Publications by authors named "Anja Richter"

56 Publications

Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes.

Neuropsychopharmacology 2021 May 3. Epub 2021 May 3.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (p = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p = 0.035); the association was negative in CHR with poor outcomes (p = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.
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http://dx.doi.org/10.1038/s41386-021-01019-0DOI Listing
May 2021

[Prehospital treatment of tension pneumothorax in children-which decisions do we make? : Results of a survey among German emergency physicians].

Anaesthesist 2021 Apr 23. Epub 2021 Apr 23.

Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland.

Background: The preclinical treatment of a traumatic or spontaneous tension pneumothorax remains a particular challenge in pediatric patients. Currently recommended interventions for decompression are either finger thoracostomy or needle decompression. Due to the tiny intercostal spaces, finger thoracostomy may not be feasible in small children and surgical preparation may be necessary. In needle decompression, the risk of injuring underlying vital structures is increased because of the smaller anatomic structures. As most emergency physicians do not regularly work in pediatric trauma care, decompression of tension pneumothorax is associated with significant uncertainty; however, in this rare emergency situation, consistent and goal-oriented action is mandatory and lifesaving. An assessment of pre-existing experience and commonly used techniques therefore seems necessary to deduce the need for future education and training.

Objective: In this study an online survey was created to evaluate the experience and the favored prehospital treatment of tension pneumothorax in children among German emergency physicians.

Material And Methods: An online survey was conducted with 43 questions on previous experience with tension pneumothorax in children, favored decompression technique and anatomical structures in different age groups. Surveyed were the emergency physicians of the ground-based emergency medical service of the University Medical Center Mannheim, the German Air Rescue Service (DRF) and the pediatric emergency medical service of the City of Munich.

Results: More than half of all respondents stated that there was uncertainty about the procedure of choice. Needle decompression was favored in smaller children and mini-thoracostomy in older children. In comparison with the literature, the thickness of the chest wall was mostly estimated correctly by the emergency medical physicians. The depth of the vital structures was underestimated at most of the possible insertion sites in all age groups. At the lateral insertion sites on the left hemithorax, however, the distance to the left ventricle was overestimated. The caliber of the needle selected for decompression tended to be too large, especially in younger children.

Conclusion: Even though having interviewed an experienced group of prehospital emergency physicians, the experience in decompression of tension pneumothorax in children is relatively scant. Knowledge of chest wall thickness and depth to vital structures is sufficient, the choice of needle calibers tends to be too large but still reasonable. For many providers a large amount of uncertainty about the right choice of technique and equipment arises from the challenge of decompressing a tension pneumothorax in children and therefore further theoretical education and regular training are required for safe performance of the procedure.
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http://dx.doi.org/10.1007/s00101-021-00966-zDOI Listing
April 2021

Seroprevalence and correlates of SARS-CoV-2 neutralizing antibodies from a population-based study in Bonn, Germany.

Nat Commun 2021 04 9;12(1):2117. Epub 2021 Apr 9.

Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

To estimate the seroprevalence and temporal course of SARS-CoV-2 neutralizing antibodies, we embedded a multi-tiered seroprevalence survey within an ongoing community-based cohort study in Bonn, Germany. We first assessed anti-SARS-CoV-2 immunoglobulin G levels with an immunoassay, followed by confirmatory testing of borderline and positive test results with a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (PRNT). Those with a borderline or positive immunoassay result were retested after 4 to 5 months. At baseline, 4771 persons participated (88% response rate). Between April 24 and June 30, 2020, seroprevalence was 0.97% (95% CI: 0.72-1.30) by immunoassay and 0.36% (95% CI: 0.21-0.61) when considering only those with two additional positive confirmatory tests. Importantly, about 20% of PRNT+ individuals lost their neutralizing antibodies within five months. Here, we show that neutralizing antibodies are detectable in only one third of those with a positive immunoassay result, and wane relatively quickly.
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http://dx.doi.org/10.1038/s41467-021-22351-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035181PMC
April 2021

Generation of iPSC lines from CPVT patient carrying heterozygous mutation p.A2254V in the ryanodine receptor 2 gene.

Stem Cell Res 2021 Feb 19;53:102259. Epub 2021 Feb 19.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany; Clinic for Cardiology and Pneumology, Universitätsmedizin Göttingen, Germany. Electronic address:

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inheritable cardiac disorder, which is characterized by life-threatening cardiac arrhythmias, syncope, seizures, or sudden cardiac death in response to physical exercise or emotional stress. This inherited disease is predominantly caused by mutations in the ryanodine receptor type 2 (RYR2). To minimize the cell line variations for disease modeling, we generated two induced pluripotency stem cell lines (hiPSCs: isCPVT1-2 and isCPVT1-3) from skin fibroblasts of one CPVT patient carrying the p.A2254V mutation using CytoTune2.0 Sendai virus cocktail for non-integration reprogramming. All generated iPSCs maintained pluripotency, normal karyotype, and spontaneous in vivo and in vitro differentiation capacity.
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http://dx.doi.org/10.1016/j.scr.2021.102259DOI Listing
February 2021

Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy.

iScience 2021 Mar 6;24(3):102151. Epub 2021 Feb 6.

Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany.

Detailed knowledge of the molecular biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is crucial for understanding of viral replication, host responses, and disease progression. Here, we report gene expression profiles of three SARS-CoV- and SARS-CoV-2-infected human cell lines. SARS-CoV-2 elicited an approximately two-fold higher stimulation of the innate immune response compared to SARS-CoV in the human epithelial cell line Calu-3, including induction of miRNA-155. Single-cell RNA sequencing of infected cells showed that genes induced by virus infections were broadly upregulated, whereas interferon beta/lambda genes, a pro-inflammatory cytokines such as IL-6, were expressed only in small subsets of infected cells. Temporal analysis suggested that transcriptional activities of interferon regulatory factors precede those of nuclear factor κB. Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 activity resulted in a reduction of viral replication and pro-inflammatory cytokine expression in primary human airway epithelial cells.
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http://dx.doi.org/10.1016/j.isci.2021.102151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866843PMC
March 2021

Dopamine multilocus genetic profiles predict sex differences in reactivity of the human reward system.

Brain Struct Funct 2021 May 12;226(4):1099-1114. Epub 2021 Feb 12.

Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.

Sex differences in the neural processing of decision-making are of high interest as they may have pronounced effects on reward- and addiction-related processes. In these, the neurotransmitter dopamine plays a central role by modulating the responsiveness of the reward circuitry. The present functional magnetic resonance imaging study aimed to explore sex and dopamine transmission interactions in decision-making. 172 subjects (111 women) performed a behavioral self-control task assessing reward-related activation during acceptance and rejection of conditioned rewards. Participants were genotyped for six key genetic polymorphisms in the dopamine system that have previously been associated with individual differences in reward sensitivity or dopaminergic transmission in the human striatum, such as rs7118900 (dopamine receptor D2 (DRD2) Taq1A), rs1554929 (DRD2 C957T), rs907094 (DARPP-32), rs12364283 (DRD2), rs6278 (DRD2), and rs107656 (DRD2). The selected polymorphisms were combined in a so-called multilocus genetic composite (MGC) score reflecting the additive effect of different alleles conferring relative increased dopamine transmission in every individual. We successfully demonstrated that reward-related activation in the ventral striatum and ventral tegmental area (VTA) was significantly modulated by biologically informed MGC profiles and sex. When comparing men and women with low MGC profiles that may indicate lower dopamine transmission, only women displayed a reduced down-regulation of activation in the mesolimbic system during reward rejection and additionally, a significant non-linear u-shape relationship between MGC score and VTA activation. Taken together, by integrating neuroimaging and genetics, the present findings contribute to a better understanding of the effects of sex differences on the human brain.
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http://dx.doi.org/10.1007/s00429-021-02227-6DOI Listing
May 2021

Interaction of variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex.

Stress 2021 Feb 8:1-9. Epub 2021 Feb 8.

Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of , a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in major allele carriers. These results point to a potential role of the rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.
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http://dx.doi.org/10.1080/10253890.2020.1855420DOI Listing
February 2021

Experiences of Patients With Borderline Personality Disorder With Imagery Rescripting in the Context of Schema Therapy-A Qualitative Study.

Front Psychiatry 2020 3;11:550833. Epub 2020 Dec 3.

Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.

Imagery Rescripting (IR) is a therapeutic technique that is used in a wide spectrum of therapeutic methods for various mental disorders. As an important component of Schema Therapy (ST), IR is frequently used in the treatment of patients with borderline personality disorder (BPD). However, little is known about how IR is experienced by individuals with BPD. The aim of this study was to explore BPD patients' experiences with receiving IR. Qualitative data were collected through semi-structured interviews with 21 individuals (86% females) with a primary diagnosis of BPD who received IR within their ST treatment. Interview data were analyzed following the procedures of qualitative content analysis. Participants reported various effects of IR including initial high emotionality and exhaustion. Long-term effects included a better understanding of schemas and an improvement regarding emotion regulation and interpersonal relationships. Participants reported factors hindering the successful implementation of IR, such as external noise, stress, and a fast pace during IR. Facilitating factors included adequate time for debriefing, a transparent structure, and preparation of IR as well as the therapist providing safety. Implications of the findings for optimizing IR in clinical practice are discussed.
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http://dx.doi.org/10.3389/fpsyt.2020.550833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744465PMC
December 2020

A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model.

Cell 2020 11 23;183(4):1058-1069.e19. Epub 2020 Sep 23.

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20359 Hamburg, Germany.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
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http://dx.doi.org/10.1016/j.cell.2020.09.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510528PMC
November 2020

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Hum Brain Mapp 2020 Oct 7. Epub 2020 Oct 7.

Neuroscience Research Australia, Sydney, Australia.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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http://dx.doi.org/10.1002/hbm.25206DOI Listing
October 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model.

bioRxiv 2020 Aug 16. Epub 2020 Aug 16.

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 A revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
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http://dx.doi.org/10.1101/2020.08.15.252320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430590PMC
August 2020

A high-resolution fMRI approach to characterize functionally distinct neural pathways within dopaminergic midbrain and nucleus accumbens during reward and salience processing.

Eur Neuropsychopharmacol 2020 07 13;36:137-150. Epub 2020 Jun 13.

Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.

Processing of reward and salience without reward association are known to critically rely on the dopamine system. A growing body of evidence from animal studies suggests that both functions may be subserved by distinct subregions in midbrain and ventral striatum, specifically nucleus accumbens (NAcc). Yet in vivo investigation of these brain structures in humans has been rare. Here we examined blood oxygen level dependent signals in response to frequently presented rewarding events and infrequently presented neutral events in 20 healthy subjects using high-resolution functional magnetic resonance imaging (fMRI) for imaging the human midbrain and NAcc. The present findings revealed distinct activation patterns in brain regions of interest, namely increased activation in substantia nigra pars compacta (SNc) and dorsolateral NAcc in response to neutral events, while the VTA and both the ventromedial and dorsolateral NAcc were significantly activated due to rewarding events. Moreover, psychophysiological interaction analyses demonstrated regionally specialized processing pathways, such as a dorsolateral pathway when processing salience per se, i.e. increased functional interactions between SNc, dorsolateral NAcc and dorsolateral and medial prefrontal cortex (PFC); and a ventromedial pathway during reward processing, i.e. increased functional coupling between VTA and ventromedial NAcc. Thus, these findings may not only accelerate the integration of animal models of brain function with human neuroscience but may also improve diagnosis and treatment in patients with neuropsychiatric disorders such as schizophrenia and depression in which dopaminergic dysfunction and aberrant attribution of salience have been implicated.
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http://dx.doi.org/10.1016/j.euroneuro.2020.05.005DOI Listing
July 2020

Local c-di-GMP Signaling in the Control of Synthesis of the E. coli Biofilm Exopolysaccharide pEtN-Cellulose.

J Mol Biol 2020 07 11;432(16):4576-4595. Epub 2020 Jun 11.

Institute of Biology/Microbiology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany. Electronic address:

In many bacteria, the biofilm-promoting second messenger c-di-GMP is produced and degraded by multiple diguanylate cyclases (DGC) and phosphodiesterases (PDE), respectively. High target specificity of some of these enzymes has led to theoretical concepts of "local" c-di-GMP signaling. In Escherichia coli K-12, which has 12 DGCs and 13 PDEs, a single DGC, DgcC, is specifically required for the biosynthesis of the biofilm exopolysaccharide pEtN-cellulose without affecting the cellular c-di-GMP pool, but the mechanistic basis of this target specificity has remained obscure. DGC activity of membrane-associated DgcC, which is demonstrated in vitro in nanodiscs, is shown to be necessary and sufficient to specifically activate cellulose biosynthesis in vivo. DgcC and a particular PDE, PdeK (encoded right next to the cellulose operon), directly interact with cellulose synthase subunit BcsB and with each other, thus establishing physical proximity between cellulose synthase and a local source and sink of c-di-GMP. This arrangement provides a localized, yet open source of c-di-GMP right next to cellulose synthase subunit BcsA, which needs allosteric activation by c-di-GMP. Through mathematical modeling and simulation, we demonstrate that BcsA binding from the low cytosolic c-di-GMP pool in E. coli is negligible, whereas a single c-di-GMP molecule that is produced and released in direct proximity to cellulose synthase increases the probability of c-di-GMP binding to BcsA several hundred-fold. This local c-di-GMP signaling could provide a blueprint for target-specific second messenger signaling also in other bacteria where multiple second messenger producing and degrading enzymes exist.
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http://dx.doi.org/10.1016/j.jmb.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397504PMC
July 2020

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

Psychol Med 2020 09 16;50(12):2034-2045. Epub 2019 Oct 16.

Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.

Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.

Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.

Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
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http://dx.doi.org/10.1017/S0033291719002149DOI Listing
September 2020

Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus.

Neuroimage Clin 2019 2;23:101920. Epub 2019 Jul 2.

Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Germany; Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany.

Accumulating evidence suggests altered function of the mesolimbic reward system resulting from exposure to early adversity. The present study investigated the combined long-term impact of adversity until young adulthood on neuronal reward processing and its interaction with individual resilience processes. In this functional magnetic resonance imaging study, 97 healthy young adults performed a reward-based decision-making task. Adversity as well as resilience were assessed retrospectively using the validated childhood trauma questionnaire, trauma history questionnaire and a resilience scale. Subjects with high adversity load showed reduced reward-related bottom-up activation in the ventral striatum (VS), ventral tegmental area (VTA) and hippocampus (HP) as compared to the low adversity group. However, high resilience traits in individuals with high adversity load were associated with an increased activation in the VTA and HP, indicating a possible resilience-related protective mechanism. Moreover, when comparing groups with high to low adversity, psychophysiological interaction analyses highlighted an increased negative functional coupling between VS and VTA as well as between VS and anteroventral prefrontal cortex (avPFC) during reward acceptance, and an impaired top-down control of the VS by the avPFC during reward rejection. In turn, combination of high adversity and high resilience traits was associated with an improved functional coupling between VTA, VS and HP. Thereby, the present findings identify neural mechanisms mediating interacting effects of adversity and resilience, which could be targeted by early intervention and prevention.
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http://dx.doi.org/10.1016/j.nicl.2019.101920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617249PMC
August 2020

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

Biol Psychiatry 2019 10 13;86(7):545-556. Epub 2019 Jun 13.

Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut; Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.

Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.

Results: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.

Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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http://dx.doi.org/10.1016/j.biopsych.2019.03.985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068800PMC
October 2019

Key Players and Individualists of Cyclic-di-GMP Signaling in .

Front Microbiol 2018 10;9:3286. Epub 2019 Jan 10.

Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

H111 is an opportunistic pathogen associated with chronic lung infections in cystic fibrosis patients. Biofilm formation, motility and virulence of are regulated by the second messenger cyclic di-guanosine monophosphate (c-di-GMP). In the present study, we analyzed the role of all 25 putative c-di-GMP metabolizing proteins of H111 with respect to motility, colony morphology, pellicle formation, biofilm formation, and virulence. We found that RpfR is a key regulator of c-di-GMP signaling in , affecting a broad spectrum of phenotypes under various environmental conditions. In addition, we identified Bcal2449 as a regulator of virulence in larvae. While Bcal2449 consists of protein domains that may catalyze both c-di-GMP synthesis and degradation, only the latter was essential for larvae killing, suggesting that a decreased c-di-GMP level mediated by the Bcal2449 protein is required for virulence of . Finally, our work suggests that some individual proteins play a role in regulating exclusively motility (CdpA), biofilm formation (Bcam1160) or both (Bcam2836).
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http://dx.doi.org/10.3389/fmicb.2018.03286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335245PMC
January 2019

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Biol Psychiatry 2018 11 14;84(9):644-654. Epub 2018 May 14.

Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.

Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.

Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2018.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177304PMC
November 2018

Pan-class I  PI3-kinase inhibitor BKM120 induces MEK1/2-dependent mitotic catastrophe in non-Hodgkin lymphoma leading to apoptosis or polyploidy determined by Bax/Bak and p53.

Cell Death Dis 2018 03 7;9(3):384. Epub 2018 Mar 7.

Department of Hematology, Oncology and Tumor Immunology, Charité - University Medicine Berlin, Campus Berlin-Buch, Lindenberger Weg 80, Berlin, 13125, Germany.

Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis. BKM120-mediated downregulation of Cyclin A and activation of the CDK1/Cyclin B1 complex facilitates mitotic entry. In addition, concomitant BKM120-mediated upregulation of Cyclin B1 expression attenuates completion of mitosis, which results in mitotic catastrophe and apoptotic cell death. In Bax and Bak deficient B-NHL, which are resistant to BKM120-induced apoptosis, BKM120-induced mitotic catastrophe results in polyploidy. Upon re-expression of wt p53 in these p53 mutated cells, BKM120-induced polyploidy is strongly reduced demonstrating that the genetic status of the cells determines the outcome of a BKM120-mediated pathway inhibition. Mitotic catastrophe and unfavorable induction of polyploidy can be prevented in this setting by additional inhibition of MEK1/2 signaling. Combining MEK1/2 inhibitors with BKM120 enhances the anti-tumor effects of BKM120, prevents prognostic unfavorable polyploidy and might be a potential strategy for the treatment of B-NHL.
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http://dx.doi.org/10.1038/s41419-018-0413-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841308PMC
March 2018

Influence of ventral tegmental area input on cortico-subcortical networks underlying action control and decision making.

Hum Brain Mapp 2018 02 22;39(2):1004-1014. Epub 2017 Nov 22.

Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, University Hospital Heidelberg, 69115, Germany.

It is argued that the mesolimbic system has a more general function in processing all salient events, including and extending beyond rewards. Saliency was defined as an event that is unexpected due to its frequency of occurrence and elicits an attentional-behavioral switch. Using functional magnetic resonance imaging (fMRI), signals were measured in response to the modulation of salience of rewarding and nonrewarding events during a reward-based decision making task, the so called desire-reason dilemma paradigm (DRD). Replicating previous findings, both frequent and infrequent, and therefore salient, reward stimuli elicited reliable activation of the ventral tegmental area (VTA) and ventral striatum (vStr). When immediate reward desiring contradicted the superordinate task-goal, we found an increased activation of the VTA and vStr when the salient reward stimuli were presented compared to the nonsalient reward stimuli, indicating a boosting of activation in these brain regions. Furthermore, we found a significantly increased functional connectivity between the VTA and vStr, confirming the boosting of vStr activation via VTA input. Moreover, saliency per se without a reward association led to an increased activation of brain regions in the mesolimbic reward system as well as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC). Finally, findings uncovered multiple increased functional interactions between cortical saliency-processing brain areas and the VTA and vStr underlying detection and processing of salient events and adaptive decision making.
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http://dx.doi.org/10.1002/hbm.23899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866482PMC
February 2018

More than Enzymes That Make or Break Cyclic Di-GMP-Local Signaling in the Interactome of GGDEF/EAL Domain Proteins of .

mBio 2017 10 10;8(5). Epub 2017 Oct 10.

Institut für Biologie/Mikrobiologie, Humboldt-Universität zu Berlin, Berlin, Germany

The bacterial second messenger bis-(3'-5')-cyclic diguanosine monophosphate (c-di-GMP) ubiquitously promotes bacterial biofilm formation. Intracellular pools of c-di-GMP seem to be dynamically negotiated by diguanylate cyclases (DGCs, with GGDEF domains) and specific phosphodiesterases (PDEs, with EAL or HD-GYP domains). Most bacterial species possess multiple DGCs and PDEs, often with surprisingly distinct and specific output functions. One explanation for such specificity is "local" c-di-GMP signaling, which is believed to involve direct interactions between specific DGC/PDE pairs and c-di-GMP-binding effector/target systems. Here we present a systematic analysis of direct protein interactions among all 29 GGDEF/EAL domain proteins of Since the effects of interactions depend on coexpression and stoichiometries, cellular levels of all GGDEF/EAL domain proteins were also quantified and found to vary dynamically along the growth cycle. Instead of detecting specific pairs of interacting DGCs and PDEs, we discovered a tightly interconnected protein network of a specific subset or "supermodule" of DGCs and PDEs with a coregulated core of five hyperconnected hub proteins. These include the DGC/PDE proteins representing the c-di-GMP switch that turns on biofilm matrix production in Mutants lacking these core hub proteins show drastic biofilm-related phenotypes but no changes in cellular c-di-GMP levels. Overall, our results provide the basis for a novel model of local c-di-GMP signaling in which a single strongly expressed master PDE, PdeH, dynamically eradicates global effects of several DGCs by strongly draining the global c-di-GMP pool and thereby restricting these DGCs to serving as local c-di-GMP sources that activate specific colocalized effector/target systems. c-di-GMP signaling in bacteria is believed to occur via changes in cellular c-di-GMP levels controlled by antagonistic and potentially interacting pairs of diguanylate cyclases (DGCs) and c-di-GMP phosphodiesterases (PDEs). Our systematic analysis of protein-protein interaction patterns of all 29 GGDEF/EAL domain proteins of , together with our measurements of cellular c-di-GMP levels, challenges both aspects of this current concept. Knocking out distinct DGCs and PDEs has drastic effects on biofilm formation without changing the cellular c-di-GMP level. In addition, rather than generally coming in interacting DGC/PDE pairs, a subset of DGCs and PDEs operates as central interaction hubs in a larger "supermodule," with other DGCs and PDEs behaving as "lonely players" without contacts to other c-di-GMP-related enzymes. On the basis of these data, we propose a novel concept of "local" c-di-GMP signaling in bacteria with multiple enzymes that make or break the second messenger c-di-GMP.
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http://dx.doi.org/10.1128/mBio.01639-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635695PMC
October 2017

Does aquatic exercise reduce hip and knee joint loading? In vivo load measurements with instrumented implants.

PLoS One 2017 20;12(3):e0171972. Epub 2017 Mar 20.

Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Aquatic exercises are widely used for rehabilitation or preventive therapies in order to enable mobilization and muscle strengthening while minimizing joint loading of the lower limb. The load reducing effect of water due to buoyancy is a main advantage compared to exercises on land. However, also drag forces have to be considered that act opposite to the relative motion of the body segments and require higher muscle activity. Due to these opposing effects on joint loading, the load-reducing effect during aquatic exercises remains unknown. The aim of this study was to quantify the joint loads during various aquatic exercises and to determine the load reducing effect of water. Instrumented knee and hip implants with telemetric data transfer were used to measure the resultant joint contact forces in 12 elderly subjects (6x hip, 6x knee) in vivo. Different dynamic, weight-bearing and non-weight-bearing activities were performed by the subjects on land and in chest-high water. Non-weight-bearing hip and knee flexion/extension was performed at different velocities and with additional Aquafins. Joint forces during aquatic exercises ranged between 32 and 396% body weight (BW). Highest forces occurred during dynamic activities, followed by weight-bearing and slow non-weight-bearing activities. Compared to the same activities on land, joint forces were reduced by 36-55% in water with absolute reductions being greater than 100%BW during weight-bearing and dynamic activities. During non-weight-bearing activities, high movement velocities and additional Aquafins increased the joint forces by up to 59% and resulted in joint forces of up to 301%BW. This study confirms the load reducing effect of water during weight-bearing and dynamic exercises. Nevertheless, high drag forces result in increased joint contact forces and indicate greater muscle activity. By the choice of activity, movement velocity and additional resistive devices joint forces can be modulated individually in the course of rehabilitation or preventive therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171972PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358747PMC
August 2017

Neuronal Differentiation Capability of Nasal Polyps of Chronic Rhinosinusitis.

Arch Immunol Ther Exp (Warsz) 2017 Oct 9;65(5):431-443. Epub 2017 Mar 9.

Department of Otorhinolaryngology, University Medical Center Schleswig-Holstein, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.

Chronic rhinosinusitis with nasal polyps is considered a subgroup of chronic rhinosinusitis and a significant health problem, but the pathogenesis remains unclear to date. Therefore, we investigated the stemness to determine the role of stem cells in nasal polyps, with additional analysis of the neuronal differentiation potential of nasal polyp cells. We determined gene and protein expression profiles of stem cells in nasal polyp tissues, using whole genome microarray, quantitative real-time PCR (qPCR), immunohistochemistry, and flow cytometry. To evaluate the neuronal differentiation potential of nasal polyp cells, we used an efficient xenogeneic co-culture model with unsliced adult rat brain biopsies, followed by qPCR, immunohistochemistry, and growth factor antibody arrays. During gene expression analysis and immunohistochemistry, we were able to detect different stem cell markers, like Oct-4, Sox2, Klf4, c-Myc, ABCG2, Nanog, CD133, and Nestin, which confirmed the existence of stem cell like cells within nasal polyps. In addition, co-culture experiments give evidence for a guided differentiation into the neuronal lineage by overexpression of Nestin, Neurofilament, and GM-CSF. Our study demonstrated the expression of stem cell-related markers in nasal polyps. Furthermore, we characterized, for the first time, the stemness and neuronal differentiation potential of nasal polyp cells. These results gave new insights into the pathogenesis of nasal polyps and its therapeutic effectiveness could represent a promising strategy in the future.
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http://dx.doi.org/10.1007/s00005-017-0456-8DOI Listing
October 2017

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma.

J Biol Chem 2017 04 1;292(16):6478-6492. Epub 2017 Feb 1.

From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany,

Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and biologicals, including TNF-related apoptosis-inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to TRAIL-induced apoptosis, in particular by down-regulation of the Bak-inhibitory Bcl-2 family protein Mcl-1. Here we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl-1 down-regulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (ΔΨ) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨ and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase-8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨ breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics, including TRAIL, in multiresistant cancers such as RCC.
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http://dx.doi.org/10.1074/jbc.M116.754184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399102PMC
April 2017

Disruptions in the left frontoparietal network underlie resting state endophenotypic markers in schizophrenia.

Hum Brain Mapp 2017 04 23;38(4):1741-1750. Epub 2016 Dec 23.

Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866857PMC
April 2017

Plasma vitamin C levels in ESRD patients and occurrence of hypochromic erythrocytes.

Hemodial Int 2017 04 12;21(2):250-255. Epub 2016 Sep 12.

University of Massachusetts, Lowell, Massachusetts, USA.

Introduction: The achievement of erythropoiesis in hemodialysis (HD) patients is typically managed with erythropoiesis-stimulating-agents (ESA's) and intravenous iron (IV-iron). Using this treatment strategy, HD patients frequently show an elevated fraction of red blood cells (RBC) with hemoglobin (Hb) content per cell that is below the normal range, called hypochromic RBC. The low Hb content per RBC is the result of the clinical challenge of providing sufficient iron content to the bone marrow during erythropoiesis. Vitamin C supplements have been used to increase Hb levels in HD patients with refractory anemia, which supports the hypothesis that vitamin C mobilizes iron needed for Hb synthesis.

Methods: We conducted a cross-sectional survey in 149 prevalent HD patients of the percent hypochromic RBC, defined as RBC with Hb < 300 ng/uL of packed RBC, in relation to plasma vitamin C levels. We also measured high-sensitivity CRP, (hs-CRP), iron, and ferritin levels. and calculated ESA dose.

Findings: High plasma levels of vitamin C were negatively associated with hypochromic RBC (P < 0.003), and high ESA doses were positively associated (P < 0.001). There was no significant association of hs-CRP with percent hypochromic RBC.

Discussion: This finding supports the hypothesis that vitamin C mobilizes iron stores, improves iron delivery to the bone marrow, and increase the fraction of RBC with normal Hb content. Further research is warranted on development of protocols for safe and effective use of supplemental vitamin C for management of renal anemia.
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http://dx.doi.org/10.1111/hdi.12467DOI Listing
April 2017

The green tea polyphenol EGCG inhibits E. coli biofilm formation by impairing amyloid curli fibre assembly and downregulating the biofilm regulator CsgD via the σ(E) -dependent sRNA RybB.

Mol Microbiol 2016 07 6;101(1):136-51. Epub 2016 May 6.

Institut für Biologie/Mikrobiologie, Humboldt-Universität zu Berlin, 10115, Berlin, Germany.

In bacterial biofilms, which are often involved in chronic infections, cells are surrounded by a self-produced extracellular matrix that contains amyloid fibres, exopolysaccharides and other biopolymers. The matrix contributes to the pronounced resistance of biofilms against antibiotics and host immune systems. Being highly inflammatory, matrix amyloids such as curli fibres of Escherichia coli can also play a role in pathogenicity. Using macrocolony biofilms of commensal and pathogenic E. coli as a model system, we demonstrate here that the green tea polyphenol epigallocatachin gallate (EGCG) is a potent antibiofilm agent. EGCG virtually eliminates the biofilm matrix by directly interfering with the assembly of curli subunits into amyloid fibres, and by triggering the σ(E) cell envelope stress response and thereby reducing the expression of CsgD - a crucial activator of curli and cellulose biosynthesis - due to csgD mRNA targeting by the σ(E) -dependent sRNA RybB. These findings highlight EGCG as a potential adjuvant for antibiotic therapy of biofilm-associated infections. Moreover, EGCG may support therapies against pathogenic E. coli that produce inflammatory curli fibres along with Shigatoxin.
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http://dx.doi.org/10.1111/mmi.13379DOI Listing
July 2016