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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.
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.
Predicting complications in pediatric Crohn's disease patients followed in CEDATA-GPGE registry
(2023)
Background
Complications of Crohn's disease (CD) often impair patients' quality of life. It is necessary to predict and prevent these complications (surgery, stricturing [B2]/penetrating [B3] disease behavior, perianal disease, growth retardation and hospitalization). Our study investigated previously suggested and additional predictors by analyzing data of the CEDATA-GPGE registry.
Methods
Pediatric patients (< 18 years) diagnosed with CD with follow up data in the registry were included in the study. Potential risk factors for the selected complications were evaluated by performing Kaplan-Meier survival curves and cox regression models.
Results
For the complication surgery, the potential risk factors older age, B3 disease, severe perianal disease and initial therapy with corticosteroids at the time of diagnosis were identified. Older age, initial therapy with corticosteroids, low weight-for-age, anemia and emesis predict B2 disease. Low weight-for-age and severe perianal disease were risk factors for B3 disease. Low weight-for-age, growth retardation, older age, nutritional therapy, and extraintestinal manifestations (EIM) of the skin were identified as risk factors for growth retardation during the disease course. High disease activity and treatment with biologicals were predictors for hospitalization. As risk factors for perianal disease, the factors male sex, corticosteroids, B3 disease, a positive family history and EIM of liver and skin were identified.
Conclusion
We confirmed previously suggested predictors of CD course and identified new ones in one of the largest registries of pediatric CD patients. This may help to better stratify patients’ according to their individual risk profile and choose appropriate treatment strategies.
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.
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.
Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.
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.
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.
Objective: The instrument THERapy-related InterACTion (THER-I-ACT) was developed to document therapeutic interactions comprehensively in the human therapist–patient setting. Here, we investigate whether the instrument can also reliably be used to characterise therapeutic interactions when a digital system with a humanoid robot as a therapeutic assistant is used.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis [n = 9] or arm ability training (AAT) for mild arm paresis [n = 8]) using the digital therapy system E-BRAiN over a course of nine sessions. Analysis of the therapeutic interaction: A total of 34 therapy sessions were videotaped. All therapeutic interactions provided by the humanoid robot during the first and the last (9th) session of daily training were documented both in terms of their frequency and time used for that type of interaction using THER-I-ACT. Any additional therapeutic interaction spontaneously given by the supervising staff or a human helper providing physical assistance (ABT only) was also documented. All ratings were performed by two trained independent raters.
Statistical analyses: Intraclass correlation coefficients (ICCs) were calculated for the frequency of occurrence and time used for each category of interaction observed.
Results: Therapeutic interactions could comprehensively be documented and were observed across the dimensions provision of information, feedback, and bond-related interactions. ICCs for therapeutic interaction category assessments from 34 therapy sessions by two independent raters were high (ICC ≥0.90) for almost all categories of the therapeutic interaction observed, both for the occurrence frequency and time used for categories of therapeutic interactions, and both for the therapeutic interaction performed by the robot and, even though much less frequently observed, additional spontaneous therapeutic interactions by the supervisory staff and a helper being present. The ICC was similarly high for an overall subjective rating of the concentration and engagement of patients (0.87).
Conclusion: Therapeutic interactions can comprehensively and reliably be documented by trained raters using the instrument THER-I-ACT not only in the traditional patient–therapist setting, as previously shown, but also in a digital therapy setting with a humanoid robot as the therapeutic agent and for more complex therapeutic settings with more than one therapeutic agent being present.
Physiological and neural synchrony in emotional and neutral stimulus processing: A study protocol
(2023)
Background: As psychotherapy involves at least two individuals, it is essential to include the interaction perspective research. During interaction, synchrony, i.e., the occurrence of simultaneous responses, can be observed at the physiological, neural, and behavioral level. Physiological responses include heart rate and electrodermal activity; neural markers can be measured using electroencephalogram. Emotionally arousing stimuli are allocated more attentional resources (motivated attention), which is reflected in physiological activation and brain potentials. Here we present a protocol for a pilot study implementing a new research methodology, and replication of the motivated attention to emotion effect in in dyads. There is evidence that higher synchrony is associated with more positive (therapeutic) relationships. Thus, the secondary outcome will be the association between physiological and neural synchrony and subjective ratings.
Methods and design: Individuals (18−30 years) will participate in same-sex pairs in two experiments. In the first experiment (triadic interaction), both participants attentively watch unpleasant, neutral and pleasant pictures, and read/listen to standardized scripts (unpleasant, neutral, and pleasant, respectively) for the imagination task. In the second experiment, participants will read out three scripts (unpleasant, neutral, pleasant) to each other, followed by a joint imagination period. Stimuli will be presented in counterbalanced orders. After each picture and imagination, participants rate their subjective arousal and valence. In the beginning and in the end of the procedure, dyads rate their relationship, sympathy, and bonds (Working Alliance Inventory subscale). Heart rate, electrodermal activity and electroencephalogram will be continuously measured during both experiments using portable devices (EcgMove4 and EdaMove4, nine-channel B-Alert X-Series mobile-wireless EEG). Synchrony analyses will include the dual electroencephalography analysis pipeline, correlational analyses and Actor–Partner Interdependence Models.
Discussion: The present study protocol provides an experimental approach to investigate interpersonal synchrony during emotion processing, allowing for the establishment of research methods in a pilot study, which can later be translated into real-life psychotherapy research. In the future, fundamental understanding of such mechanisms in dyadic interactions is essential in order to promote therapeutic relationships, and thus, treatment effectiveness and efficiency.
Objective: To characterize a socially active humanoid robot’s therapeutic interaction as a therapeutic assistant when providing arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis or arm ability training (AAT) for mild arm paresis) to stroke survivors when using the digital therapeutic system Evidence-Based Robot-Assistant in Neurorehabilitation (E-BRAiN) and to compare it to human therapists’ interaction.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., ABT [n = 9] or AAT [n = 8]) using E-BRAiN over a course of nine sessions and twenty-one other stroke survivors receiving arm rehabilitation sessions (i.e., ABT [n = 6] or AAT [n = 15]) in a conventional 1:1 therapist–patient setting. Analysis of therapeutic interaction: Therapy sessions were videotaped, and all therapeutic interactions (information provision, feedback, and bond-related interaction) were documented offline both in terms of their frequency of occurrence and time used for the respective type of interaction using the instrument THER-I-ACT. Statistical analyses: The therapeutic interaction of the humanoid robot, supervising staff/therapists, and helpers on day 1 is reported as mean across subjects for each type of therapy (i.e., ABT and AAT) as descriptive statistics. Effects of time (day 1 vs. day 9) on the humanoid robot interaction were analyzed by repeated-measures analysis of variance (rmANOVA) together with the between-subject factor type of therapy (ABT vs. AAT). The between-subject effect of the agent (humanoid robot vs. human therapist; day 1) was analyzed together with the factor therapy (ABT vs. AAT) by ANOVA.
Main results and interpretation: The overall pattern of the therapeutic interaction by the humanoid robot was comprehensive and varied considerably with the type of therapy (as clinically indicated and intended), largely comparable to human therapists’ interaction, and adapted according to needs for interaction over time. Even substantially long robot-assisted therapy sessions seemed acceptable to stroke survivors and promoted engaged patients’ training behavior.
Conclusion: Humanoid robot interaction as implemented in the digital system E-BRAiN matches the human therapeutic interaction and its modification across therapies well and promotes engaged training behavior by patients. These characteristics support its clinical use as a therapeutic assistant and, hence, its application to support specific and intensive restorative training for stroke survivors.
Mendelian randomization indicates causal effects of estradiol levels on kidney function in males
(2023)
Context: Chronic kidney disease (CKD) is a public health burden worldwide. Epidemiological studies observed an association between sex hormones, including estradiol, and kidney function.
Objective: We conducted a Mendelian randomization (MR) study to assess a possible causal effect of estradiol levels on kidney function in males and females.
Design: We performed a bidirectional two-sample MR using published genetic associations of serum levels of estradiol in men (n = 206,927) and women (n = 229,966), and of kidney traits represented by estimated glomerular filtration rate (eGFR, n = 567,460), urine albumin-to-creatinine ratio (UACR, n = 547,361), and CKD (n = 41,395 cases and n = 439,303 controls) using data obtained from the CKDGen Consortium. Additionally, we conducted a genome-wide association study using UK Biobank cohort study data (n = 11,798 men and n = 6,835 women) to identify novel genetic associations with levels of estradiol, and then used these variants as instruments in a one-sample MR.
Results: The two-sample MR indicated that genetically predicted estradiol levels are significantly associated with eGFR in men (beta = 0.077; p = 5.2E-05). We identified a single locus at chromosome 14 associated with estradiol levels in men being significant in the one-sample MR on eGFR (beta = 0.199; p = 0.017). We revealed significant results with eGFR in postmenopausal women and with UACR in premenopausal women, which did not reach statistical significance in the sensitivity MR analyses. No causal effect of eGFR or UACR on estradiol levels was found.
Conclusions: We conclude that serum estradiol levels may have a causal effect on kidney function. Our MR results provide starting points for studies to develop therapeutic strategies to reduce kidney disease.
Polypharmacy in patients with multiple sclerosis and the impact on levels of care and therapy units
(2023)
Background: The aim of this study was to examine the societal costs of polypharmacy in patients with multiple sclerosis (MS). We therefore focused on the association between the number of medications on the level of care (LOC), the German classification of the need for care, and the number of therapy sessions (TTU).
Methods: In addition to demographic information and medication, 101 MS patients performed the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS). Medications were subdivided into a total number of medications (TD), MS-related medication [MSD, i.e., disease-modifying drugs (DMDs) and symptomatic treatment (SD)], and medication for comorbidities (CDs). Multivariate linear regression models were performed to estimate if the amount of each medication type affects LOC or TTU.
Results: Polypharmacy appeared in 54 patients at the time of the survey. The relative risk (RR) of LOC 1 increased significantly by 2.46 (p = 0.001) per TD and by 2.55 (p = 0.004) per MSD, but not per CD (RR 1.44; p = 0.092). The effect of RR on MSD was driven by SD (RR 2.2; p = 0.013) but not DMD (RR 2.6; p = 0.4). RR of MSD remained significant for LOC 2 (1.77; p = 0.009) and LOC 3/4 (1.91; p = 0.015), with a strong trend in RR of SD, but not DMD. TTU increased significantly per MSD (p = 0.012), but not per TD (p = 0.081) and CD (p = 0.724).
Conclusion: The number of MSDs is related to the likelihood of a higher level of care and the number of therapy sessions and is therefore a good indication of the extent of the societal costs.
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.
Manual sleep scoring for research purposes and for the diagnosis of sleep disorders is labor-intensive and often varies significantly between scorers, which has motivated many attempts to design automatic sleep stage classifiers. With the recent introduction of large, publicly available hand-scored polysomnographic data, and concomitant advances in machine learning methods to solve complex classification problems with supervised learning, the problem has received new attention, and a number of new classifiers that provide excellent accuracy. Most of these however have non-trivial barriers to use. We introduce the Greifswald Sleep Stage Classifier (GSSC), which is free, open source, and can be relatively easily installed and used on any moderately powered computer. In addition, the GSSC has been trained to perform well on a large variety of electrode set-ups, allowing high performance sleep staging with portable systems. The GSSC can also be readily integrated into brain-computer interfaces for real-time inference. These innovations were achieved while simultaneously reaching a level of accuracy equal to, or exceeding, recent state of the art classifiers and human experts, making the GSSC an excellent choice for researchers in need of reliable, automatic sleep staging.
Background: Methanogenic archaea represent a less investigated and likely underestimated part of the intestinal tract microbiome in swine.
Aims/Methods: This study aims to elucidate the archaeome structure and function in the porcine intestinal tract of healthy and H1N1 infected swine. We performed multi-omics analysis consisting of 16S rRNA gene profiling, metatranscriptomics and metaproteomics.
Results and discussion: We observed a significant increase from 0.48 to 4.50% of archaea in the intestinal tract microbiome along the ileum and colon, dominated by genera Methanobrevibacter and Methanosphaera. Furthermore, in feces of naïve and H1N1 infected swine, we observed significant but minor differences in the occurrence of archaeal phylotypes over the course of an infection experiment. Metatranscriptomic analysis of archaeal mRNAs revealed the major methanogenesis pathways of Methanobrevibacter and Methanosphaera to be hydrogenotrophic and methyl-reducing, respectively. Metaproteomics of archaeal peptides indicated some effects of the H1N1 infection on central metabolism of the gut archaea.
Conclusions/Take home message: Finally, this study provides the first multi-omics analysis and high-resolution insights into the structure and function of the porcine intestinal tract archaeome during a non-lethal Influenza A virus infection of the respiratory tract, demonstrating significant alterations in archaeal community composition and central metabolic functions.
Background
Lower cortisol concentrations in adulthood were repeatedly associated with more severe childhood maltreatment. Additionally, childhood maltreatment was reported to promote health risk behavior, such as smoking or alcohol consumption, and to increase the risk of mental and somatic diseases during adulthood, such as major depressive disorders or obesity. The present study investigated if health risk behavior and disease symptoms in adults mediate the associations between past childhood maltreatment and present basal serum cortisol concentrations.
Methods
Data from two independent adult cohorts of the general population-based Study of Health in Pomerania (SHIP-TREND-0: N = 3,517; SHIP-START-2: N = 1,640) was used. Childhood maltreatment was assessed via the Childhood Trauma Questionnaire (CTQ). Cortisol concentrations were measured in single-point serum samples. Health risk behavior and mental and physical symptoms were used as mediators. Mediation analyses were calculated separately for both cohorts; results were integrated via meta-analyses.
Results
In mediator-separated analyses, associations between childhood maltreatment and basal serum cortisol concentrations were partly mediated by depressive symptoms (BDI-II: βindirect effect = -.011, pFDR = .017, 21.0% mediated) and subjective somatic health complaints (somatic complaints: βindirect effect = -.010, pFDR = .005, 19.4% mediated). In the second step, both mediators were simultaneously integrated into one mediation model. The model replicated the mediation effects of the subjective somatic health complaints (whole model: βindirect effect = -.014, p = .001, 27.6% mediated; BDI-II: βindirect effect = -.006, p = .163, 11.4% mediated, somatic complaints: βindirect effect = -.020, p = .020, 15.5% mediated).
Conclusion
The results support the hypothesis that the long-lasting effects of childhood maltreatment on the stress response system are partly mediated through self-perceived disease symptoms. However, no mediation was found for health risk behavior or physically measured mediators. Mediation models with multiple simultaneous mediators pointed to a relevant overlap between the potential mediators. This overlap should be focused on in future studies.
In musculoskeletal surgery, the treatment of large bone defects is challenging and can require the use of bone graft substitutes to restore mechanical stability and promote host-mediated regeneration. The use of bone allografts is well-established in many bone regenerative procedures, but is associated with low rates of ingrowth due to pre-therapeutic graft processing. Cold physical plasma (CPP), a partially ionized gas that simultaneously generates reactive oxygen (O2) and nitrogen (N2) species, is suggested to be advantageous in biomedical implant processing. CPP is a promising tool in allograft processing for improving surface characteristics of bone allografts towards enhanced cellularization and osteoconduction. However, a preclinical assessment regarding the feasibility of pre-therapeutic processing of allogeneic bone grafts with CPP has not yet been performed. Thus, this pilot study aimed to analyze the bone morphology of CPP processed allografts using synchrotron radiation-based microcomputed tomography (SR-µCT) and to analyze the effects of CPP processing on human bone cell viability and function. The analyzes, including co-registration of pre- and post-treatment SR-µCT scans, revealed that the main bone morphological properties (total volume, mineralized volume, surface area, and porosity) remained unaffected by CPP treatment if compared to allografts not treated with CPP. Varying effects on cellular metabolic activity and alkaline phosphatase activity were found in response to different gas mixtures and treatment durations employed for CPP application. It was found that 3 min CPP treatment using a He + 0.1% N2 gas mixture led to the most favourable outcome regarding a significant increase in bone cell viability and alkaline phosphatase activity. This study highlights the promising potential of pre-therapeuthic bone allograft processing by CPP prior to intraoperative application and emphasizes the need for gas source and treatment time optimization for specific applications.
Introduction
Heart rate variability (HRV), defined as the variability of consecutive heart beats, is an important biomarker for dysregulations of the autonomic nervous system (ANS) and is associated with the development, course, and outcome of a variety of mental and physical health problems. While guidelines recommend using 5 min electrocardiograms (ECG), recent studies showed that 10 s might be sufficient for deriving vagal-mediated HRV. However, the validity and applicability of this approach for risk prediction in epidemiological studies is currently unclear to be used.
Methods
This study evaluates vagal-mediated HRV with ultra-short HRV (usHRV) based on 10 s multichannel ECG recordings of N = 4,245 and N = 2,392 participants of the Study of Health in Pomerania (SHIP) from two waves of the SHIP-TREND cohort, additionally divided into a healthy and health-impaired subgroup. Association of usHRV with HRV derived from long-term ECG recordings (polysomnography: 5 min before falling asleep [N = 1,041]; orthostatic testing: 5 min of rest before probing an orthostatic reaction [N = 1,676]) and their validity with respect to demographic variables and depressive symptoms were investigated.
Results
High correlations (r = .52–.75) were revealed between usHRV and HRV. While controlling for covariates, usHRV was the strongest predictor for HRV. Furthermore, the associations of usHRV and HRV with age, sex, obesity, and depressive symptoms were similar.
Conclusion
This study provides evidence that usHRV derived from 10 s ECG might function as a proxy of vagal-mediated HRV with similar characteristics. This allows the investigation of ANS dysregulation with ECGs that are routinely performed in epidemiological studies to identify protective and risk factors for various mental and physical health problems.
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.
Background: Only approximately a third of people with depressive symptoms seek professional health care. Furthermore, people labelled as mentally ill may experience stigmatisation, which can impede help-seeking behaviour.
Aim: To examine the effects of three vignette-based interventions endorsing biopsychosocial causal beliefs and strengthening self-efficacy on help-seeking intention and behaviour, as well as the predictive values of these variables and previous treatment experience.
Method: A quasi-experimental online study utilising a fractioned factorial design was carried out. People were screened for depressive symptoms and their current treatment status. After baseline assessment, they were randomly allocated into one of 24 groups receiving a combination of interventional messages. Actual help-seeking behaviour was measured at follow-ups 3 and 6 months after baseline.
Results: Altogether, N = 1,368 participants were included in the final analyses and N = 983 provided data on their help-seeking behaviour within 3 to 6 months after the baseline assessment. The intention to seek help from a general practitioner or a mental health professional was significantly influenced by the interventions. However, help-seeking behaviour was not influenced by the interventions. On a conceptual level, biopsychosocial causal beliefs (β = 0.09–0.23) and self-efficacy to seek help (β = 0.16–0.25) predicted help-seeking intention. There was a negative interaction effect of both self-efficacy beliefs on intention and behaviour, which changed depending on depression severity. In all models, the intention was the main predictor of actual behaviour. Treatment experience predicted both help-seeking intention and behaviour.
Conclusion: Biopsychosocial causal beliefs and self-efficacy have a direct effect on help-seeking intention. Interventions should include information on how to actually seek help as a means to strengthen self-efficacy beliefs and simulate previous treatment experience. Further research is needed to investigate the respective interaction effects on intention and behaviour.
Clinical Trial Registration: https://drks.de/search/de/trial/DRKS00023557, German Clinical Trials Register: DRKS00023557. Registered 11 December 2020. World Health Organization, Universal Trial Number: U1111–1264-9954. Registered 16 February 2021.
Multidrug-resistant gram-negative pathogens such as Escherichia coli have become increasingly difficult to treat and therefore alternative treatment options are needed. Targeting virulence factors like biofilm formation could be one such option. Inhibition of biofilm-related structures like curli and cellulose formation in E. coli has been shown for different phenolic natural compounds like epigallocatechin gallate. This study demonstrates this effect for other structurally unrelated phenolics, namely octyl gallate, scutellarein and wedelolactone. To verify whether these structurally different compounds influence identical pathways of biofilm formation in E. coli a broad comparative RNA-sequencing approach was chosen with additional RT-qPCR to gain initial insights into the pathways affected at the transcriptomic level. Bioinformatical analysis of the RNA-Seq data was performed using DESeq2, BioCyc and KEGG Mapper. The comparative bioinformatics analysis on the pathways revealed that, irrespective of their structure, all compounds mainly influenced similar biological processes. These pathways included bacterial motility, chemotaxis, biofilm formation as well as metabolic processes like arginine biosynthesis and tricarboxylic acid cycle. Overall, this work provides the first insights into the potential mechanisms of action of novel phenolic biofilm inhibitors and highlights the complex regulatory processes of biofilm formation in E. coli.
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.
Objective: The study aimed to test the reliability of a semi-structured telephone interview for the classification of headache disorders according to the ICHD-3.
Background: Questionnaire-based screening tools are often optimized for single primary headache diagnoses [e.g., migraine (MIG) and tension headache (TTH)] and therefore insufficiently represent the diagnostic precision of the ICHD-3, which limits epidemiological research of rare headache disorders. Brief semi-structured telephone interviews could be an effective alternative to improve classification.
Methods: A patient population representative of different primary and secondary headache disorders (n = 60) was recruited from the outpatient clinic (HSA) of a tertiary care headache center. These patients completed an established population-based questionnaire for the classification of MIG, TTH, or trigeminal autonomic cephalalgia (TAC). In addition, they received a semi-structured telephone interview call from three blinded headache specialists individually. The agreement of diagnoses made either using the questionnaires or interviews with the HSA diagnoses was evaluated.
Results: Of the 59 patients (n = 1 dropout), 24% had a second-order and 5% had a third-order headache disorder. The main diagnoses were as follows: frequent primary headaches with 61% MIG, 10% TAC, 9% TTH, and 5% rare primary and 16% secondary headaches. Second-order diagnosis was chronic migraine throughout, and third-order diagnoses were medication overuse headache and TTH. Agreement between main headaches from the HSA was significantly better for the telephone interview than for the questionnaire (questionnaire: κ = 0.330; interview: κ = 0.822; p < 0.001). Second-order diagnoses were not adequately captured by questionnaires, while there was a trend for good agreement with the telephone interview (κ = 0.433; p = 0.074). Headache frequency and psychiatric comorbidities were independent predictors of HSA and telephone interview agreement. Male sex, headache frequency, severity, and depressive disorders were independently predictive for agreement between the questionnaire and HSA. The telephone interview showed high sensitivity (≥71%) and specificity (≥92%) for all primary headache disorders, whereas the questionnaire was below 50% in either sensitivity or specificity.
Conclusion: The semi-structured telephone interview appears to be a more reliable tool for accurate diagnosis of headache disorders than self-report questionnaires. This offers the potential to improve epidemiological headache research and care even in underserved areas.
Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.
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.
Essential Oils as Multicomponent Mixtures and Their Potential for Human Health and Well-Being
(2022)
Essential oils (EOs) and their individual volatile organic constituents have been an inherent part of our civilization for thousands of years. They are widely used as fragrances in perfumes and cosmetics and contribute to a healthy diet, but also act as active ingredients of pharmaceutical products. Their antibacterial, antiviral, and anti-inflammatory properties have qualified EOs early on for both, the causal and symptomatic therapy of a number of diseases, but also for prevention. Obtained from natural, mostly plant materials, EOs constitute a typical example of a multicomponent mixture (more than one constituent substances, MOCS) with up to several hundreds of individual compounds, which in a sophisticated composition make up the property of a particular complete EO. The integrative use of EOs as MOCS will play a major role in human and veterinary medicine now and in the future and is already widely used in some cases, e.g., in aromatherapy for the treatment of psychosomatic complaints, for inhalation in the treatment of respiratory diseases, or topically administered to manage adverse skin diseases. The diversity of molecules with different functionalities exhibits a broad range of multiple physical and chemical properties, which are the base of their multi-target activity as opposed to single isolated compounds. Whether and how such a broad-spectrum effect is reflected in natural mixtures and which kind of pharmacological potential they provide will be considered in the context of ONE Health in more detail in this review.
Background
Longitudinal observational studies play on an important role for evidence-based research on health services and psychiatric rehabilitation. However, information is missing about the reasons, why patients participate in such studies, and how they evaluate their participation experience.
Methods
Subsequently to their final assessment in a 2-year follow-up study on supported housing for persons with severe mental illness, n = 182 patients answered a short questionnaire on their study participation experience (prior experiences, participation reasons, burden due to study assessments, intention to participate in studies again). Basic respondent characteristics as well as symptom severity (SCL-K9) were also included in the descriptive and analytical statistics.
Results
To help other people and curiosity were cited as the main initial reasons for study participation (>85%). Further motives were significantly associated with demographic and/or clinical variables. For instance, “relieve from boredom” was more frequently reported by men and patients with substance use disorders (compared to mood disorders), and participants ‘motive” to talk about illness” was associated with higher symptom severity at study entry. Furthermore, only a small proportion of respondents indicated significant burdens by study participation and about 87% would also participate in future studies.
Conclusions
The respondents gave an overall positive evaluation regarding their participation experience in an observational study on psychiatric rehabilitation. The results additionally suggest that health and social care professionals should be responsive to the expectations and needs of patients with mental illness regarding participation in research.
Cryptochromes are evolutionary ancient blue-light photoreceptors that are part of the circadian clock in the nervous system of many organisms. Cryptochromes transfer information of the predominant light regime to the clock which results in the fast adjustment to photoperiod. Therefore, the clock is sensitive to light changes and can be affected by anthropogenic Artificial Light At Night (ALAN). This in turn has consequences for clock associated behavioral processes, e.g., diel vertical migration (DVM) of zooplankton. In freshwater ecosystems, the zooplankton genus Daphnia performs DVM in order to escape optically hunting predators and to avoid UV light. Concomitantly, Daphnia experience circadian changes in food-supply during DVM. Daphnia play the keystone role in the carbon-transfer to the next trophic level. Therefore, the whole ecosystem is affected during the occurrence of cyanobacteria blooms as cyanobacteria reduce food quality due to their production of digestive inhibitors (e.g., protease inhibitors). In other organisms, digestion is linked to the circadian clock. If this is also the case for Daphnia, the expression of protease genes should show a rhythmic expression following circadian expression of clock genes (e.g., cryptochrome 2). We tested this hypothesis and demonstrated that gene expression of the clock and of proteases was affected by ALAN. Contrary to our expectations, the activity of one type of proteases (chymotrypsins) was increased by ALAN. This indicates that higher protease activity might improve the diet utilization. Therefore, we treated D. magna with a chymotrypsin-inhibitor producing cyanobacterium and found that ALAN actually led to an increase in Daphnia’s growth rate in comparison to growth on the same cyanobacterium in control light conditions. We conclude that this increased tolerance to protease inhibitors putatively enables Daphnia populations to better control cyanobacterial blooms that produce chymotrypsin inhibitors in the Anthropocene, which is defined by light pollution and by an increase of cyanobacterial blooms due to eutrophication.
Gallic acid, protocatechuic acid, catechol, and pyrogallol are only a few examples of industrially relevant aromatics. Today much attention is paid to the development of new microbial factories for the environmentally friendly biosynthesis of industrially relevant chemicals with renewable resources or organic pollutants as the starting material. The non–conventional yeast, Blastobotrys raffinosifermentans, possesses attractive properties for industrial bio-production processes such as thermo- and osmotolerance. An additional advantage is its broad substrate spectrum, with tannins at the forefront. The present study is dedicated to the characterization of catechol-1,2-dioxygenase (Acdo1p) and the analysis of its function in B. raffinosifermentans tannic acid catabolism. Acdo1p is a dimeric protein with higher affinity for catechol (KM = 0.004 ± 0.001 mM, kcat = 15.6 ± 0.4 s–1) than to pyrogallol (KM = 0.1 ± 0.02 mM, kcat = 10.6 ± 0.4 s–1). It is an intradiol dioxygenase and its reaction product with catechol as the substrate is cis,cis-muconic acid. B. raffinosifermentans G1212/YIC102-AYNI1-ACDO1-6H, which expresses the ACDO1 gene under the control of the strong nitrate-inducible AYNI1 promoter, achieved a maximum catechol-1,2-dioxygenase activity of 280.6 U/L and 26.9 U/g of dry cell weight in yeast grown in minimal medium with nitrate as the nitrogen source and 1.5% glucose as the carbon source. In the same medium with glucose as the carbon source, catechol-1,2-dioxygenase activity was not detected for the control strain G1212/YIC102 with ACDO1 expression under the regulation of its respective endogenous promoter. Gene expression analysis showed that ACDO1 is induced by gallic acid and protocatechuic acid. In contrast to the wild-type strain, the B. raffinosifermentans strain with a deletion of the ACDO1 gene was unable to grow on medium supplemented with gallic acid or protocatechuic acid as the sole carbon source. In summary, we propose that due to its substrate specificity, its thermal stability, and its ability to undergo long-term storage without significant loss of activity, B. raffinosifermentans catechol-1,2-dioxygenase (Acdo1p) is a promising enzyme candidate for industrial applications.
Chronic Background Radiation Correlates With Sperm Swimming Endurance in Bank Voles From Chernobyl
(2022)
Sperm quantity and quality are key features explaining intra- and interspecific variation in male reproductive success. Spermatogenesis is sensitive to ionizing radiation and laboratory studies investigating acute effects of ionizing radiation have indeed found negative effects of radiation on sperm quantity and quality. In nature, levels of natural background radiation vary dramatically, and chronic effects of low-level background radiation exposure on spermatogenesis are poorly understood. The Chernobyl region offers a unique research opportunity for investigating effects of chronic low-level ionizing radiation on reproductive properties of wild organisms. We captured male bank voles (Myodes glareolus) from 24 locations in the Chernobyl exclusion zone in 2011 and 2015 and collected information on sperm morphology and kinetics. The dataset is limited in size and there overall was a relatively weak correlation between background radiation and sperm quality. Still, some correlations are worth discussing. First, mid-piece segments of spermatozoa tended to be smaller in bank vole males from areas with elevated background radiation levels. Second, we demonstrated a significant positive relationship between background radiation dose rates and the proportion of static spermatozoa among males within and among study locations after 10 as well as 60 min of incubation. Our results provide novel evidence of damaging effects of low dose ionizing radiation on sperm performance in wild rodent populations, and highlight that this topic requires further study across the natural gradients of background radiation that exist in nature.
Complex problem solving (CPS) can be interpreted as the number of psychological mechanisms that allow us to reach our targets in difficult situations, that can be classified as complex, dynamic, non-transparent, interconnected, and multilayered, and also polytelic. The previous results demonstrated associations between the personality dimensions neuroticism, conscientiousness, and extraversion and problem-solving performance. However, there are no studies dealing with personality disorders in connection with CPS skills. Therefore, the current study examines a clinical sample consisting of people with personality and/or depressive disorders. As we have data for all the potential personality disorders and also data from each patient regarding to potential depression, we meet the whole range from healthy to impaired for each personality disorder and for depression. We make use of a unique operationalization: CPS was surveyed in a simulation game, making use of the microworld approach. This study was designed to investigate the hypothesis that personality traits are related to CPS performance. Results show that schizotypal, histrionic, dependent, and depressive persons are less likely to successfully solve problems, while persons having the additional behavioral characteristics of resilience, action orientation, and motivation for creation are more likely to successfully solve complex problems.
Feasible Cluster Model Method for Simulating the Redox Potentials of Laccase CueO and Its Variant
(2022)
Laccases are regarded as versatile green biocatalysts, and recent scientific research has focused on improving their redox potential for broader industrial and environmental applications. The density functional theory (DFT) quantum mechanics approach, sufficiently rigorous and efficient for the calculation of electronic structures, is conducted to better comprehend the connection between the redox potential and the atomic structural feature of laccases. According to the crystal structure of wild type laccase CueO and its variant, a truncated miniature cluster model method was established in this research. On the basic of thermodynamic cycle, the overall Gibbs free energy variations before and after the one-electron reduction were calculated. It turned out that the trends of redox potentials to increase after variant predicted by the theoretical calculations correlated well with those obtained by experiments, thereby validating the feasibility of this cluster model method for simulating the redox potentials of laccases.
Editorial: Streptococci in infectious diseases – pathogenic mechanisms and host immune responses
(2022)
Madagascar houses one of the Earth’s biologically richest, but also one of most endangered, terrestrial ecoregions. Although it is obvious that humans substantially altered the natural ecosystems during the past decades, the timing of arrival of early inhabitants on Madagascar as well as their environmental impact is still intensively debated. This research aims to study the beginning of early human impact on Malagasy natural ecosystems, specifically on Nosy Be island (NW Madagascar) by targeting the sedimentary archive of Lake Amparihibe, an ancient volcanic crater. Based on pollen, fungal spore, other non-pollen palynomorph, charcoal particle and diatom analyses combined with high-resolution sediment-physical and (in)organic geochemical data, paleoenvironmental dynamics during the past three millennia were reconstructed. Results indicate a major environmental change at ca. 1300 cal BP characterized by an abrupt development of grass (C4) dominated and fire disturbed landscape showing the alteration of natural rain forest. Further, increased soil erodibility is suggested by distinct increase in sediment accumulation rates, a strong pulse of nutrient input, higher water turbidity and contemporaneous increase in spores of mycorrhizal fungi. These parameters are interpreted to show a strong early anthropogenic transformation of the landscape from rain forest to open grassland. After ca. 1000 cal BP, fires remain frequent and vegetation is dominated by forest/grassland mosaic. While natural vegetation should be dominated by rain forest on Nosy Be, these last results indicate that human continuously impacted the landscapes surrounding the lake. At a local scale, our data support the “subsistence shift hypothesis” which proposed that population expansion with development of herding/farming altered the natural ecosystems. However, a precise regional synthesis is challenging, since high-resolution multi-proxy records from continuous sedimentary archives as well as records located further north and in the hinterland are still scarce in Madagascar. The lack of such regional synthesis also prevents precise comparison between different regions in Madagascar to detect potential (dis)similarities in climate dynamics, ecosystem responses and anthropogenic influences at the island’s scale during the (late) Holocene.
Particle-in-Cell (PIC) simulations are used to model the MS4 test thruster of Thales Deutschland. Given as input the geometric shape, material components, magnetic field and the operating parameters of the experiment, the model is able to reproduce the experimentally observed emission pattern in the plume. This is determined by the magnetic field line structure and the resulting plasma dynamics in the near-field region close to the exit.
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.
Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their communication via neurotransmitters and neuropeptides depends on a high protein and lipid turnover. The endoplasmic Reticulum (ER) is fundamental to provide these necessary requirements for optimal neuronal function. Accumulation of misfolded proteins in the ER lumen, reactive oxygen species and exogenous stimulants like infections, chemical irritants and mechanical harm can induce ER stress, often followed by an ER stress response to reinstate cellular homeostasis. Imbedded between glial-, endothelial-, stromal-, and immune cells neurons are constantly in communication and influenced by their local environment. In this review, we discuss concepts of tissue homeostasis and innate immunity in the central and peripheral nervous system with a focus on its influence on ER stress, the unfolded protein response, and implications for health and disease.
Case Report: Intraarticular Iliopsoas Tendon causes Groin Pain Following Periacetabular Osteotomy
(2022)
A 43-year-old female patient reported persistent iliopsoas-related groin pain following periacetabular osteotomy (PAO) combined with femoroplasty via a direct anterior approach due to CAM morphology. Concomitantly with the planned removal of screws, hip arthroscopy was performed, and the iliopsoas tendon was found to run intraarticularly, resulting in the tendon being impaired in its mobility and being entrapped. The tendon was arthroscopically released. The patient reported relief of the groin pain after the arthroscopic tendon debridement. During PAO combined with capsulotomy, the postoperatively observed intraarticular position of the iliopsoas tendon should be prevented by careful closure of the joint capsule.
To reduce global greenhouse gas emissions in order to limit global warming to 1.5°C, individuals and households play a key role. Behavior change interventions to promote pro-environmental behavior in individuals are needed to reduce emissions globally. This systematic literature review aims to assess the a) evidence-based effectiveness of such interventions and b) the content of very successful interventions without limiting the results to specific emitting sectors or countries. Based on the “PICOS” mnemonic and PRISMA statement, a search strategy was developed, and eligibility criteria were defined. Three databases (Embase, PsycInfo, and Web of Science) were searched to retrieve and review potential literature. As a result, 54 publications from 2010 to 2021 were included in the analysis. The results show that most interventions only have small positive effects or none at all. A total of 15 very successful interventions focused on the sectors of mobility, energy, and waste and incorporated improved (infra-) structures, education, feedback, enablement or made the sustainable option the default. Six evidence-based recommendations for content, timing, and setting are deducted and given for interventions on enhancing pro-environmental behavior (PEB). In summary, although the various interventions and intervention types to promote PEB differ in their effectiveness, very successful interventions have common elements. Future research should focus on high-/low-impact and high-/low-cost behavior to develop interventions that aim at high-impact but low-cost behavior changes, or avoid low-impact but high-cost behavior.
Infective/bacterial endocarditis is a rare but life-threatening disease with a hospital mortality rate of 22.7% and a 1-year mortality rate of 40%. Therefore, continued research efforts to develop efficient anti-infective implant materials are of the utmost importance. Equally important is the development of test systems that allow the performance of new materials to be comprehensively evaluated. In this study, a novel antibacterial coating based on dalbavancin was tested in comparison to rifampicin/minocycline, and the suitability of a recently developed mouse tail vein model for testing the implant coatings was validated. Small polymeric stent grafts coated with a poly-L-lactic acid (PLLA) layer and incorporated antibiotics were colonized with Staphylococcus (S.) aureus before implantation into the tail vein of mice. The main assessment criteria were the hematogenous spread of the bacteria and the local tissue reaction to the contaminated implant. For this purpose, colony-forming units (CFU) in the blood, spleen and kidneys were determined. Tail cross sections were prepared for histological analysis, and plasma cytokine levels and expression values of inflammation-associated genes were examined. Both antibiotic coatings performed excellently, preventing the onset of infection. The present study expands the range of available methods for testing the anti-infectivity of cardiovascular implants, and the spectrum of agents for effective surface coating.
According to the conservation of resources theory, social support provides resources to help overcome challenges. Although some empirical findings have emphasized the pivotal role of teacher support and/or peer support for students’ stress and academic achievement, multilevel analyses that consider contextual class and individual student effects are scarce. The current study addresses this gap and further includes gender, socio-economic status, and neuroticism as covariates. Multilevel analyses in Mplus were conducted. All measures were taken at the student level and then aggregated to the classroom level to estimate class-level relationships. Results revealed that on the individual level, teacher support was related to higher ability to cope and lower levels of helplessness, while on the class level, peer support by classmates was related to higher ability to cope and academic achievement. The context effects also show that in classes with higher peer support, students are more likely to benefit in terms of coping ability and achievement, whereas in classes with higher teacher support, students tend to show less coping ability.
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.
Many of the world’s most biodiverse regions are found in the poorest and second most populous continent of Africa; a continent facing exceptional challenges. Africa is projected to quadruple its population by 2100 and experience increasingly severe climate change and environmental conflict—all of which will ravage biodiversity. Here we assess conservation threats facing Africa and consider how these threats will be affected by human population growth, economic expansion, and climate change. We then evaluate the current capacity and infrastructure available to conserve the continent’s biodiversity. We consider four key questions essential for the future of African conservation: (1) how to build societal support for conservation efforts within Africa; (2) how to build Africa’s education, research, and management capacity; (3) how to finance conservation efforts; and (4) is conservation through development the appropriate approach for Africa? While the challenges are great, ways forward are clear, and we present ideas on how progress can be made. Given Africa’s current modest capacity to address its biodiversity crisis, additional international funding is required, but estimates of the cost of conserving Africa’s biodiversity are within reach. The will to act must build on the sympathy for conservation that is evident in Africa, but this will require building the education capacity within the continent. Considering Africa’s rapidly growing population and the associated huge economic needs, options other than conservation through development need to be more effectively explored. Despite the gravity of the situation, we believe that concerted effort in the coming decades can successfully curb the loss of biodiversity in Africa.
Upon antigen recognition by the T cell receptor (TCR), a complex signaling network orchestrated by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) regulates the transmission of the extracellular signal to the nucleus. The role of the PTPs Src-homology 2 (SH2) domain-containing phosphatase 1 (SHP1, Ptpn6) and Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2, Ptpn11) have been studied in various cell types including T cells. Whereas SHP1 acts as an essential negative regulator of the proximal steps in T cell signalling, the role of SHP2 in T cell activation is still a matter of debate. Here, we analyzed the role of the constitutively active SHP2-D61Y-mutant in T cell activation using knock-in mice expressing the mutant form Ptpn11D61Y
in T cells. We observed reduced numbers of CD8+ and increased numbers of CD4+ T cells in the bone marrow and spleen of young and aged SHP2-D61Y-mutant mice as well as in Influenza A Virus (IAV)-infected mice compared to controls. In addition, we found elevated frequencies of effector memory CD8+ T cells and an upregulation of the programmed cell death protein 1 (PD-1)-receptor on both CD4+ and CD8+ T cells. Functional analysis of SHP2-D61Y-mutated T cells revealed an induction of late apoptosis/necrosis, a reduced proliferation and altered signaling upon TCR stimulation. However, the ability of D61Y-mutant mice to clear viral infection was not affected. In conclusion, our data indicate an important regulatory role of SHP2 in T cell function, where the effect is determined by the kinetics of SHP2 phosphatase activity and differs in the presence of the permanently active and the temporally regulated phosphatase. Due to interaction of SHP2 with the PD-1-receptor targeting the protein-tyrosine phosphatase might be a valuable tool to enhance T cell activities in immunotherapy.
Photosynthetic activity in both algae and cyanobacteria changes in response to cues of predation
(2022)
A plethora of adaptive responses to predation has been described in microscopic aquatic producers. Although the energetic costs of these responses are expected, with their consequences going far beyond an individual, their underlying molecular and metabolic mechanisms are not fully known. One, so far hardly considered, is if and how the photosynthetic efficiency of phytoplankton might change in response to the predation cues. Our main aim was to identify such responses in phytoplankton and to detect if they are taxon-specific. We exposed seven algae and seven cyanobacteria species to the chemical cues of an efficient consumer, Daphnia magna, which was fed either a green alga, Acutodesmus obliquus, or a cyanobacterium, Synechococcus elongatus (kairomone and alarm cues), or was not fed (kairomone alone). In most algal and cyanobacterial species studied, the quantum yield of photosystem II increased in response to predator fed cyanobacterium, whereas in most of these species the yield did not change in response to predator fed alga. Also, cyanobacteria tended not to respond to a non-feeding predator. The modal qualitative responses of the electron transport rate were similar to those of the quantum yield. To our best knowledge, the results presented here are the broadest scan of photosystem II responses in the predation context so far.
Loneliness and lack of belonging as paramount theme in identity descriptions of Children Born of War
(2022)
Objective
Children Born of War (CBOW) are an international and timeless phenomenon that exists in every country involved in war or armed conflict. Nevertheless, little is known on a systematic level about those children, who are typically fathered by a foreign or enemy soldier and born to a local mother. In particular, the identity issues that CBOW often report have remained largely uninvestigated. In the current qualitative study we began filling this gap in the scientific literature by asking how CBOW construct their identity in self-descriptions.
Method
We utilized thematic content analysis of N = 122 German CBOWs' answers to an open-ended questionnaire item asking how they see themselves and their identity in the context of being a CBOW.
Results
We identified five key themes in CBOW' identity accounts. Loneliness and lack of belonging appeared as a paramount aspect of their self-descriptions next to narratives about belonging and positive relationship. On a less interpersonal basis, we found fighting and surviving and searching for truth and completion overarching aspects of their identities. There were also few accounts growing up unaffected by the fact of being born a CBOW. Although all themes portray different perspectives, they all (but the last one) clearly indicate the impeded circumstances under which CBOW had to grow up.
Conclusions
Integrating our findings with existing interdisciplinary literature regarding identity, we discuss implications for future research and clinical and political practice.
Background
Postoperative pancreatic fistula (POPF) is the most critical complication after pancreatoduodenectomy (PD). Preoperative identification of high-risk patients and optimal pancreatic reconstruction technique can be a way to reduce postoperative complications.
Methods
A series of 386 patients underwent PD over a 10-year period (2009–2019). On routinely performed preoperative computed tomography (CT) images, the ventro-dorsal diameters of duct (D) and parenchyma (P) were measured in the cutting plane at the superior mesenteric vein. Then, the ratio of both values was calculated (D/P ratio) Double-layer pancreatojejunostomy with alignment of duct and mucosa (ADAM) by two monofilament threads (MFT) was performed in 359 patients and pancreatogastrostomy (PG) in 27 patients. The incidence of POPF was diagnosed according to the International Study Group for Pancreatic Fistula criteria.
Results
The overall rate of POPF was 21% (n = 80), and the rate of clinically relevant type B/C fistulas 6.5% (n = 25). A D/P ratio of <0.2 was significantly associated with type B/C fistula (11%, p < 0.01). In low-risk patients (D/P ratio >0.2), type B/C fistula occurred only in 2%, and in high-risk patients (D/P ratio <0.2) in 9%. ADAM anastomosis was performed safely by two different surgeons. A PG anastomosis had double-digit POPF rates in all groups.
Conclusion
Preoperative CT imaging with D/P measurement may predict the risk of POPF development. A cut off D/P ratio of <0.2 was significantly associated with clinical relevant POPF. ADAM anastomosis may be an option for pancreatojejunostomy. However, preoperative knowledge of the D/P ratio could guide decision-making for primary pancreatectomy when pancreatic reconstruction is critical.