 [ng/L] + 1.11 × EDTA-plasma NfL [ng/L]. Linear regression coefficients for the associations between NfL and renal function did not vary between the different NfL measurements. In MEMO, one standard deviation increase in serum NfL was associated with greater changes in the outcomes than in BiDirect.
Conclusion
Although there are differences between serum and EDTA-plasma NfL, results can be used interchangeably if standardized values are used.
Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP+. In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance.
Background: Granulocytes and monocytes are the first cells to invade the brain post stroke and are also being discussed as important cells in early neuroinflammation after seizures. We aimed at understanding disease specific and common pathways of brain-immune-endocrine-interactions and compared immune alterations induced by stroke and seizures. Therefore, we compared granulocytic and monocytic subtypes between diseases and investigated inflammatory mediators. We additionally investigated if seizure type determines immunologic alterations.
Material and Methods: We included 31 patients with acute seizures, 17 with acute stroke and two control cohorts. Immune cells were characterized by flow cytometry from blood samples obtained on admission to the hospital and the following morning. (i) Monocytes subpopulations were defined as classical (CD14++CD16−), (ii) intermediate (CD14++CD16+), and (iii) non-classical monocytes (CD14dimCD16+), while granulocyte subsets were characterized as (i) “classical granulocytes” (CD16++CD62L+), (ii) pro-inflammatory (CD16dimCD62L+), and (iii) anti-inflammatory granulocytes (CD16++CD62L−). Stroke patient's blood was additionally drawn on days 3 and 5. Cerebrospinal fluid mitochondrial DNA was quantified by real-time PCR. Plasma High-Mobility-Group-Protein-B1, metanephrine, and normetanephrine were measured by ELISA.
Results: HLA-DR expression on monocytes and their subpopulations (classical, intermediate, and non-classical monocytes) was reduced after stroke or seizures. Expression of CD32 was increased on monocytes and subtypes in epilepsy patients, partly similar to stroke. CD32 and CD11b regulation on granulocytes and subpopulations (classical, anti-inflammatory, pro-inflammatory granulocytes) was more pronounced after stroke compared to seizures. On admission, normetanephrine was upregulated in seizures, arguing for the sympathetic nervous system as inducer of immune alterations similar to stroke. Compared to partial seizures, immunologic changes were more pronounced in generalized tonic-clonic seizures.
Conclusion: Seizures lead to immune alterations within the immediate postictal period similar but not identical to stroke. The type of seizures determines the extent of immune alterations.
Alternative splicing (AS) is a major mechanism for gene expression in eukaryotes, increasing proteome diversity but also regulating transcriptome abundance. High temperatures have a strong impact on the splicing profile of many genes and therefore AS is considered as an integral part of heat stress response. While many studies have established a detailed description of the diversity of the RNAome under heat stress in different plant species and stress regimes, little is known on the underlying mechanisms that control this temperature-sensitive process. AS is mainly regulated by the activity of splicing regulators. Changes in the abundance of these proteins through transcription and AS, post-translational modifications and interactions with exonic and intronic cis-elements and core elements of the spliceosomes modulate the outcome of pre-mRNA splicing. As a major part of pre-mRNAs are spliced co-transcriptionally, the chromatin environment along with the RNA polymerase II elongation play a major role in the regulation of pre-mRNA splicing under heat stress conditions. Despite its importance, our understanding on the regulation of heat stress sensitive AS in plants is scarce. In this review, we summarize the current status of knowledge on the regulation of AS in plants under heat stress conditions. We discuss possible implications of different pathways based on results from non-plant systems to provide a perspective for researchers who aim to elucidate the molecular basis of AS under high temperatures.
Identification and Regulation of Tomato Serine/Arginine-Rich Proteins Under High Temperatures
(2021)
Alternative splicing is an important mechanism for the regulation of gene expression in eukaryotes during development, cell differentiation or stress response. Alterations in the splicing profiles of genes under high temperatures that cause heat stress (HS) can impact the maintenance of cellular homeostasis and thermotolerance. Consequently, information on factors involved in HS-sensitive alternative splicing is required to formulate the principles of HS response. Serine/arginine-rich (SR) proteins have a central role in alternative splicing. We aimed for the identification and characterization of SR-coding genes in tomato (Solanum lycopersicum), a plant extensively used in HS studies. We identified 17 canonical SR and two SR-like genes. Several SR-coding genes show differential expression and altered splicing profiles in different organs as well as in response to HS. The transcriptional induction of five SR and one SR-like genes is partially dependent on the master regulator of HS response, HS transcription factor HsfA1a. Cis-elements in the promoters of these SR genes were predicted, which can be putatively recognized by HS-induced transcription factors. Further, transiently expressed SRs show reduced or steady-state protein levels in response to HS. Thus, the levels of SRs under HS are regulated by changes in transcription, alternative splicing and protein stability. We propose that the accumulation or reduction of SRs under HS can impact temperature-sensitive alternative splicing.
Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia
(2013)
Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection.
Purpose: The cyclin-dependent kinase (Cdk) inhibitor p27Kip1 may be involved in regulating re-entry of residual hepatocytes into the cell cycle upon loss of liver tissue by partial hepatectomy (PH). As yet, changes in Kip1 expression during the initial period following PH are not well-characterized. We investigated immediate changes in Kip1 mRNA and protein levels as well as changes in Kip1 phosphorylation in liver tissue within the relevant time window between surgery and the onset of DNA synthesis at 10–12 h.
Methods: We used real-time PCR, quantitative Western blotting, and immune histochemistry on tissue samples of adult rats obtained during or between 2 and 10 h after surgical removal of two thirds of the liver to analyze Kip1 mRNA or protein levels, respectively, or to quantify nuclear expression of Kip1.
Results: Kip1 mRNA was down-regulated within 4 h after PH by 60% and remained unchanged thereafter up to 10 h. With a lag phase of 2–3 h, Kip1-protein was down-regulated to a level of 40% of the control. The level of Thr187-phosphorylated Kip1 started to increase at 4 h and reached a maximum level at 8–10 h after PH. Kip1 immunoreactivity was observed in 30% of the hepatocytes before PH. Within 6–8 h after PH, more than half of the hepatocytes lost nuclear Kip1 signals. Kip1-specific micro-RNAs (miRNA221, miRNA222) were not changed upon PH.
Conclusions: A portion of hepatocytes in adult rats constitutively express Kip1 and down-regulate Kip1 immediately upon PH. This response involves transcriptional processes (loss of Kip1 mRNA) as well as accelerated degradation of existing protein (increase in pThr187-phosphorylation mediating polyubiquitinylation and proteasomal degradation of Kip1). Kip1 down-regulation occurs precisely within the intervall between surgery and onset of DNA synthesis which supports the hypothesis that it mediates activation of G0/0S-phase Cdk/cyclin-complexes and re-entry of hepatocytes into the cell cycle.
Background: Cognitive Training (CT) may contribute to the maintenance and even enhancement of cognitive functions in healthy older adults. However, the question who benefits most from multi-domain CTs is still highly under-investigated.
Objective: The goal is to investigate prognostic factors and models for changes in cognitive test performance in healthy older adults after a multi-domain CT.
Methods: The data bases MEDLINE, Web of Science Core Collection, CENTRAL, and PsycInfo were searched up to July 2019. Studies investigating prognostic factors and/or models on cognitive outcomes (global cognition, memory, attention, executive functions, language, visuo-spatial abilities) after conducting a multi-domain CT in healthy older adults were included. Risk of Bias was assessed using the QUIPS and the PROBAST tool.
Results: 23 prognostic factor and model studies were included. Results indicate a high heterogeneity regarding the conducted multi-domain CTs, the investigated prognostic factors, the investigated outcomes, and the used statistical approaches. Age and neuropsychological performance at study entry were the most investigated predictors, yet they show inconsistent results.
Conclusion: Data on prognostic factors and models of changes after multi-domain CT are still too rare and inconsistent to draw clear conclusions due to statistical shortcomings and low reporting quality. Approaches for future research are outlined.
Registration: https://www.crd.york.ac.uk/prospero/, ID: CRD42020147531
The modification of male pedipalps into secondary sexual intromittent organs is one of the hallmark characteristics of spiders, yet understanding the development and evolution of male genitalia across the order remains a challenging prospect. The embolus – the sclerite bearing the efferent spermatic duct or spermophor, and used to deliver sperm directly to the female genitalia during copulation – has always been considered the single unambiguously homologous palpal sclerite shared by all spider species, fundamental to the bauplan of the order and to the evolution and functional morphology of spider reproductive systems. Indeed, after two centuries of comparative research on spider reproduction, the presence of a single spermophor and embolus on each of a male spider’s two pedipalps remains a central tenet of evolutionary arachnology. Our findings challenge this premise, and reveal a remarkable twin intromittent organ sperm transfer system in a lineage of Australian palpimanoid spiders, characterized by a bifurcate spermophor and the presence of two efferent ducts leading to a pair of embolic sclerites on each pedipalp. This is the first time such a remarkable conformation has been observed in any group of arachnids with direct sperm transfer, complicating our understanding of palpal sclerite homologies, and challenging ideas about the evolution of spider genitalia.
Chronic kidney disease (CKD) is a major public health burden affecting more than 500 million people worldwide. Podocytopathies are the main cause for the majority of CKD cases due to pathogenic morphological as well as molecular biological alterations of postmitotic podocytes. Podocyte de-differentiation is associated with foot process effacement subsequently leading to proteinuria. Since currently no curative drugs are available, high throughput screening methods using a small number of animals are a promising and essential tool to identify potential drugs against CKD in the near future. Our study presents the implementation of the already established mouse GlomAssay as a semi-automated high-throughput screening method—shGlomAssay—allowing the analysis of several hundreds of FDA-verified compounds in combination with downstream pathway analysis like transcriptomic and proteomic analyses from the same samples, using a small number of animals. In an initial prescreening we have identified vitamin D3 and its analog calcipotriol to be protective on podocytes. Furthermore, by using RT-qPCR, Western blot, and RNA sequencing, we found that mRNA and protein expression of nephrin, the vitamin D receptor and specific podocyte markers were significantly up-regulated due to vitamin D3- and calcipotriol-treatment. In contrast, kidney injury markers were significantly down-regulated. Additionally, we found that vitamin D3 and calcipotriol have had neither influence on the expression of the miR-21 and miR-30a nor on miR-125a/b, a miRNA described to regulate the vitamin D receptor. In summary, we advanced the established mouse GlomAssay to a semi-automated high-throughput assay and combined it with downstream analysis techniques by using only a minimum number of animals. Hereby, we identified the vitamin D signaling pathway as podocyte protective and to be counteracting their de-differentiation.
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.
Introduction: Splenic B cells exhibit a high expression of the G protein-coupled sphingosine-1-phosphate (S1P) receptor type 4 (S1PR4). Little is known about the functional relevance of S1PR4 expression on those cells.
Methods: In this study, S1PR4-deficient mice were used to study the role of S1PR4-mediated S1P signaling in B cell motility in vitro and for the maintenance of the splenic architecture under steady state conditions as well as in polymicrobial abdominal sepsis in vivo. Finally, the impact of S1PR4 deficiency on antibody production after immunization with T cell dependent antigens was assessed.
Results: Loss of S1PR4 resulted in minor alterations of the splenic architecture concerning the presence of B cell follicles. After sepsis induction, the germinal center response was severely impaired in S1PR4-deficient animals. Splenic B cells showed reduced motility in the absence of S1PR4. However, titres of specific antibodies showed only minor reductions in S1PR4-deficient animals.
Discussion: These observations suggest that S1P signaling mediated by S1PR4 modifies chemokine-induced splenic B cell chemotaxis, thus modulating splenic microarchitecture, GC formation and T-cell dependent antibody production.
People smile in various emotional contexts, for example, when they are amused or angry or simply being polite. We investigated whether younger and older adults differ in how well they are able to identify the emotional experiences accompanying smile expressions, and whether the age of the smiling person plays a role in this respect. With this aim, we produced 80 video episodes of three types of smile expressions: positive-affect smiles had been spontaneously displayed by target persons as they were watching amusing film clips and cartoons. Negative-affect smiles had been displayed spontaneously by target persons during an interaction in which they were being unfairly accused. Affectively neutral smiles were posed upon request. Differences in the accompanying emotional experiences were validated by target persons' self-reports. These smile videos served as experimental stimuli in two studies with younger and older adult participants. In Study 1, older participants were less likely to attribute positive emotions to smiles, and more likely to assume that a smile was posed. Furthermore, younger participants were more accurate than older adults at identifying emotional experiences accompanying smiles. In Study 2, both younger and older participants attributed positive emotions more frequently to smiles shown by older as compared to younger target persons, but older participants did so less frequently than younger participants. Again, younger participants were more accurate than older participants in identifying emotional experiences accompanying smiles, but this effect was attenuated for older target persons. Older participants could better identify the emotional state accompanying smiles shown by older than by younger target persons. Taken together, these findings indicate that there is an age-related decline in the ability to decipher the emotional meaning of smiles presented without context, which, however, is attenuated when the smiling person is also an older adult.
The nature and origin of electronic nematicity remains a significant challenge in our
understanding of the iron-based superconductors. This is particularly evident in the
iron chalcogenide, FeSe, where it is currently unclear how the experimentally
determined Fermi surface near the M point evolves from having two electron pockets
in the tetragonal state, to exhibiting just a single electron pocket in the nematic state. This
has posed a major theoretical challenge, which has become known as the missing electron
pocket problem of FeSe, and is of central importance if we wish to uncover the secrets
behind nematicity and superconductivity in the wider iron-based superconductors. Here,
we review the recent experimental work uncovering this nematic Fermi surface of FeSe
from both ARPES and STM measurements, as well as current theoretical attempts to
explain this missing electron pocket of FeSe, with a particular focus on the emerging
importance of incorporating the dxy orbital into theoretical descriptions of the nematic
state. Furthermore, we will discuss the consequence this missing electron pocket has on
the theoretical understanding of superconductivity in this system and present several
remaining open questions and avenues for future research.
The recent developments in artificial intelligence have the potential to facilitate new research methods in ecology. Especially Deep Convolutional Neural Networks (DCNNs) have been shown to outperform other approaches in automatic image analyses. Here we apply a DCNN to facilitate quantitative wood anatomical (QWA) analyses, where the main challenges reside in the detection of a high number of cells, in the intrinsic variability of wood anatomical features, and in the sample quality. To properly classify and interpret features within the images, DCNNs need to undergo a training stage. We performed the training with images from transversal wood anatomical sections, together with manually created optimal outputs of the target cell areas. The target species included an example for the most common wood anatomical structures: four conifer species; a diffuse-porous species, black alder (Alnus glutinosa L.); a diffuse to semi-diffuse-porous species, European beech (Fagus sylvatica L.); and a ring-porous species, sessile oak (Quercus petraea Liebl.). The DCNN was created in Python with Pytorch, and relies on a Mask-RCNN architecture. The developed algorithm detects and segments cells, and provides information on the measurement accuracy. To evaluate the performance of this tool we compared our Mask-RCNN outputs with U-Net, a model architecture employed in a similar study, and with ROXAS, a program based on traditional image analysis techniques. First, we evaluated how many target cells were correctly recognized. Next, we assessed the cell measurement accuracy by evaluating the number of pixels that were correctly assigned to each target cell. Overall, the “learning process” defining artificial intelligence plays a key role in overcoming the issues that are usually manually solved in QWA analyses. Mask-RCNN is the model that better detects which are the features characterizing a target cell when these issues occur. In general, U-Net did not attain the other algorithms’ performance, while ROXAS performed best for conifers, and Mask-RCNN showed the highest accuracy in detecting target cells and segmenting lumen areas of angiosperms. Our research demonstrates that future software tools for QWA analyses would greatly benefit from using DCNNs, saving time during the analysis phase, and providing a flexible approach that allows model retraining.