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- Frontiers Media S.A. (364) (remove)
Patients with atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non-ST-segment elevation myocardial infarction) during an acute episode of AF. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography, which suggests that AF itself influences myocardial blood flow. The present review summarizes the effect of AF on the occurrence of ventricular oxidative stress, redox-sensitive signaling pathways and gene expression, and microcirculatory flow abnormalities in the left ventricle.
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.
Musicians use different kinds of imagery. This review focuses on kinesthetic imagery, which has been shown to be an effective complement to actively playing an instrument. However, experience in actual movement performance seems to be a requirement for a recruitment of those brain areas representing movement ideation during imagery. An internal model of movement performance might be more differentiated when training has been more intense or simply performed more often. Therefore, with respect to kinesthetic imagery, these strategies are predominantly found in professional musicians. There are a few possible reasons as to why kinesthetic imagery is used in addition to active training; one example is the need for mental rehearsal of the technically most difficult passages. Another reason for mental practice is that mental rehearsal of the piece helps to improve performance if the instrument is not available for actual training as is the case for professional musicians when they are traveling to various appearances. Overall, mental imagery in musicians is not necessarily specific to motor, somatosensory, auditory, or visual aspects of imagery, but integrates them all. In particular, the audiomotor loop is highly important, since auditory aspects are crucial for guiding motor performance. All these aspects result in a distinctive representation map for the mental imagery of musical performance. This review summarizes behavioral data, and findings from functional brain imaging studies of mental imagery of musical performance.
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.
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.
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 Role of Pregnancy-Associated Hormones in the Development and Function of Regulatory B Cells
(2014)
During mammalian pregnancy, highly specialized mechanisms of immune tolerance are triggered in order to allow the semi-allogeneic fetus to grow within the maternal uterus in harmony with the maternal immune system. Among other mechanisms, changes in the endocrine status have been proposed to be at least part of the machinery responsible for the induction of immune tolerance during pregnancy. Indeed, pregnancy-associated hormones, estradiol, progesterone, and human chorionic gonadotropin are known to confer immune suppressive capacity to innate as well as adaptive immune cells. Regulatory B cells, a subpopulation of B lymphocytes with strong immunosuppressive functions, were shown to expand during pregnancy. Furthermore, it is well-known that some women suffering from multiple sclerosis, significantly improve their symptoms during pregnancy and this was attributed to the effect of female sex hormones. Accordingly, estradiol protects mice from developing experimental autoimmune encephalomyelitis by triggering the expansion and activation of regulatory B cells. In this review, we discuss different mechanisms associated with the development, activation, and function of regulatory B cells with a special focus on those involving pregnancy-associated hormones.
During pregnancy, the maternal immune system faces a double dilemma: tolerate the growing semi-allogeneic fetus and at the same time protect the mother and the progeny against pathogens. This requires a fine and extremely regulated equilibrium between immune activation and tolerance. As professional antigen presenting cells, B cells and in particular B-1a B cells, can activate or tolerize T cells and thus participate in the generation or regulation of the immune response. B-1a B cells were involved in the humoral immune response leading to pre-eclampsia, one of the main medical complications during pregnancy. Here we demonstrated that B-1a B cells are additionally involved in cellular immune mechanisms associated with pregnancy complications. Using a mouse model of pregnancy disturbances, we showed that B-1a B cells from animals suffering pregnancy disturbances but not from those developing normal pregnancies induce the differentiation of naïve T cells into Th17 and Th1 cells. This differential role of B-1a B cells during pregnancy seems to be associated with the co-stimulatory molecule CD86 as normal pregnant mice showed lower percentages of CD86 expressing B-1a B cells as compared to pregnant mice developing pregnancy disturbances or to non-pregnant animals. Our data bring to light a new and not explored role of B-1a B cells in the context of pregnancy.
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.
Neural characteristics of verbal creativity as assessed by word generation tasks have been recently identified, but differences in resting-state functional connectivity (rFC) between experts and non-experts in creative writing have not been reported yet. Previous electroencephalography (EEG) coherence measures during rest demonstrated a decreased cooperation between brain areas in association with creative thinking ability. Here, we used resting-state functional magnetic resonance imaging to compare 20 experts in creative writing and 23 age-matched non-experts with respect to rFC strengths within a brain network previously found to be associated with creative writing. Decreased rFC for experts was found between areas 44 of both hemispheres. Increased rFC for experts was observed between right hemispheric caudate and intraparietal sulcus. Correlation analysis of verbal creativity indices (VCIs) with rFC values in the expert group revealed predominantly negative associations, particularly of rFC between left area 44 and left temporal pole. Overall, our data support previous findings of reduced connectivity between interhemispheric areas and increased right-hemispheric connectivity during rest in highly verbally creative individuals.
Children as young as 3 years can remember an object’s location within an arrangement and can retrieve it from a novel viewpoint (Nardini et al., 2006). However, this ability is impaired if the arrangement is rotated to compensate for the novel viewpoint, or, if the arrangement is rotated and children stand still. There are two dominant explanations for this phenomenon: self-motion induces an automatic spatial updating process which is beneficial if children move around the arrangement, but misleading if the children’s movement is matched by the arrangement and not activated if children stand still and only the arrangement is moved (see spatial updating; Simons and Wang, 1998). Another explanation concerns reference frames: spatial representations might depend on peripheral spatial relations concerning the surrounding room instead on proximal relations within the arrangement, even if these proximal relations are sufficient or more informative. To evaluate these possibilities, we rotated children (N = 120) aged between 3 and 6 years with an occluded arrangement. When the arrangement was in misalignment to the surrounding room, 3- and 4-year-olds’ spatial memory was impaired and 5-year-olds’ was lightly impaired suggesting that they relied on peripheral references of the surrounding room for retrieval. In contrast, 6-years-olds’ spatial representation seemed robust against misalignment indicating a successful integration of spatial representations.
The current cross-national study investigates the potential buffering role of socio-motivational relationships for the association of achievement drive (AD) and test anxiety (TX) in secondary school students from Canada and Germany. One thousand and eighty-eight students (54% girls, Mage = 13.71, SD = 0.53, age span 12–15 years) from the state of Brandenburg and 389 students from Quebéc (55.9% girls, Mage = 13.43, SD = 0.82, age span 12–16 years) were asked about their socio-motivational relationships with their teachers and peers, their drive for achievement, and TX. Multigroup latent moderated structural equations were conducted to test for the moderator role of socio-motivational relationships that would buffer feelings of TX related to the drive for achievement. The analyses revealed the two-sided role socio-motivational relationships can have for students with different levels of AD; intensifying or mitigating feelings of TX. Thereby, the results of this study extend the buffering hypothesis by Cohen and Wills (1985). Cross-national differences between Canada and Germany were found concerning the studied moderators on the association of AD and TX: While for German students teacher–student relationships acted as moderator, for Canadian students student–student relationships and teachers acting as positive motivators displayed a moderator role.
The shared decline in cognitive abilities, sensory functions (e.g., vision and hearing), and physical health with increasing age is well documented with some research attributing this shared age-related decline to a single common cause (e.g., aging brain). We evaluate the extent to which the common cause hypothesis predicts associations between vision and physical health with social cognition abilities specifically face perception and face memory. Based on a sample of 443 adults (17–88 years old), we test a series of structural equation models, including Multiple Indicator Multiple Cause (MIMIC) models, and estimate the extent to which vision and self-reported physical health are related to face perception and face memory through a common factor, before and after controlling for their fluid cognitive component and the linear effects of age. Results suggest significant shared variance amongst these constructs, with a common factor explaining some, but not all, of the shared age-related variance. Also, we found that the relations of face perception, but not face memory, with vision and physical health could be completely explained by fluid cognition. Overall, results suggest that a single common cause explains most, but not all age-related shared variance with domain specific aging mechanisms evident.
Invasion of the bacterial pathogen Listeria monocytogenes into human host cells requires specialized surface molecules for attachment and induction of phagocytosis. However, efficient invasion is also dependent on factors with house-keeping functions, such as SecA2-dependent secretion of autolysins for post-divisional segregation of daughter cells. Mutations in this pathway prevent degradation of peptidoglycan cross-walls, so that long cell chains are formed that cannot be phagocytosed. The extreme chaining of such mutants manifests as rough colony phenotype. One rough clone was isolated from a transposon library with a transposon insertion in the uncharacterized lmo0720 gene (lftS) together with a spontaneous point mutation in the secA2 gene. We separated both mutations and demonstrated that this point mutation in the intramolecular regulator 2 domain of SecA2 was sufficient to inactivate the protein. In contrast, lftS deletion did not cause a ΔsecA2-like phenotype. lftS is located in an operon with lftR (lmo0719), encoding a PadR-like transcriptional regulator, and lftR deletion affected growth, invasion and day-light dependent coordination of swarming. Inactivation of lftS partially suppressed these phenotypes, suggesting a functional relationship between LftR and LftS. However, the invasion defect of the ΔlftR mutant was only marginally suppressed by lftS removal. LftR regulates expression of the lmo0979–0980 (lieAB) operon, encoding a putative multidrug resistance transporter and lieAB transcription was strongly upregulated in the absence of LftR. Deletion of lieAB in the ΔlftR background restores wild type-like invasion levels. Hence, we conclude that tight transcriptional repression of the lieAB operon is essential for efficient listerial host cell invasion.
Certain pathogenic bacteria adopt an intracellular lifestyle and proliferate in eukaryotic host cells. The intracellular niche protects the bacteria from cellular and humoral components of the mammalian immune system, and at the same time, allows the bacteria to gain access to otherwise restricted nutrient sources. Yet, intracellular protection and access to nutrients comes with a price, i.e., the bacteria need to overcome cell-autonomous defense mechanisms, such as the bactericidal endocytic pathway. While a few bacteria rupture the early phagosome and escape into the host cytoplasm, most intracellular pathogens form a distinct, degradation-resistant and replication-permissive membranous compartment. Intracellular bacteria that form unique pathogen vacuoles include Legionella, Mycobacterium, Chlamydia, Simkania, and Salmonella species. In order to understand the formation of these pathogen niches on a global scale and in a comprehensive and quantitative manner, an inventory of compartment-associated host factors is required. To this end, the intact pathogen compartments need to be isolated, purified and biochemically characterized. Here, we review recent progress on the isolation and purification of pathogen-modified vacuoles and membranes, as well as their proteomic characterization by mass spectrometry and different validation approaches. These studies provide the basis for further investigations on the specific mechanisms of pathogen-driven compartment formation.
This multi-methodological study applied functional magnetic resonance imaging to investigate neural activation in a group of adolescent students (N = 88) during a probabilistic reinforcement learning task. We related patterns of emerging brain activity and individual learning rates to socio-motivational (in-)dependence manifested in four different motivation types (MTs): (1) peer-dependent MT, (2) teacher-dependent MT, (3) peer-and-teacher-dependent MT, (4) peer-and-teacher-independent MT. A multinomial regression analysis revealed that the individual learning rate predicts students’ membership to the independent MT, or the peer-and-teacher-dependent MT. Additionally, the striatum, a brain region associated with behavioral adaptation and flexibility, showed increased learning-related activation in students with motivational independence. Moreover, the prefrontal cortex, which is involved in behavioral control, was more active in students of the peer-and-teacher-dependent MT. Overall, this study offers new insights into the interplay of motivation and learning with (1) a focus on inter-individual differences in the role of peers and teachers as source of students’ individual motivation and (2) its potential neurobiological basis.
High-Frequency Binaural Beats Increase Cognitive Flexibility: Evidence from Dual-Task Crosstalk
(2016)
Increasing evidence suggests that cognitive-control processes can be configured to optimize either persistence of information processing (by amplifying competition between decision-making alternatives and top-down biasing of this competition) or flexibility (by dampening competition and biasing). We investigated whether high-frequency binaural beats, an auditory illusion suspected to act as a cognitive enhancer, have an impact on cognitive-control configuration. We hypothesized that binaural beats in the gamma range bias the cognitive-control style toward flexibility, which in turn should increase the crosstalk between tasks in a dual-task paradigm. We replicated earlier findings that the reaction time in the first-performed task is sensitive to the compatibility between the responses in the first and the second task—an indication of crosstalk. As predicted, exposing participants to binaural beats in the gamma range increased this effect as compared to a control condition in which participants were exposed to a continuous tone of 340 Hz. These findings provide converging evidence that the cognitive-control style can be systematically biased by inducing particular internal states; that high-frequency binaural beats bias the control style toward more flexibility; and that different styles are implemented by changing the strength of local competition and top-down bias.
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.
Induction of Central Host Signaling Kinases during Pneumococcal Infection of Human THP-1 Cells
(2016)
Streptococcus pneumoniae is a widespread colonizer of the mucosal epithelia of the upper respiratory tract of human. However, pneumococci are also responsible for numerous local as well as severe systemic infections, especially in children under the age of five and the elderly. Under certain conditions, pneumococci are able to conquer the epithelial barrier, which can lead to a dissemination of the bacteria into underlying tissues and the bloodstream. Here, specialized macrophages represent an essential part of the innate immune system against bacterial intruders. Recognition of the bacteria through different receptors on the surface of macrophages leads thereby to an uptake and elimination of bacteria. Accompanied cytokine release triggers the migration of leukocytes from peripheral blood to the site of infection, where monocytes differentiate into mature macrophages. The rearrangement of the actin cytoskeleton during phagocytosis, resulting in the engulfment of bacteria, is thereby tightly regulated by receptor-mediated phosphorylation cascades of different protein kinases. The molecular cellular processes including the modulation of central protein kinases are only partially solved. In this study, the human monocytic THP-1 cell line was used as a model system to examine the activation of Fcγ and complement receptor-independent signal cascades during infection with S. pneumoniae. Pneumococci cultured either in chemically defined or complex medium showed no significant differences in pneumococcal phagocytosis by phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells. Double immuno-fluorescence microscopy and antibiotic protection assays demonstrated a time-dependent uptake and killing of S. pneumoniae 35A inside of macrophages. Infections of THP-1 cells in the presence of specific pharmacological inhibitors revealed a crucial role of actin polymerization and importance of the phosphoinositide 3-kinase (PI3K) and Protein kinase B (Akt) as well during bacterial uptake. The participation of essential host cell signaling kinases in pneumococcal phagocytosis was deciphered for the kinase Akt, ERK1/2, and p38 and phosphoimmunoblots showed an increased phosphorylation and thus activation upon infection with pneumococci. Taken together, this study deciphers host cell kinases in innate immune cells that are induced upon infection with pneumococci and interfere with bacterial clearance after phagocytosis.
Connectivity-Based Predictions of Hand Motor Outcome for Patients at the Subacute Stage After Stroke
(2016)
Background: Connectivity-based predictions of hand motor outcome have been proposed to be useful in stroke patients. We intended to assess the prognostic value of different imaging methods on short-term (3 months) and long-term (6 months) motor outcome after stroke.
Methods: We measured resting state functional connectivity (rsFC), diffusion weighted imaging (DWI) and grip strength in 19 stroke patients within the first days (5–9 days) after stroke. Outcome measurements for short-term (3 months) and long-term (6 months) motor function was assessed by the Motricity Index (MI) of the upper limb and the box and block test (BB). Patients were predominantly mildly affected since signed consent was necessary at inclusion. We performed a multiple stepwise regression analysis to compare the predictive value of rsFC, DWI and clinical measurements.
Results: Patients showed relevant improvement in both motor outcome tests. As expected grip strength at inclusion was a predictor for short- and long-term motor outcome as assessed by MI. Diffusion-based tract volume (DTV) of the tracts between ipsilesional primary motor cortex and contralesional anterior cerebellar hemisphere showed a strong trend (p = 0.05) for a predictive power for long-term motor outcome as measured by MI. DTV of the interhemispheric tracts between both primary motor cortices was predictive for both short- and long-term motor outcome in BB. rsFC was not associated with motor outcome.
Conclusions: Grip strength is a good predictor of hand motor outcome concerning strength-related measurements (MI) for mildly affected subacute patients. Therefore additional connectivity measurements seem to be redundant in this group. Using more complex movement recruiting bilateral motor areas as an outcome parameter, DTV and in particular interhemispheric pathways might enhance predictive value of hand motor outcome.
Background
There is a lack of data concerning socioeconomic outcome and quality of life (QoL) in patients after status epilepticus (SE) in Germany.
Patients and methods
Adult patients treated between 2011 and 2015 due to SE at the university hospitals in Frankfurt, Greifswald, and Marburg were asked to fill out a questionnaire regarding long-term outcome of at least 3 months after discharge. The SE cohort consisted of 25.9% patients with an acute symptomatic, 42% with a remote symptomatic and previous epilepsy, 22.2% with a new-onset remote symptomatic, and 9.9% with other or unknown etiology. A matched case–control analysis was applied for comparison with patients with drug refractory epilepsy and seizure remission, both not previously affected by SE.
Results
A total of 81 patients (mean age: 58.7 ± 18.0 years; 58% female) participated. A non-refractory course was present in 59.3%, while 27.2% had a refractory SE (RSE) and 13.6% had a superrefractory SE (SRSE). Before admission, a favorable modified Rankin Scale (mRS) of 0–3 was found in 82.7% (67/81), deteriorating to 38.3% (31/81) (p = 0.003) at discharge. The majority returned home [51.9% (42/81)], 32.1% entered a rehabilitation facility, while 12.3% were transferred to a nursing home and 3.7% to another hospital. The overall mRS at follow-up did not change; 61.8% (45/74) reached an mRS of 0–3. In RSE and SRSE, the proportion with a favorable mRS increased from 45.5% at discharge to 70% at follow-up, while QoL was comparable to a non-refractory SE course. Matched epilepsy controls in seizure remission were treated with a lower mean number of anticonvulsants (1.3 ± 0.7) compared to controls with drug refractory epilepsy (1.9 ± 0.8; p < 0.001) or SE (1.9 ± 1.1; p < 0.001). A major depression was found in 32.8% of patients with SE and in 36.8% of drug refractory epilepsy, but only in 20.3% of patients in seizure remission. QoL was reduced in all categories (QOLIE-31) in SE patients in comparison with patients in seizure remission, but was comparable to patients with drug refractory epilepsy.
Discussion
Patients after SE show substantial impairments in their QoL and daily life activities. However, in the long term, patients with RSE and SRSE had a relatively favorable outcome comparable to that of patients with a non-refractory SE course. This underlines the need for efficient therapeutic options in SE.
For the normal development of pregnancy, a balance between immune tolerance and defense is crucial. However, the mechanisms mediating such a balance are not fully understood. CD83 is a transmembrane protein whose expression has been linked to anti-inflammatory functions of T and B cells. The soluble form of CD83, released by cleavage of the membrane-bound protein, has strong anti-inflammatory properties and was successfully tested in different mouse models. It is assumed that this molecule contributes to the establishment of immune tolerance. Therefore, we postulated that the expression of CD83 is crucial for immune tolerance during pregnancy in mice. Here, we demonstrated that the membrane-bound form of CD83 was upregulated in T and B cells during allogeneic murine pregnancies. An upregulation was also evident in the main splenic B cell subtypes: marginal zone, follicular zone, and transitional B cells. We also showed that there was an augmentation in the number of CD83+ cells toward the end of pregnancy within splenic B and CD4+ T cells, while CD83+ dendritic cells were reduced in spleen and inguinal lymph nodes of pregnant mice. Additionally, B lymphocytes in late-pregnancy presented a markedly higher sensitivity to LPS in terms of CD83 expression and sCD83 release. Progesterone induced a dosis-dependent upregulation of CD83 on T cells. Our data suggest that the regulation of CD83 expression represents a novel pathway of fetal tolerance and protection against inflammatory threats during pregnancy.
Resource and cost constraints in hospitals demand thorough planning of operating room schedules. Ideally, exact start times and durations are known in advance for each case. However, aside from the first case’s start, most factors are hard to predict. While the role of the start of the first case for optimal room utilization has been shown before, data for to-follow cases are lacking. The present study therefore aimed to analyze all elective surgery cases of a university hospital within 1 year in search of visible patterns. A total of 14,014 cases scheduled on 254 regular working days at a university hospital between September 2015 and August 2016 underwent screening. After eliminating 112 emergencies during regular working hours, 13,547 elective daytime cases were analyzed, out of which 4,346 ranked first, 3,723 second, and 5,478 third or higher in the daily schedule. Also, 36% of cases changed start times from the day before to 7:00 a.m., with half of these (52%) resulting in a delay of more than 15 min. After 7:00 a.m., 87% of cases started more than 10 min off schedule, with 26% being early and 74% late. Timeliness was 15 ± 72 min (mean ± SD) for first, 21 ± 84 min for second, and 25 ± 93 min for all to-follow cases, compared to preoperative day planning, and 21 ± 45, 23 ± 61, and 19 ± 74 min compared to 7:00 a.m. status. Start time deviations were also related to procedure duration, with cases of 61–90 min duration being most reliable (deviation 9.8 ± 67 min compared to 7:00 a.m.), regardless of order. In consequence, cases following after 61–90 min long cases had the shortest deviations of incision time from schedule (16 ± 66 min). Taken together, start times for elective surgery cases deviate substantially from schedule, with first and second cases falling into the highest mean deviation category. Second cases had the largest deviations from scheduled times compared to first and all to-follow cases. While planned vs. actual start times differ among specialties, cases of 61–90 min duration had the most reliable start times, with neither shorter nor longer cases seeming to improve timeliness of start times.
Existing literature evidences the association between adolescents’ school self-concept and engagement, both concepts being related to students’ perception of teachers and peers as motivators. However, few longitudinal studies explore the interplay of these factors. The present study aims to close this gap, applying latent cross-lagged panel design to two-wave data from German adolescent students [1088 8th grade students at T1 (Mage = 13.7, SD = 0.53; 53.9% girls) and 845 9th grade students at T2 (Mage = 14.86; SD = 0.57; 55% girls) from the initial sample]. Besides direct effects, three cross-lagged over-time paths were found to be significant: students’ perception of peers as positive motivators (PPMs) at the beginning of 8th grade (T1) positively predicts their behavioral school engagement at the end of 9th grade (T2), as well as emotional school engagement at the beginning of 8th grade positively predicts students’ perception of PPMs 1.5 years later. Furthermore, behavioral school engagement at T1 functions as a predictor of a student’s school self-concept at T2.
Longitudinal Effects of Student-Perceived Classroom Support on Motivation – A Latent Change Model
(2017)
This two-wave longitudinal study examined how developmental changes in students’ mastery goal orientation, academic effort, and intrinsic motivation were predicted by student-perceived support of motivational support (support for autonomy, competence, and relatedness) in secondary classrooms. The study extends previous knowledge that showed that support for motivational support in class is related to students’ intrinsic motivation as it focused on the developmental changes of a set of different motivational variables and the relations of these changes to student-perceived motivational support in class. Thus, differential classroom effects on students’ motivational development were investigated. A sample of 1088 German students was assessed in the beginning of the school year when students were in grade 8 (Mean age = 13.70, SD = 0.53, 54% girls) and again at the end of the next school year when students were in grade 9. Results of latent change models showed a tendency toward decline in mastery goal orientation and a significant decrease in academic effort from grade 8 to 9. Intrinsic motivation did not decrease significantly across time. Student-perceived support of competence in class predicted the level and change in students’ academic effort. The findings emphasized that it is beneficial to create classroom learning environments that enhance students’ perceptions of competence in class when aiming to enhance students’ academic effort in secondary school classrooms.
Background
Signs of an inflammatory process have been described in major depression.
Methods
In a double-blind, randomized study of celecoxib or placebo add-on to reboxetine in 40 depressed patients, celecoxib treatment has beneficial effects. In order to evaluate the tryptophan/kynurenine metabolism and to identify predictors for remission, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were estimated in the serum of 32 patients before and after treatment and in a group of 20 healthy controls.
Results
KYN levels were significantly lower in patients (p = 0.008), and the QUIN/KYN ratios were significantly higher (p = 0.028). At baseline, the higher KYN/TRP ratio was predictive for remission during celecoxib add-on treatment (p = 0.04) as well as for remission in the overall patient group (p = 0.01). In the placebo group, remitters showed a higher KYNA/QUIN ratio (p = 0.032). In the overall group, remitters showed lower KYNA/KYN (p = 0.035) and QUIN/KYN (p = 0.011) ratios. The lower the formation of downstream metabolites, especially QUIN, the better the treatment outcome.
Conclusion
The high KYN/TRP ratio predicted remission after treatment with celecoxib in this small sample of depressed patients. Eventually, the KYN/TRP ratio might be a marker for those patients, which benefit from an additional anti-inflammatory treatment.
Purpose
Due to the demographic change morbidity raises the demand for medical hospital services as well as a need for medical specialization, while economic and human resources are diminishing. Unlike other industries hospitals do not have sufficient data and adequate models to relate growing demands and increasing performance to growth in staff capacity and to increase in staff competences.
Method
Based on huge medical data sample covering the years from 2010 to 2014 with more than 150,000 operations of the Department for Anesthesiology at the University Hospital Muenster, Germany, comparisons are drawn between the development of medical services and the development of personnel capacity and expertise.
Results
The numbers of surgical operations increased by 21% and “skin incision to closure” time by 17%. Simultaneously, personnel capacity grew by 16% largely resting upon recruiting first-time employees. Expertise measured as “years of professional experience” dwindled from 10 years to 5.4 years on average and staff turnover accelerated.
Conclusion
Static benchmark data collected at fixed reference dates do not sufficiently reflect the nexus between capacity and competence and do not reflect the dynamic changes in a hospital’s requirements for expertise and specialization, at all. Staff turnover leads to a loss of experience, which jeopardizes patient safety and hampers medical specialization. In consequence of the dramatic shortage of medical specialists, drop-off rates must be reduced and retention rates must be increased. To that end, working conditions need to be fundamentally converted for a multigeneration, multicultural, and increasingly female workforce.
Introduction
Primary immunodeficiency disorders (PIDs) are a heterogeneous group of more than 200 rare diseases. Timely diagnosis is of uttermost importance. Therefore, we aimed to develop a diagnostic questionnaire with computerized pattern-recognition in order to support physicians to identify suspicious patient histories.
Materials and methods
Standardized interviews were conducted with guardians of children with PID. The questionnaire based on parental observations was developed using Colaizzis’ framework for content analysis. Answers from 64 PID patients and 62 controls were analyzed by data mining methods in order to make a diagnostic prediction. Performance was evaluated by k-fold stratified cross-validation.
Results
The diagnostic support tool achieved a diagnostic sensitivity of up to 98%. The analysis of 12 interviews revealed 26 main phenomena observed by parents in the pre-diagnostic period. The questions were systematically phrased and selected resulting in a 36-item questionnaire. This was answered by 126 patients with or without PID to evaluate prediction. Item analysis revealed significant questions.
Discussion
Our approach proved suitable for recognizing patterns and thus differentiates between observations of PID patients and control groups. These findings provide the basis for developing a tool supporting physicians to consider a PID with a questionnaire. These data support the notion that patient’s experience is a cornerstone in the diagnostic process.
Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional in vitro characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.
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.
The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.
Structural alterations in the corpus callosum (CC), the major white matter tract connecting functionally related brain regions in the two hemispheres, have been shown to be associated with emotional instability, impulsivity and suicidality in various mental disorders. To explore whether structural alterations of the CC would be similarly associated with emotional instability, impulsivity and suicidality in borderline personality disorder (BPD), we used diffusion tensor imaging (DTI) to assess the structural integrity of the CC in 21 BPD and 20 healthy control (HC) participants. Our hypothesis-driven analyses revealed a positive correlation between BPD participants’ suicidal behavior and fractional anisotropy (FA) in the splenium and genu of the CC and a negative correlation between BPD participants’ suicidal behavior and mean diffusivity (MD) in the splenium of CC. Our exploratory analyses suggested that suicidal BPD participants showed less FA and more MD in these regions than HC participants but that non-suicidal BPD participants showed similar FA and MD in these regions as HC participants. Taken together, our findings suggest an association between BPD participants’ suicidal behavior and structural alterations in regions of the CC that are connected with brain regions implicated in emotion regulation and impulse control. Structural alterations of the CC may, thus, account for deficits in emotion regulation and impulse control that lead to suicidal behavior in BPD. However, these findings should be considered as preliminary until replicated and extended in future studies that comprise larger samples of suicidal and non-suicidal BPD participants.
In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50–80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARM p = 0.059, Cohen's d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARM p = 0.061, Cohen's d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.
Introduction
We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation.
Materials and methods
Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3–174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2–253.6 Gy10) and the prescribed PTV BED10 ranged 23.6–151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed.
Results
Median follow-up was 14.5 months (1–72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05–0.63, p = 0.01), GTV/PTV (HR 1.01–1.02, CI 1.01–1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97–0.99, CI 0.96–0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1–2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur.
Conclusion
Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.
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.
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Medical education research has focused almost entirely on the education of future physicians. In comparison, findings on other health-related occupations, such as medical assistants, are scarce. With the current study, we wanted to examine the knowledge-is-power hypothesis in a real life educational setting and add to the sparse literature on medical assistants. Acquisition of vocational knowledge in vocational education and training (VET) was examined for medical assistant students (n = 448). Differences in domain-specific vocational knowledge were predicted by crystallized and fluid intelligence in the course of VET. A multiple matrix design with 3 year-specific booklets was used for the vocational knowledge tests of the medical assistants. The unique and joint contributions of the predictors were investigated with structural equation modeling. Crystallized intelligence emerged as the strongest predictor of vocational knowledge at every stage of VET, while fluid intelligence only showed weak effects. The present results support the knowledge-is-power hypothesis, even in a broad and more naturalistic setting. This emphasizes the relevance of general knowledge for occupations, such as medical assistants, which are more focused on learning hands-on skills than the acquisition of academic knowledge.
Do We Need to Rethink the Epidemiology and Healthcare Utilization of Parkinson's Disease in Germany?
(2018)
Epidemiological aspects of Parkinson's disease (PD), co-occurring diseases and medical healthcare utilization of PD patients are still largely elusive. Based on claims data of 3.7 million statutory insurance members in Germany in 2015 the prevalence and incidence of PD was determined. PD cases had at least one main hospital discharge diagnosis of PD, or one physician diagnosis confirmed by a subsequent or independent diagnosis or by PD medication in 2015. Prevalence of (co-)occurring diseases, mortality, and healthcare measures in PD cases and matched controls were compared. In 2015, 21,714 prevalent PD cases (standardized prevalence: 511.4/100,000 persons) and 3,541 incident PD cases (standardized incidence: 84.1/100,000 persons) were identified. Prevalence of several (co-)occurring diseases/complications, e.g., dementia (PD/controls: 39/13%), depression (45/22%), bladder dysfunction (46/22%), and diabetes (35/31%), as well as mortality (10.7/5.8%) differed between PD cases and controls. The annual healthcare utilization was increased in PD cases compared to controls, e.g., regarding mean ± SD physician contacts (15.2 ± 7.6/12.2 ± 7.3), hospitalizations (1.3 ± 1.8/0.7 ± 1.4), drug prescriptions (overall: 37.7 ± 24.2/21.7 ± 19.6; anti-PD medication: 7.4 ± 7.4/0.1 ± 0.7), assistive/therapeutic devices (47/30%), and therapeutic remedies (57/16%). The standardized prevalence and incidence of PD in Germany as well as mortality in PD may be substantially higher than reported previously. While frequently diagnosed with co-occurring diseases/complications, such as dementia, depression, bladder dysfunction and diabetes, the degree of healthcare utilization shows large variability between PD patients. These findings encourage a rethinking of the epidemiology and healthcare utilization in PD, at least in Germany. Longitudinal studies of insurance claims data should further investigate the individual and epidemiological progression and healthcare demands in PD.
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.
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.
Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood–brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds.
The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders—such as rubella, human immunodeficiency virus, and herpesviruses—and human distal-less homeobox (DLX) proteins expressed in developing brain—namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity—that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens.
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.
Two decades of research indicate that visual processing is typically enhanced for items that are in the space near the hands (near-hand space). Enhanced attention and cognitive control have been thought to be responsible for the observed effects, amongst others. As accumulating experimental evidence and recent theories of dual-tasking suggest an involvement of cognitive control and attentional processes during dual tasking, dual-task performance may be modulated in the near-hand space. Therefore, we performed a series of three experiments that aimed to test if the near-hand space affects the shift between task-component processing in two visual-manual tasks. We applied a Psychological Refractory Period Paradigm (PRP) with varying stimulus-onset asynchrony (SOA) and manipulated stimulus-hand proximity by placing hands either on the side of a computer screen (near-hand condition) or on the lap (far-hand condition). In Experiment 1, Task 1 was a number categorization task (odd vs. even) and Task 2 was a letter categorization task (vowel vs. consonant). Stimulus presentation was spatially segregated with Stimulus 1 presented on the right side of the screen, appearing first and then Stimulus 2, presented on the left side of the screen, appearing second. In Experiment 2, we replaced Task 2 with a color categorization task (orange vs. blue). In Experiment 3, Stimulus 1 and Stimulus 2 were centrally presented as a single bivalent stimulus. The classic PRP effect was shown in all three experiments, with Task 2 performance declining at short SOA while Task 1 performance being relatively unaffected by task-overlap. In none of the three experiments did stimulus-hand proximity affect the size of the PRP effect. Our results indicate that the switching operation between two tasks in the PRP paradigm is neither optimized nor disturbed by being processed in near-hand space.
Three-year-olds and 4-year-olds have severe difficulties solving standard mental rotation tasks. Only 5-year-olds solve such tasks above chance reliably. In contrast studies relying on simplified mental rotation tasks indicate that infants discriminate between an object and its mirror image. Furthermore in another simplified mental rotation task with 3-year-olds, a linear relation between angular disparity and reaction time typical for mental rotation was revealed. Therefore it was assumed that 3-year-olds’ capabilities are underestimated. In the current study, 3-year-olds were trained in two isolated sessions to solve standard mental rotation tasks and were tested in a third session. Three-year-olds solved this test above chance as a group – a substantial number of them doing so on an individual level. However, a linear relation between angular disparity and reaction time, that would indicate an analog mental transformation, was not discernable. Nevertheless, these findings are in accordance with a continuous line describing mental rotation in infants and older children. And, these also indicate that children’s mental rotation capabilities might be underestimated.
Submerged macrophytes play a key role in north temperate shallow lakes by stabilizing clear-water conditions. Eutrophication has resulted in macrophyte loss and shifts to turbid conditions in many lakes. Considerable efforts have been devoted to shallow lake restoration in many countries, but long-term success depends on a stable recovery of submerged macrophytes. However, recovery patterns vary widely and remain to be fully understood. We hypothesize that reduced external nutrient loading leads to an intermediate recovery state with clear spring and turbid summer conditions similar to the pattern described for eutrophication. In contrast, lake internal restoration measures can result in transient clear-water conditions both in spring and summer and reversals to turbid conditions. Furthermore, we hypothesize that these contrasting restoration measures result in different macrophyte species composition, with added implications for seasonal dynamics due to differences in plant traits. To test these hypotheses, we analyzed data on water quality and submerged macrophytes from 49 north temperate shallow lakes that were in a turbid state and subjected to restoration measures. To study the dynamics of macrophytes during nutrient load reduction, we adapted the ecosystem model PCLake. Our survey and model simulations revealed the existence of an intermediate recovery state upon reduced external nutrient loading, characterized by spring clear-water phases and turbid summers, whereas internal lake restoration measures often resulted in clear-water conditions in spring and summer with returns to turbid conditions after some years. External and internal lake restoration measures resulted in different macrophyte communities. The intermediate recovery state following reduced nutrient loading is characterized by a few macrophyte species (mainly pondweeds) that can resist wave action allowing survival in shallow areas, germinate early in spring, have energy-rich vegetative propagules facilitating rapid initial growth and that can complete their life cycle by early summer. Later in the growing season these plants are, according to our simulations, outcompeted by periphyton, leading to late-summer phytoplankton blooms. Internal lake restoration measures often coincide with a rapid but transient colonization by hornworts, waterweeds or charophytes. Stable clear-water conditions and a diverse macrophyte flora only occurred decades after external nutrient load reduction or when measures were combined.
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.
The social context plays a decisive role in the formation of the academic self-concept (ASC) and has been widely studied as the big-fish-little-pond-effect (BFLPE). This effect describes that comparable talented students in high-achieving school settings have a lower ASC compared to equally talented students attending low-achieving settings. Past research has focused on students’ domain-specific ASC, while little is known about the relation of achievement-related classroom compositions and the various facets of ASC. Additionally, BFLPE-research has been critiqued to build its theoretical frame on social comparison theory, without providing sufficient empirical support. To address this gap, we analyzed how the single student’s social, criterial, absolute, and individual ASC relate to class-level achievement of 8th graders. Applying Multilevel Structural Equation Modeling (MLSEM) we found that all facets of ASC were significantly related to average-class achievement, while student’s social ASC revealed the strongest associated. The results reveal explicitly that average-class achievement is strongly related to social comparison processes.
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.
Species of the genus Wolffia are traditionally used as human food in some of the Asian countries. Therefore, all 11 species of this genus, identified by molecular barcoding, were investigated for ingredients relevant to human nutrition. The total protein content varied between 20 and 30% of the freeze-dry weight, the starch content between 10 and 20%, the fat content between 1 and 5%, and the fiber content was ~25%. The essential amino acid content was higher or close to the requirements of preschool-aged children according to standards of the World Health Organization. The fat content was low, but the fraction of polyunsaturated fatty acids was above 60% of total fat and the content of n-3 polyunsaturated fatty acids was higher than that of n-6 polyunsaturated fatty acids in most species. The content of macro- and microelements (minerals) not only depended on the cultivation conditions but also on the genetic background of the species. This holds true also for the content of tocopherols, several carotenoids and phytosterols in different species and even intraspecific, clonal differences were detected in Wolffia globosa and Wolffia arrhiza. Thus, the selection of suitable clones for further applications is important. Due to the very fast growth and the highest yield in most of the nutrients, Wolffia microscopica has a high potential for practical applications in human nutrition.
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.
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.
Action comprehension that is related to language or gestural integration has been shown to engage the motor system in the brain, thus providing preliminary evidence for the gestural-verbal embodiment concept. Based on the involvement of the sensorimotor cortex (M1) in language processing, we aimed to further explore its role in the cognitive embodiment necessary for gestural-verbal integration. As such, we applied anodal (excitatory) and sham transcranial direct current stimulation (tDCS) over the left M1 (with reference electrode over the contralateral supraorbital region) during a gestural-verbal integration task where subjects had to make a decision about the semantic congruency of the gesture (prime) and the word (target). We used a cross-over within-subject design in young subjects. Attentional load and simple reaction time (RT) tasks served as control conditions, applied during stimulation (order of three tasks was counterbalanced). Our results showed that anodal (atDCS) compared to sham tDCS (stDCS) reduced RTs in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, with no effect on control task performance. Our findings provide evidence for the involvement of the sensorimotor system in gestural-verbal integration performance. Further, our results suggest that functional modulation induced by sensorimotor tDCS may be specific to gestural-verbal integration. Future studies should now evaluate the modulatory effect of tDCS on semantic congruency by using tDCS over additional brain regions and include assessments of neural connectivity.
A Metabolic Labeling Strategy for Relative Protein Quantification in Clostridioides difficile
(2018)
Arm Ability Training (AAT) has been specifically designed to promote manual dexterity recovery for stroke patients who have mild to moderate arm paresis. The motor control problems that these patients suffer from relate to a lack of efficiency in terms of the sensorimotor integration needed for dexterity. Various sensorimotor arm and hand abilities such as speed of selective movements, the capacity to make precise goal-directed arm movements, coordinated visually guided movements, steadiness, and finger dexterity all contribute to our “dexterity” in daily life. All these abilities are deficient in stroke patients who have mild to moderate paresis causing focal disability. The AAT explicitly and repetitively trains all these sensorimotor abilities at the individual's performance limit with eight different tasks; it further implements various task difficulty levels and integrates augmented feedback in the form of intermittent knowledge of results. The evidence from two randomized controlled trials indicates the clinical effectiveness of the AAT with regard to the promotion of “dexterity” recovery and the reduction of focal disability in stroke patients with mild to moderate arm paresis. In addition, the effects have been shown to be superior to time-equivalent “best conventional therapy.” Further, studies in healthy subjects showed that the AAT induced substantial sensorimotor learning. The observed learning dynamics indicate that different underlying sensorimotor arm and hand abilities are trained. Capacities strengthened by the training can, in part, be used by both arms. Non-invasive brain stimulation experiments and functional magnetic resonance imaging data documented that at an early stage in the training cortical sensorimotor network areas are involved in learning induced by the AAT, yet differentially for the tasks trained. With prolonged training over 2 to 3 weeks, subcortical structures seem to take over. While behavioral similarities in training responses have been observed in healthy volunteers and patients, training-induced functional re-organization in survivors of a subcortical stroke uniquely involved the ipsilesional premotor cortex as an adaptive recruitment of this secondary motor area. Thus, training-induced plasticity in healthy and brain-damaged subjects are not necessarily the same.
Mast cells reside on and near the cerebral vasculature, the predominant site of pneumococcal entry into the central nervous system (CNS). Although mast cells have been reported to be crucial in protecting from systemic bacterial infections, their role in bacterial infections of the CNS remained elusive. Here, we assessed the role of mast cells in pneumococcal infection in vitro and in vivo. In introductory experiments using mouse bone marrow-derived mast cells (BMMC), we found that (i) BMMC degranulate and release selected cytokines upon exposure to Streptococcus pneumoniae, (ii) the response of BMMC varies between different pneumococcal serotypes and (iii) is dependent on pneumolysin. Intriguingly though, apart from a slight enhancement of cerebrospinal fluid (CSF) pleocytosis, neither two different mast cell-deficient Kit mutant mouse strains (WBB6F1-KitW/Wv and C57BL/6 KitW-sh/W-sh mice) nor pharmacologic mast cell stabilization with cromoglycate had any significant impact on the disease phenotype of experimental pneumococcal meningitis. The incomplete reversal of the enhanced CSF pleocytosis by local mast cell engraftment suggests that this phenomenon is caused by other c-Kit mutation-related mechanisms than mast cell deficiency. In conclusion, our study suggests that mast cells can be activated by S. pneumoniae in vitro. However, mast cells do not play a significant role as sentinels of pneumococcal CSF invasion and initiators of innate immunity in vivo.
Juvenile Myoclonic Epilepsy Shows Potential Structural White Matter Abnormalities: A TBSS Study
(2018)
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.
The obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The production of both toxins was found strongly connected to the metabolism and the nutritional status of the growth environment. Here, we systematically investigated the changes of the gene regulatory, proteomic and metabolic networks of C. difficile 630Δerm underlying the adaptation to the non-growing state in the stationary phase. Integrated data from time-resolved transcriptome, proteome and metabolome investigations performed under defined growth conditions uncovered multiple adaptation strategies. Overall changes in the cellular processes included the downregulation of ribosome production, lipid metabolism, cold shock proteins, spermine biosynthesis, and glycolysis and in the later stages of riboflavin and coenzyme A (CoA) biosynthesis. In contrast, different chaperones, several fermentation pathways, and cysteine, serine, and pantothenate biosynthesis were found upregulated. Focusing on the Stickland amino acid fermentation and the central carbon metabolism, we discovered the ability of C. difficile to replenish its favored amino acid cysteine by a pathway starting from the glycolytic 3-phosphoglycerate via L-serine as intermediate. Following the growth course, the reductive equivalent pathways used were sequentially shifted from proline via leucine/phenylalanine to the central carbon metabolism first to butanoate fermentation and then further to lactate fermentation. The toxin production was found correlated mainly to fluxes of the central carbon metabolism. Toxin formation in the supernatant was detected when the flux changed from butanoate to lactate synthesis in the late stationary phase. The holistic view derived from the combination of transcriptome, proteome and metabolome data allowed us to uncover the major metabolic strategies that are used by the clostridial cells to maintain its cellular homeostasis and ensure survival under starvation conditions.
Background: Biomarkers for gains of evidence based interventions for upper limb motor training in the subacute stage following stroke have rarely been described. Information about these parameters might help to identify patients who benefit from specific interventions and to determine individually expected behavioral gains for a certain period of therapy.
Objective: To evaluate predictors for hand motor outcome after arm ability training in the subacute stage after stroke selected from known potentially relevant parameters (initial motor strength, structural integrity of the pyramidal tract and functional motor cortex integrity).
Methods: We applied the arm ability training (AAT) over 3 weeks to a subpopulation of stroke patients with mild arm paresis, i.e., in 14 patients on average 4 weeks after stroke. The following biomarkers were measured before therapy onset: grip strength on the affected hand, transcranial magnetic stimulation recruitment curve steepness over the primary motor hand area [slope ratio between the ipsilesional hemisphere (IH) and contralesional hemisphere (CH)], and diffusion weighted MRI fractional anisotropy (FA) in the posterior limb of the internal capsule (PLIC; determined as a lateralization index between IH and CH). Outcome was assessed as the AATgain (percentage improvement over training). The “Test d'Evaluation des Membres Supérieurs de Personnes Âgées” (TEMPA) was assessed before and after training to test for possible associations of AAT with activity of daily living.
Results: A stepwise linear regression identified the lateralization index of PLIC FA as the only significant predictor for AAT-gain (R2 = 0.519; P = 0.029). AAT-gain was positively associated (r = 0.59; P = 0.028) with improvement in arm function during daily activities (TEMPA).
Conclusions: While all mildly affected patients achieved a clinically relevant therapeutic effect, pyramidal tract integrity nevertheless had a modifying role for clinical benefit.
Tree growth at northern boreal treelines is generally limited by summer temperature, hence tree rings serve as natural archives of past climatic conditions. However, there is increasing evidence that a changing summer climate as well as certain micro-site conditions can lead to a weakening or loss of the summer temperature signal in trees growing in treeline environments. This phenomenon poses a challenge to all applications relying on stable temperature-growth relationships such as temperature reconstructions and dynamic vegetation models. We tested the effect of differing ecological and climatological conditions on the summer temperature signal of Scots pine at its northern distribution limits by analyzing twelve sites distributed along a 2200 km gradient from Finland to Western Siberia (Russia). Two frequently used proxies in dendroclimatology, ring width and maximum latewood density, were correlated with summer temperature for the period 1901–2013 separately for (i) dry vs. wet micro-sites and (ii) years with dry/warm vs. wet/cold climate regimes prevailing during the growing season. Differing climate regimes significantly affected the temperature signal of Scots pine at about half of our sites: While correlations were stronger in wet/cold than in dry/warm years at most sites located in Russia, differing climate regimes had only little effect at Finnish sites. Both tree-ring proxies were affected in a similar way. Interestingly, micro-site differences significantly affected absolute tree growth, but had only minor effects on the climatic signal at our sites. We conclude that, despite the treeline-proximal location, growth-limiting conditions seem to be exceeded in dry/warm years at most Russian sites, leading to a weakening or loss of the summer temperature signal in Scots pine here. With projected temperature increase, unstable summer temperature signals in Scots pine tree rings might become more frequent, possibly affecting dendroclimatological applications and related fields.
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.
In the present study, we investigated whether inter-individual differences in vagally mediated heart rate variability (vmHRV) would be associated with inter-individual differences in empathy and alexithymia. To this end, we determined resting state HF-HRV in 90 individuals that also completed questionnaires assessing inter-individual differences in empathy and alexithymia. Our categorical and dimensional analyses revealed that inter-individual differences in HF-HRV were differently associated with inter-individual differences in empathy and alexithymia. We found that individuals with high HF-HRV reported more empathy and less alexithymia than individuals with low HF-HRV. Moreover, we even found that an increase in HF-HRV was associated with an increase in empathy and a decrease in alexithymia across all participants. Taken together, these findings indicate that individuals with high HF-HRV are more empathetic and less alexithymic than individuals with low HF-HRV. These differences in empathy and alexithymia may explain why individuals with high HF-HRV are more successful in sharing and understanding the mental and emotional states of others than individuals with low HF-HRV.
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.
Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis
(2018)
Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function.
Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.
Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.
Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.
Research has shown that parental pressure is negatively whereas parental support is positively associated with various scholastic outcomes, such as school engagement, motivation, and achievement. However, only few studies investigate boys' and girls' perception of mother and father pressure/support in detail. This might be particularly essential when it comes to girls' and boys' achievement in STEM subjects, as girls and boys might profit differently from parental pressure/support regarding their achievement in STEM and vice versa. This study aims to shed light on this topic and explores potential within—and over time associations between students' perception of parental pressure/support and grades in mathematics and biology. Using self-report data from 1,088 8th grade students at T1 (Mage = 13.70, SD = 0.53, 54% girls) from Brandenburg, Germany, multigroup cross-lagged models were conceptualized with Mplus. The results indicate that there are gender differences in the interplay of students' grades in mathematics, biology, and their perception of parental pressure and support: Whereas, mother support plays a central beneficial role for girls' achievement in STEM subjects as well as for the other parental variables over time, for boys mother support is negatively associated with math performance over time. Within-time associations further show that boys—in contrast to girls—do not benefit from any parental support regarding their performance in mathematics or biology. Finally, results suggest that the relationship between adolescents' STEM achievement and parental pressure/support is rather mono-directional than bi-directional over time.
Extracts from the leaves and flowers of Crataegus spp. (i.e., hawthorn species) have been traditionally used with documented preclinical and clinical activities in cardiovascular medicine. Based on reported positive effects on heart muscle after ischemic injury and the overall cardioprotective profile, the present study addressed potential contributions of Crataegus extracts to cardiopoietic differentiation from stem cells. The quantified Crataegus extract WS®1442 stimulated cardiomyogenesis from murine and human embryonic stem cells (ESCs). Mechanistically, this effect was found to be induced by promoting differentiation of cardiovascular progenitor cell populations but not by proliferation. Bioassay-guided fractionation, phytochemical and analytical profiling suggested high-molecular weight ingredients as the active principle with at least part of the activity due to oligomeric procyanidines (OPCs) with a degree of polymerization between 3 and 6 (DP3–6). Transcriptome profiling in mESCs suggested two main, plausible mechanisms: These were early, stress-associated cellular events along with the modulation of distinct developmental pathways, including the upregulation of brain-derived neurotrophic factor (BDNF) and retinoic acid as well as the inhibition of transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) and fibroblast growth factor (FGF) signaling. In addition, WS®1442 stimulated angiogenesis ex vivo in Sca-1+ progenitor cells from adult mice hearts. These in vitro data provide evidence for a differentiation promoting activity of WS®1442 on distinct cardiovascular stem/progenitor cells that could be valuable for therapeutic heart regeneration after myocardial infarction. However, the in vivo relevance of this new pharmacological activity of Crataegus spp. remains to be investigated and active ingredients from bioactive fractions will have to be further characterized.
Type I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic 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.
Duckweeds include the world's smallest and fastest growing flowering plants that have the capacity to produce huge biomass with a broad range of potential applications like production of feed and food, biofuel and biogas. In order to achieve optimal and sustainable commercial system, it is necessary that suitable species and clones of duckweeds be identified and selected based on appropriate strategies. However, a high degree of reduction in their structural complexity poses serious problems in identification of closely related species of duckweeds, on a morphological basis. Use of molecular taxonomic tools is the present solution. The state of the art of molecular taxonomy of all the five genera of duckweeds (Spirodela, Landoltia, Lemna, Wolffiella, and Wolffia) is based mainly on the techniques of fingerprinting by amplified fragment length polymorphism (AFLP) and barcoding using sequences of plastidic DNA fragments. After more than 15 years of molecular taxonomic investigations, a certain viewpoint is now available demonstrating all five genera to be monophyletic. Also, the phenetic analyses had made huge progress in delineating the currently defined 36 species of duckweeds, although, all species cannot yet be defined with confidence. Wolffiella has turned out to be the most complicated genus as only 6 to 7 species out of the 10 can be reliably delineated. Further progress in the phylogenetic and phenetic analyses requires more advanced methods like next generation and/or whole genome sequencing. First results using the method genotyping-by-sequencing in the genus Lemna (in combination with metabolomic profiling by matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF-MS) as well as AFLP and barcoding by plastidic sequences) are more promising: The species Lemna valdiviana and Lemna yungensis were united to one species, Lemna valdiviana. This reduced the total number of Lemnaceae species to 36.
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.
Despite major research interest regarding gender differences in emotion regulation, it is still not clear whether men and women differ in their basic capacity to implement specific emotion regulation strategies, as opposed to indications of the habitual use of these strategies in self-reports. Similarly, little is known on how such basic capacities relate to indices of well-being in both sexes. This study took a novel approach by investigating gender differences in the capacity for generating cognitive reappraisals in adverse situations in a sample of 67 female and 59 male students, using a maximum performance test of the inventiveness in generating reappraisals. Participants’ self-perceived efficacy in emotion regulation was additionally assessed. Analyses showed that men and women did not differ in their basic capacity to generate alternative appraisals for anxiety-eliciting scenarios, suggesting similar functional cognitive mechanisms in the implementation of this strategy. Yet, higher cognitive reappraisal capacity predicted fewer depressive daily-life experiences in men only. These findings suggest that in the case of cognitive reappraisal, benefits for well-being in women might depend on a more complex combination of basic ability, habits, and efficacy-beliefs, along with the use of other emotion regulation strategies. The results of this study may have useful implications for psychotherapy research and practice.
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.
Finding suitable places to establish a mussel farm is challenging, as many aspects like mussel growth, clearance effect and the risk of low oxygen conditions, have to be considered. We present a tailor-made approach, combining field experiments with a spatially explicit model tool, to support the planning process. A case study was set up in the German part of Szczecin (Oder) Lagoon (Baltic Sea), as it shows all typical eutrophication problems and has a strong need and high potential for nutrient retention measures. Farming zebra mussels (Dreissena polymorpha) is an innovative approach that utilizes a species which is often perceived as a pest. The practical applicability and water quality improvement potential was proven by a pilot farm. Combining the gained knowledge with the simulation model led to a cascade of mussel farm options that differ in purpose, location, and biomass. Placing a mussel farm in an enclosed bay resulted in a remarkable water quality improvement (Secchi Depth increased up to 2 m), but the effect stayed local, the growth was limited and the potential annual nutrient removal reached a threshold of ~30 t N and 2.8 t P. The same nutrient removal could be reached with much smaller farms in an open sea area, whereas the change of water transparency or bottom oxygen conditions were neglectable. A maximal nutrient removal potential of 1,750 t N and 160 t P per year was estimated, when nearly the entire German part of Szczecin Lagoon with mussel farms was used. This led to a strong reduction of phytoplankton and an increase of Secchi Depth, but also a rising risk of anoxia. Overall, all mussel farm options are only a supportive measure, but not sufficient to reach the Good Environmental Status demanded by the Water Framework Directive. At once, the nutrient export from Szczecin Lagoon to the open Baltic was reduced by up to 3,500 t N and 420 t P per year, making the large-scale mussel farm option also a potential measure within the Marine Strategy Framework Directive.
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.
Autosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either CCM1 (KRIT1), CCM2 or CCM3 (PDCD10) can be identified in 87–98% of CCM families with at least two affected individuals. However, the interpretation of novel sequence variants in the 5′-region of CCM2 remains challenging as there are various alternatively spliced transcripts and different transcription start sites. Comprehensive genetic and clinical data of CCM2 patients with variants in cassette exons that are either skipped or included into alternative CCM2 transcripts in the splicing process can significantly facilitate clinical variant interpretation. We here report novel pathogenic CCM2 variants in exon 3 and the adjacent donor splice site, describe the natural history of CCM disease in mutation carriers and provide further evidence for the classification of the amino acids encoded by the nucleotides of this cassette exon as a critical region within CCM2. Finally, we illustrate the advantage of a combined single nucleotide and copy number variation detection approach in NGS-based CCM1/CCM2/CCM3 gene panel analyses which can significantly reduce diagnostic turnaround time.
Type I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and- effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-a, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.
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.
Introduction: Hearing and vision loss are highly prevalent in elderly adults, and thus frequently occur in conjunction with cognitive impairments. Studies have shown that hearing impairment is associated with a higher risk of dementia. However, evidence concerning the association between vision loss and dementia, as well as the co-occurrence of vision and hearing loss and dementia, has been inconclusive.
Objectives: To assess the association between: (i) either hearing or vision loss and the risk of dementia, as well as between; and (ii) the combination of both sensory impairments and the risk of dementia.
Methods: This case-control study was based on a 5-year data set that included patients aged 65 years and older who had initially been diagnosed with dementia diseases by one of 1,203 general practitioners in Germany between January 2013 and December 2017. In total, 61,354 identified dementia cases were matched to non-dementia controls, resulting in a sample size of 122,708 individuals. Hearing loss and vision loss were identified using the ICD-10 diagnoses documented in the general practitioners’ files prior to the initial dementia diagnosis. Multivariate logistic regression models were fitted to evaluate the associations between visual and/or hearing impairment and the risk of dementia and controlled for sociodemographic and clinical variables.
Results: Hearing impairment was documented in 11.2% of patients with a dementia diagnosis and 9.5% of patients without such a diagnosis. Some form of vision impairment was documented in 28.4% of patients diagnosed with dementia and 28.8% of controls. Visual impairment was not significantly associated with dementia (OR = 0.97, CI = 95% 0.97–1.02, p = 0.219). However, patients with hearing impairment were at a significantly higher risk of developing dementia (OR = 1.26, CI = 95% 1.15–1.38, p < 0.001), a finding that very likely led to the observed significant association of the combination of both visual and hearing impairments and the risk of dementia (OR = 1.14, CI = 95% 1.04–1.24, p = 0.005).
Discussion: This analysis adds important evidence that contributes to the limited body of knowledge about the association between hearing and/or vision loss and dementia. It further demonstrates that, of the two, only hearing impairment affects patients’ cognition and thus contributes to dementia risk.
Determining the effect of a changing climate on tree growth will ultimately depend on our understanding of wood formation processes and how they can be affected by environmental conditions. In this context, monitoring intra-annual radial growth with high temporal resolution through point dendrometers has often been used. Another widespread approach is the microcoring method to follow xylem and phloem formation at the cellular level. Although both register the same biological process (secondary growth), given the limitations of each method, each delivers specific insights that can be combined to obtain a better picture of the process as a whole. To explore the potential of visualizing combined dendrometer and histological monitoring data and scrutinize intra-annual growth data on both dimensions (dendrometer → continuous; microcoring → discrete), we developed DevX (Dendrometer vs. Xylogenesis), a visualization application using the “Shiny” package in the R programming language. The interactive visualization allows the display of dendrometer curves and the overlay of commonly used growth model fits (Gompertz and Weibull) as well as the calculation of wood phenology estimates based on these fits (growth onset, growth cessation, and duration). Furthermore, the growth curves have interactive points to show the corresponding histological section, where the amount and development stage of the tissues at that particular time point can be observed. This allows to see the agreement of dendrometer derived phenology and the development status at the cellular level, and by this help disentangle shrinkage and swelling due to water uptake from actual radial growth. We present a case study with monitoring data for Acer pseudoplatanus L., Fagus sylvatica L., and Quercus robur L. trees growing in a mixed stand in northeastern Germany. The presented application is an example of the innovative and easy to access use of programming languages as basis for data visualization, and can be further used as a learning tool in the topic of wood formation and its ecology. Combining continuous dendrometer data with the discrete information from histological-sections provides a tool to identify active periods of wood formation from dendrometer series (calibrate) and explore monitoring datasets.
Background and Objective: Transcranial random noise stimulation (tRNS) is an emerging non-invasive brain stimulation technique to modulate brain function, with previous studies highlighting its considerable benefits in therapeutic stimulation of the motor system. However, high variability of results and bidirectional task-dependent effects limit more widespread clinical application. Task dependency largely results from a lack of understanding of the interaction between externally applied tRNS and the endogenous state of neural activity during stimulation. Hence, the aim of this study was to investigate the task dependency of tRNS-induced neuromodulation in the motor system using a finger-tapping task (FT) versus a go/no-go task (GNG). We hypothesized that the tasks would modulate tRNS’ effects on corticospinal excitability (CSE) and task performance in opposite directions.
Methods: Thirty healthy subjects received 10 min of tRNS of the dominant primary motor cortex in a double-blind, sham-controlled study design. tRNS was applied during two well-established tasks tied to diverging brain states. Accordingly, participants were randomly assigned to two equally-sized groups: the first group performed a simple motor training task (FT task), known primarily to increase CSE, while the second group performed an inhibitory control task (go/no-go task) associated with inhibition of CSE. To establish task-dependent effects of tRNS, CSE was evaluated prior to- and after stimulation with navigated transcranial magnetic stimulation.
Results: In an ‘activating’ motor task, tRNS during FT significantly facilitated CSE. FT task performance improvements, shown by training-related reductions in intertap intervals and increased number of finger taps, were similar for both tRNS and sham stimulation. In an ‘inhibitory’ motor task, tRNS during GNG left CSE unchanged while inhibitory control was enhanced as shown by slowed reaction times and enhanced task accuracy during and after stimulation.
Conclusion: We provide evidence that tRNS-induced neuromodulatory effects are task-dependent and that resulting enhancements are specific to the underlying task-dependent brain state. While mechanisms underlying this effect require further investigation, these findings highlight the potential of tRNS in enhancing task-dependent brain states to modulate human behavior.
Genetic Regulation of Liver Metabolites and Transcripts Linking to Biochemical-Clinical Parameters
(2019)
Given the central metabolic role of the liver, hepatic metabolites and transcripts reflect the organismal physiological state. Biochemical-clinical plasma biomarkers, hepatic metabolites, transcripts, and single nucleotide polymorphism (SNP) genotypes of some 300 pigs were integrated by weighted correlation networks and genome-wide association analyses. Network-based approaches of transcriptomic and metabolomics data revealed linked of transcripts and metabolites of the pentose phosphate pathway (PPP). This finding was evidenced by using a NADP/NADPH assay and HDAC4 and G6PD transcript quantification with the latter coding for first limiting enzyme of this pathway and by RNAi knockdown experiments of HDAC4. Other transcripts including ARG2 and SLC22A7 showed link to amino acids and biomarkers. The amino acid metabolites were linked with transcripts of immune or acute phase response signaling, whereas the carbohydrate metabolites were highly enrich in cholesterol biosynthesis transcripts. Genome-wide association analyses revealed 180 metabolic quantitative trait loci (mQTL) (p < 10-4). Trans-4-hydroxy-L-proline (p = 6 × 10-9), being strongly correlated with plasma creatinine (CREA), showed strongest association with SNPs on chromosome 6 that had pleiotropic effects on PRODH2 expression as revealed by multivariate analysis. Consideration of shared marker association with biomarkers, metabolites, and transcripts revealed 144 SNPs associated with 44 metabolites and 69 transcripts that are correlated with each other, representing 176 mQTL and expression quantitative trait loci (eQTL). This is the first work to report genetic variants associated with liver metabolite and transcript levels as well as blood biochemical-clinical parameters in a healthy porcine model. The identified associations provide links between variation at the genome, transcriptome, and metabolome level molecules with clinically relevant phenotypes. This approach has the potential to detect novel biomarkers displaying individual variation and promoting predictive biology in medicine and animal breeding.
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.
Neurobiological theories suggest that inter-individual differences in vagally mediated heart rate variability (vmHRV) have the potential to serve as a biomarker for inter-individual differences in emotion regulation that are due to inter-individual differences regarding the engagement of prefrontal and (para-)limbic brain regions during emotion processing. To test these theories, we investigated whether inter-individual differences in vmHRV would be associated with inter-individual differences in emotion regulation. We determined resting state vmHRV in a sample of 176 individuals that had also completed a short self-report measure of reappraisal and suppression use. Resting state vmHRV was derived from short-term (300 s) and ultra-short-term (120 s, 60 s) recordings of participants’ heart rate to determine the robustness of possible findings. Irrespective of recording length, we found that an increase in resting state vmHRV was associated with an increase in self-reported reappraisal but not suppression use. However, this association was only evident among male but not female participants, indicating a sex-specific association between inter-individual differences in resting state vmHRV and inter-individual differences in self-reported emotion regulation. These findings, which are consistent with previous ones, support theoretical claims that inter-individual differences in vmHRV serve as a biomarker for inter-individual differences in emotion regulation. Combing (ultra-)short-term measures of resting state vmHRV with short self-report measures of emotion regulation may, thus, be useful for researchers who have to investigate the neurobiological mechanisms of emotion regulation in a time- and resource-efficient manner.
Neurobiological theories suggest that inter-individual differences in vagally mediated heart rate variability (vmHRV) have the potential to serve as a biomarker for interindividual differences in emotion regulation that are due to inter-individual differences regarding the engagement of prefrontal and (para-)limbic brain regions during emotion processing. To test these theories, we investigated whether inter-individual differences in
vmHRV would be associated with inter-individual differences in emotion regulation. We determined resting state vmHRV in a sample of 176 individuals that had also completed a short self-report measure of reappraisal and suppression use. Resting state vmHRV was derived from short-term (300 s) and ultra-short-term (120 s, 60 s) recordings of participants’ heart rate to determine the robustness of possible findings. Irrespective of recording length, we found that an increase in resting state vmHRV was associated with an increase in self-reported reappraisal but not suppression use. However, this association was only evident among male but not female participants, indicating a sex-specific association between inter-individual differences in resting state vmHRV and inter-individual differences in self-reported emotion regulation. These findings, which are consistent with previous ones, support theoretical claims that inter-individual differences in vmHRV serve as a biomarker for inter-individual differences in emotion regulation. Combing (ultra-)short-term measures of resting state vmHRV with short selfreport measures of emotion regulation may, thus, be useful for researchers who have to investigate the neurobiological mechanisms of emotion regulation in a time- and resource-efficient manner.