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Clinical outcomes after a first-episode of psychosis (FEP) are heterogeneous. Many patient-related factors such as gender and comorbidity have been studied to predict symptomatic outcomes. However, psychiatrist-related factors such as prescription behaviour and gender have received little attention. We assessed the relationship between patients' psychiatrists, psychosis severity and daily functioning in 201 patients remitted from an FEP for a duration of one year, treated by 18 different psychiatrists. We controlled for baseline severity, dose and type of antipsychotic medication, frequency of visits, and patients' education. Symptom severity, daily functioning, and antipsychotic drug use were assessed at baseline and at 3, 6, and, 12 months follow-up. We found that psychiatrists accounted for 9.1% of the explained variance in patients' symptom severity and 10.1% of the explained variance in daily functioning.These effects persisted even when controlling for factors such as baseline severity and the prescribed dose. The effect of prescribed dose on symptom severity and daily functioning differed between psychiatrists. Treatment centre, session frequency, and medication nonadherence were not related to symptom severity. Our results emphasize the importance of individual psychiatrist factors in symptomatic outcomes after an FEP. Further identification of psychiatrist-related factors such as the quality of therapeutic alliances and shared decision-making, may optimize psychiatrists' training with the goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

One largely neglected focus in the analysis of mission-oriented innovation policies is mission cocreation between stakeholder groups advocating different solution directions. In this paper, we introduce the innovation management concept of ambidexterity to study how mission cocreation in different mission arenas is influenced by actors aiming to continue existing innovation pathways (exploitative innovation) and actors advocating alternative pathways (explorative innovation). Our case study on the Dutch circular agriculture mission highlights how an initial top-down strategy development was dominated by exploitative forces, despite ambitions to secure broad stakeholder participation. Government-led efforts to still engage exploration-minded actors, and restore ambidexterity, were hampered by potential contributors feeling excluded from the policy process. These findings underline the risk that openness of missions, required for broad stakeholder involvement, might also reinforce pre-existing contestation and innovation pathways. Overall, our findings demonstrate a trade-off between maximizing efficiency and speed versus obtaining novel perspectives and wide societal legitimacy. [ABSTRACT FROM AUTHOR]

Background: Methods to call, analyze and visualize copy number variations (CNVs) from massive parallel sequencing data have been widely adopted in clinical practice and genetic research. To enable a streamlined analysis of CNV data, comprehensive annotations and good visualizations are indispensable. The ability to detect single exon CNVs is another important feature for genetic testing. Nonetheless, most available open-source tools come with limitations in at least one of these areas. One additional drawback is that available tools deliver data in an unstructured and static format which requires subsequent visualization and formatting efforts. Results: Here we present CNVizard, an interactive Streamlit app allowing a comprehensive visualization of CNVkit data. Furthermore, combining CNVizard with the CNVand pipeline allows the annotation and visualization of CNV or SV VCF files from any CNV caller. Conclusion: CNVizard, in combination with CNVand, enables the comprehensive and streamlined analysis of short- and long-read sequencing data and provide an intuitive webapp-like experience enabling an interactive visualization of CNV data. [ABSTRACT FROM AUTHOR]

The aerospace sector is looking for lighter, more robust, and less fuel-consuming aircraft by using advanced lightweight materials. Fibre-reinforced polymers and lightweight alloys are pivotal to this aim, owing to their favourable strength-to-weight ratio and mechanical properties. Therefore, assembling hybrid stacks of these materials offers customisation opportunities to optimise performance and structural integrity. This research explores one-up drilling techniques for hybrid stacks of carbon fibre-reinforced polymer (CFRP) laminates and aluminium alloy sheets, which are essential in the fabrication of advanced aircraft structures. The experimental procedure consists of first drilling individual materials separately to optimise the process parameters for each material and then drilling a hybrid stack configuration (CFRP/AA7075-T6) with an innovative approach using spindle active power monitoring to implement a self-adapting strategy of process parameters at the interface between the two materials. This flexible methodology offers a practical solution for streamlining the drilling process in aerospace applications. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cells use transient membraneless organelles to regulate biological reaction networks. For example, stress granules selectively store mRNA to downregulate protein expression in response to heat or oxidative stress. Models mimicking this active behavior should be established to better understand in vivo regulation involving compartmentalization. Here we use active, complex coacervate droplets as a model for membraneless organelles to spatiotemporally control the activity of a catalytic DNA (DNAzyme). Upon partitioning into these peptide‐RNA droplets, the DNAzyme unfolds and loses its ability to catalyze the cleavage of a nucleic acid strand. We can transiently pause the DNAzyme activity upon inducing droplet formation with fuel. After fuel consumption, the DNAzyme activity autonomously restarts. We envision this system could be used to up and downregulate multiple reactions in a network, helping understand the complexity of a cell's pathways. By creating a network where the DNAzyme could reciprocally regulate the droplet properties, we would have a powerful tool for engineering synthetic cells. [ABSTRACT FROM AUTHOR]

Informal interactions are vital in daily workplace communication, shaping performance, well-being, collaboration, and overall organizational functioning. However, as the ongoing trends of remote and hybrid work present significant changes and challenges to these interactions, supporting remote informal communication (RIC) becomes urgent. To address this pressing issue, we adopt a socio-technical systems perspective to gain in-depth insights into the enabling and constraining factors related to RIC. Our findings of semi-structured interviews with working adults (N=33) reveal important changes and challenges related to informal communication in the remote work context. We identify eleven interrelated socio-contextual, intrapersonal, and technological factors, culminating in a comprehensive conceptual framework of RIC. Based on our findings, we provide practical recommendations to effectively facilitate RIC in organizations and discuss future research avenues for understanding effective RIC in organizations. [ABSTRACT FROM AUTHOR]

We present DiasMorph, a dataset of images and traits of diaspores from 1,442 taxa in 519 genera, and 96 families from Central Europe, totalling 94,214 records. The dataset was constructed following a standardised and reproducible image analysis method. The image dataset consists of diaspores against a high-contrast background, enabling a simple and efficient segmentation process. The quantitative traits records go beyond traditional morphometric measurements, and include colour and contour features, which are made available for the first time in a large dataset. These measurements correspond to individual diaspores, an input currently unavailable in traits databases, and allow for several approaches to explore the morphological traits of these species. Additionally, information regarding the presence and absence of appendages and structures both in the images and diaspores of the assessed taxa is also included. By making these data available, we aim to encourage initiatives to advance on new tools for diaspore identification, further our understanding of morphological traits functions, and provide means for the continuous development of image analyses applications. [ABSTRACT FROM AUTHOR]

Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε−3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes. Diabetes complications are attributed to reactive by-products of glycolysis, but cells consuming lactate and pyruvate are not spared. Here, the authors show that the reactive dicarbonyl dimethylglyoxal is formed from pyruvate, rises in diabetes, and potentially causes neurological complications of diabetes. [ABSTRACT FROM AUTHOR]

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms. Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient 'biotypes' characterized by partially distinct disease mechanisms. [ABSTRACT FROM AUTHOR]

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms. Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient 'biotypes' characterized by partially distinct disease mechanisms. [ABSTRACT FROM AUTHOR]

Copyright of Bautechnik is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Although nonwork mastery generates personal resources and improves employee well-being and performance, employees must invest personal resources to experience mastery during nonwork time. Drawing on conservation of resources theory and resource exchange perspectives, the purpose of this study is to examine the role of day-to-day provisions of affiliation resources by the leader in generating the personal resources necessary for employees to engage in nonwork mastery. Design/methodology/approach: Daily diary data were collected from 198 employees (768 days). The proposed model was tested using Bayesian multilevel path analysis. Findings: The results showed that on days when employees perceived that their leader provided more affiliation resources, they reported higher self-esteem and work engagement and, in turn, experienced higher levels of mastery. Furthermore, employees in high-quality (vs low-quality) leader–member exchange (LMX) relationships benefitted more from the affiliation resources provided by their leader in terms of work engagement. Practical implications: The findings suggest that leaders can actively manage their employees' daily experience and functioning through seemingly ordinary demonstrations of warmth, care, and positive regard. Originality/value: This study highlights the important role of leaders in improving employee daily work and nonwork experience and functioning and sheds light on the tangible resource provisions in the work context and the associated personal resources that account for daily variations in mastery. By distinguishing between daily affiliation resources and general perceptions of LMX relationship quality, this study contributes to a more nuanced understanding of the implications that resource provisions by the leader have for employees. [ABSTRACT FROM AUTHOR]

Copyright of Reproductive Medicine & Biology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Childhood trauma may impact the course of schizophrenia spectrum disorders (SSD), specifically in relation to the increased severity of depressive or negative symptoms. The type and impact of trauma may differ between sexes. In a large sample of recent-onset patients, we investigated the associations of depressive and negative symptoms with childhood trauma and whether these are sex-specific. Methods: A total of 187 first-episode psychosis patients in remission (Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment study) and 115 recent-onset SSD patients (Simvastatin study) were included in this cross-sectional study (men: n = 218; women: n = 84). Total trauma score and trauma subtypes were assessed using the Childhood Trauma Questionnaire Short Form; depressive and negative symptoms were rated using the Positive And Negative Symptoms Scale. Sex-specific regression analyses were performed. Results: Women reported higher rates of sexual abuse than men (23.5% v. 7.8%). Depressive symptoms were associated with total trauma scores and emotional abuse ratings in men (β : 0.219–0.295; p ≤ 0.001). In women, depressive symptoms were associated with sexual abuse ratings (β : 0.271; p = 0.011). Negative symptoms were associated with total trauma score and emotional neglect ratings in men (β : 0.166–0.232; p ≤ 0.001). Negative symptoms in women were not linked to childhood trauma, potentially due to lack of statistical power. Conclusions: Depressive symptom severity was associated with different types of trauma in men and women with recent-onset SSD. Specifically, in women, depressive symptom severity was associated with childhood sexual abuse, which was reported three times as often as in men. Our results emphasize the importance of sex-specific analyses in SSD research. [ABSTRACT FROM AUTHOR]

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3 -, FLVCR1 - and NGF -associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Psychosomatische Medizin und Psychotherapie is the property of Vandenhoeck & Ruprecht GmbH & Co. KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Imaging and image processing is the fundamental pillar of interventional oncology in which diagnostic, procedure planning, treatment and follow‐up are sustained. Knowing all the possibilities that the different image modalities can offer is capital to select the most appropriate and accurate guidance for interventional procedures. Despite there is a wide variability in physicians preferences and availability of the different image modalities to guide interventional procedures, it is important to recognize the advantages and limitations for each of them. In this review, we aim to provide an overview of the most frequently used image guidance modalities for interventional procedures and its typical and future applications including angiography, computed tomography (CT) and spectral CT, magnetic resonance imaging, Ultrasound and the use of hybrid systems. Finally, we resume the possible role of artificial intelligence related to image in patient selection, treatment and follow‐up. [ABSTRACT FROM AUTHOR]

Background: Ixodes ricinus ticks are infected with a large diversity of vertically and horizontally transmitted symbionts. While horizontally transmitted symbionts rely on a vertebrate host for their transmission, vertically transmitted symbionts rely more on the survival of their invertebrate host for transmission. We therefore hypothesized horizontally transmitted symbionts to be associated with increased tick activity to increase host contact rate and vertically transmitted symbionts to be associated with higher tick weight and lipid fraction to promote tick survival. Methods: We used a behavioural assay to record the questing activity of I. ricinus ticks. In addition, we measured weight and lipid fraction and determined the presence of ten symbiont species in these ticks using qPCR, of which six were vertically transmitted and four horizontally transmitted. Results: Vertically transmitted symbionts (e.g. Midichloria mitochondrii) were associated with an increase in tick weight, whereas horizontally transmitted symbionts (e.g. Borrelia burgdorferi sensu lato) were often associated with lower weight and lipid fraction of ticks. Moreover, horizontally transmitted symbionts (e.g. B. burgdorferi s.l.) were associated with increased tick activity, which may benefit pathogen transmission and increases tick-borne disease hazard. Conclusions: Our study shows that horizontally and vertically transmitted symbionts differentially influence the behaviour and physiology of I. ricinus and warrants future research to study the underlying mechanisms and effects on transmission dynamics of tick-borne pathogens. [ABSTRACT FROM AUTHOR]

A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing discussion whether skin-infiltrating Th17 cells may underlie this phenomenon. This study aimed to investigate the potential of allergen-induced, immune-cell derived IL-17 on the induction of inflammatory processes in keratinocytes. Peripheral blood mononuclear cells derived from respectively sensitized AD patients were stimulated with house dust mite (HDM) extract and cell culture supernatants were applied subsequently in absence or presence of secukinumab to primary human keratinocytes. Hereby we confirm that the immune response of sensitized AD patients to HDM contains aside from type-2 cytokines significant amounts of IL-17. Blocking IL-17 efficiently reduced the stimulation-induced changes in keratinocyte gene expression. IL-17-dependent transcriptional changes included increased expression of the cytokines IL-20 and IL-24 as well as Suppressor of Cytokine Siganling 3 (SOCS3), a negative feedback-regulator of the STAT3/IL-17/IL-24 immune response. We conclude that the immune response to HDM can induce pro-inflammatory cytokines from keratinocytes in AD, which in part is mediated via IL-17. Targeting IL-17 may turn out to be a reasonable alternative therapy in a subgroup of patients with moderate to severe AD and HDM sensitization. [ABSTRACT FROM AUTHOR]

A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing discussion whether skin-infiltrating Th17 cells may underlie this phenomenon. This study aimed to investigate the potential of allergen-induced, immune-cell derived IL-17 on the induction of inflammatory processes in keratinocytes. Peripheral blood mononuclear cells derived from respectively sensitized AD patients were stimulated with house dust mite (HDM) extract and cell culture supernatants were applied subsequently in absence or presence of secukinumab to primary human keratinocytes. Hereby we confirm that the immune response of sensitized AD patients to HDM contains aside from type-2 cytokines significant amounts of IL-17. Blocking IL-17 efficiently reduced the stimulation-induced changes in keratinocyte gene expression. IL-17-dependent transcriptional changes included increased expression of the cytokines IL-20 and IL-24 as well as Suppressor of Cytokine Siganling 3 (SOCS3), a negative feedback-regulator of the STAT3/IL-17/IL-24 immune response. We conclude that the immune response to HDM can induce pro-inflammatory cytokines from keratinocytes in AD, which in part is mediated via IL-17. Targeting IL-17 may turn out to be a reasonable alternative therapy in a subgroup of patients with moderate to severe AD and HDM sensitization. [ABSTRACT FROM AUTHOR]

Steel structures, such as bridges, must be continuously maintained. Due to increasing traffic loads, design and execution shortcomings, many steel bridges are subject to various types of damage, such as cracks. The bridges must be maintained by crack removal and re‐welding the cracks. During this work, the bridge is closed for traffic in order to suppress the crack flank movement during welding. As a result, traffic loads on other routes are higher, which increases further damage on detour routes and subsequently additional welding work and costs on these structures. Therefore, the aim is to provide a method that allows welding work on steel structures under running traffic, respectively under cyclic loads. First, measurements at a representative steel bridge were conducted to derive gap opening parameters of amplitude and frequency for welding tests under cyclic loads. Monitoring cracks shows that the crack behavior is complex and the description of the force redistribution during welding is a challenge. In order to quantify the influence of different boundary conditions during welding on weld quality and fatigue, experimental investigations were carried out under displacement control only and force control only. For both, the weld quality and the fatigue strength was comparable to the standard requirements, so that welding under service conditions is possible under certain aspects. [ABSTRACT FROM AUTHOR]

Steel structures, such as bridges, must be continuously maintained. Due to increasing traffic loads, design and execution shortcomings, many steel bridges are subject to various types of damage, such as cracks. The bridges must be maintained by crack removal and re‐welding the cracks. During this work, the bridge is closed for traffic in order to suppress the crack flank movement during welding. As a result, traffic loads on other routes are higher, which increases further damage on detour routes and subsequently additional welding work and costs on these structures. Therefore, the aim is to provide a method that allows welding work on steel structures under running traffic, respectively under cyclic loads. First, measurements at a representative steel bridge were conducted to derive gap opening parameters of amplitude and frequency for welding tests under cyclic loads. Monitoring cracks shows that the crack behavior is complex and the description of the force redistribution during welding is a challenge. In order to quantify the influence of different boundary conditions during welding on weld quality and fatigue, experimental investigations were carried out under displacement control only and force control only. For both, the weld quality and the fatigue strength was comparable to the standard requirements, so that welding under service conditions is possible under certain aspects. [ABSTRACT FROM AUTHOR]

Background: Hyperglycaemia is frequent in acute ischemic stroke and denotes a bad prognosis, even in the absence of pre-existing diabetes. However, in clinical trials treatment of elevated glucose levels with insulin did not improve stroke outcome, suggesting that collateral effects rather than hyperglycaemia itself aggravate ischemic brain damage. As reactive glucose metabolites, glyoxal and methylglyoxal are candidates for mediating the deleterious effects of hyperglycaemia in acute stroke. Methods: In 135 patients with acute stroke, we used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to measure glyoxal, methylglyoxal and several of their glycated amino acid derivatives in serum. Results were verified in a second cohort of 61 stroke patients. The association of serum concentrations with standard stroke outcome scales (NIHSS, mRS) was tested. Results: Glucose, glyoxal, methylglyoxal, and the glyoxal-derived glycated amino acid Nδ-(5-hydro-4-imidazolon-2-yl)ornithine (G-H1) were positively correlated with a bad stroke outcome at 3 months as measured by mRS90, at least in one of the two cohorts. However, the glycated amino acids Nε-carboxyethyllysine (CEL) and in one cohort pyrraline showed an inverse correlation with stroke outcome probably reflecting lower food intake in severe stroke. Patients with a poor outcome had higher serum concentrations of glyoxal and methylglyoxal. Conclusions: The glucose-derived α-dicarbonyl glyoxal and glycated amino acids arising from a reaction with glyoxal are associated with a poor outcome in ischemic stroke. Thus, lowering α-dicarbonyls or counteracting their action could be a therapeutic strategy for hyperglycaemic stroke. [ABSTRACT FROM AUTHOR]

Accumulation of plastic litter in aquatic environments negatively impacts ecosystems and human livelihood. Urban areas are assumed to be the main source of plastic pollution in these environments because of high anthropogenic activity. Yet, the drivers of plastic emissions, abundance, and retention within these systems and subsequent transport to river systems are poorly understood. In this study, we demonstrate that urban water systems function as major contributors to river plastic pollution, and explore the potential driving factors contributing to the transport dynamics. Monthly visual counting of floating litter at six outlets of the Amsterdam water system results in an estimated 2.7 million items entering the closely connected IJ river annually, ranking it among the most polluting systems measured in the Netherlands and Europe. Subsequent analyses of environmental drivers (including rainfall, sunlight, wind speed, and tidal regimes) and litter flux showed very weak and insignificant correlations (r = - 0.19–0.16), implying additional investigation of potential drivers is required. High-frequency observations at various locations within the urban water system and advanced monitoring using novel technologies could be explored to harmonize and automate monitoring. Once litter type and abundance are well-defined with a clear origin, communication of the results with local communities and stakeholders could help co-develop solutions and stimulate behavioral change geared to reduce plastic pollution in urban environments. [ABSTRACT FROM AUTHOR]

Workplace gossip, a ubiquitous organizational behavior broadly defined as talking about an absent target in an evaluative way, has received increasing scientific attention over the past few years. The complexity and dynamism of the workplace gossip phenomenon create challenging research conditions such that studies focusing on the allegedly same type of workplace gossip can produce differential findings. To address this problem and better align theory and methodology, our manuscript first proposes a framework of workplace gossip that accounts for the interdependencies of the context-embeddedness and dynamism of workplace gossip. Guided by this framework, we systematically evaluate extant workplace gossip research, spanning a total of N = 104 empirical research articles. Highlighting current methodological challenges that indicate a neglect of the dynamic nuances and contexts of workplace gossip, we argue that previous organizational research painted an overly simplistic picture of workplace gossip. By looking beyond traditional organizational research designs, we derive recommendations to advance research on workplace gossip and, ultimately, to establish it as a complex and dynamic social interaction behavior. [ABSTRACT FROM AUTHOR]

The rapid and dynamic implementation of Next-Generation Sequencing (NGS)-based assays has revolutionized genetic testing, and in the near future, nearly all molecular alterations of the human genome will be diagnosable via massive parallel sequencing. While this progress will further corroborate the central role of human genetics in the multidisciplinary management of patients with genetic disorders, it must be accompanied by quality assurance measures in order to allow the safe and optimal use of knowledge ascertained from genome diagnostics. To achieve this, several valuable tools and guidelines have been developed to support the quality of genome diagnostics. In this paper, authors with experience in diverse aspects of genomic analysis summarize the current status of quality assurance in genome diagnostics, with the aim of facilitating further standardization and quality improvement in one of the core competencies of the field. [ABSTRACT FROM AUTHOR]

Background: As the technology of next generation sequencing rapidly develops and costs are constantly reduced, the clinical availability of whole genome sequencing (WGS) increases. Thereby, it remains unclear what exact advantage WGS offers in comparison to whole exome sequencing (WES) for the diagnosis of genetic diseases using current technologies. Methods: Trio‐WGS was conducted for 20 patients with developmental or epileptic encephalopathies who remained undiagnosed after WES and chromosomal microarray analysis. Results: A diagnosis was reached for four patients (20%). However, retrospectively all pathogenic variants could have been detected in a WES analysis conducted with today's methods and knowledge. Conclusion: The additional diagnostic yield of WGS versus WES is currently largely explained by new scientific insights and the general technological progress. Nevertheless, it is noteworthy that whole genome sequencing has greater potential for the analysis of small copy number and copy number neutral variants not seen with WES as well as variants in noncoding regions, especially as potentially more knowledge of the function of noncoding regions arises. We, therefore, conclude that even though today the added value of WGS versus WES seems to be limited, it may increase substantially in the future. [ABSTRACT FROM AUTHOR]

AC1‐004 is a potent inhibitor of the hypoxia‐inducible factor alpha (HIF‐1α) pathway, essential for tumour growth, angiogenesis and metastasis. We modelled a series of gold(I) complexes on AC1‐004, retaining its 5‐carboalkoxybenzimidazole as an NHC ligand while replacing its 2‐aryloxymethyl residue with modified thiolato gold(I) fragments. The intention was to augment a potential HIF‐1α inhibition by conducive effects typical of NHC gold complexes, such as an inhibition of tumoural thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), and cytotoxic and antiangiogenic effects. We report on the synthesis and biological effects of twelve such N,N'‐dialkylbenzimidazol‐2‐ylidene gold(I) complexes, obtained in average yields of 65 % for the thiophenolato and 45 % for the novel 4‐(adamant‐2‐yl)benzenethiol complexes. The structure of one complex was validated via single‐crystal X‐ray diffraction. Structure‐activity relationships (SAR) were derived by variation of the N‐substituents (Me, Et, iPr, pentyl, Bn) and the thiolato ligand. Their cytotoxicity against various human cancer cell lines of different entities reached IC50 values in the single‐digit micromolar range. The complexes were also assayed for the induction of tumour cell apoptosis (activation of caspase‐3/7), TrxR inhibition and antiangiogenic effects in zebrafish. Cyclopropene‐bearing congeners were employed in click reactions to examine the subcellular accumulation of the complexes. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. Methods: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. Results: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. Conclusions: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes. [ABSTRACT FROM AUTHOR]

Aim: There is an ongoing debate regarding the optimal timing of discontinuation of antipsychotic drugs for patients with first episode psychosis. Although most guidelines recommend maintenance therapy for at least 1 or 2 years after reaching remission, study results indicate that early discontinuation may be beneficial for at least a subsample of patients. To date, little is known about which medication strategies are applied in patients recovering from a first psychotic episode. In this study, we examined the beliefs and practices of clinicians on medication discontinuation. Methods: We performed a survey among 50 experienced Dutch psychiatrists to assess how often specific treatment strategies have been applied in the past 12 months, as well as their knowledge and expectations with respect to medication discontinuation. Results: Psychiatrists estimated that, after remission, they continued medication at the same dose for at least 12 months in 51.2% of cases, continued in a reduced dose in 33.8% of cases and discontinued medication in 9.1% of cases after 4.4 months of remission on average. Although the medication is discontinued in only a relatively small proportion of patients, almost half of all clinicians (45.9%) used this strategy at least once in the past 12 months. Conclusions: There is substantial practice variation in antipsychotic medication strategies after remission from a first psychotic episode. Future research on long‐term effects of early medication discontinuation can guide clinicians in making evidence‐based decisions when treating first‐episode patients. [ABSTRACT FROM AUTHOR]

Mixing under high pressure conditions plays a central role in several engineering applications, such as direct-injection engines and liquid rocket engines. Numerical flow simulations have become a complementary tool to study the mixing process under these conditions but require complex thermodynamic modeling as well as validation with accurate experimental data. For this reason, we use experiments of supercritical single-phase jet mixing from the literature, where the mixing is quantified by the mixture speed of sound, as a reference for our work. We here focus on the thermodynamic modeling of multi-component flows under high pressure conditions and the analytical calculation of the mixture speed of sound. Our thermodynamic model is based on cubic equations of state extended for multi-components. Using an extension of OpenFOAM, we perform large-eddy simulations of hexane and pentane injections and compare our results with the experimentally measured mixture speed of sound at specific positions. The simulation results show the same characteristic trends, indicating that the mixing effects are well reproduced in the simulations. Additionally, the effect of the sub-grid scale modeling is assessed by comparing results using different models (Smagorinsky, Vreman, and Wall-Adapting Local Eddy-viscosity). The comprehensive simulation data presented here, in combination with the experimental data, provide a benchmark for numerical simulations of jet mixing in high pressure conditions. [ABSTRACT FROM AUTHOR]

Background: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking. Results: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype–phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues. Conclusions: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID. [ABSTRACT FROM AUTHOR]

Circadian clocks are important regulators of physiology and behavior. In the brain, circadian clocks have been described in many centers of the central reward system. They affect neurotransmitter signaling, neuroendocrine circuits, and the sensitivity to external stimulation. Circadian disruption affects reward signaling, promoting the development of behavioral and substance use disorders. In this review, we summarize our current knowledge of circadian clock‐reward crosstalk. We show how chronodisruption affects reward signaling in different animal models. We then translate these findings to circadian aspects of human reward (dys‐) function and its clinical implications. Finally, we devise approaches to and challenges in implementing the concepts of circadian medicine in the therapy of substance use disorders. [ABSTRACT FROM AUTHOR]

Background and Hypothesis The social deafferentation hypothesis (SDA) has been proposed as an explanatory mechanism of hallucinations, based on the theory that social withdrawal triggers the initial phase of schizophrenia. The current study tests the SDA by assessing how loneliness is associated with different types of hallucinations. Under the SDA, increased loneliness is hypothesized to affect the occurrence of hallucinations that carry social meaning, but not of nonsocial hallucinations. Study Design As part of an online survey, 2038 adolescents and young adults from the general population (median age 21 years; 75% female) filled out the Questionnaire for Psychotic Experiences, and the shortened De Jong Gierveld Loneliness Scale. Binomial logistic regression was used to investigate the effects of loneliness severity on past month prevalence of hallucinations, and on the presence of social versus nonsocial hallucinations. Study Results Loneliness increased the prevalence of hallucinations across modalities in the past month. Moreover, stronger degree of loneliness increased the likelihood of hearing voices or laughter, and of hallucinating being touched. Conversely, loneliness decreased the likelihood of experiencing the nonsocial hallucination of a tingling feeling. As expected, loneliness did not increase the prevalence of experiencing nonsocial hallucinations. Surprisingly, neither was loneliness associated with experiencing felt presence. Conclusions Our results are novel in showing that loneliness specifically increases the likelihood of hearing human sounds such as voices or laughter, or feeling a human touch. Hallucinations without social meaning were not more likely to be experienced with increasing loneliness. This forms a confirmation of the SDA. [ABSTRACT FROM AUTHOR]

Background: Childhood trauma increases risk for psychopathology and cognitive impairment. Prior research mainly focused on the hippocampus and amygdala in single diagnostic categories. However, other brain regions may be impacted by trauma as well, and effects may be independent of diagnosis. This cross-sectional study investigated cortical and subcortical gray matter volume in relation to childhood trauma severity. Methods: We included 554 participants: 250 bipolar-I patients, 84 schizophrenia-spectrum patients and 220 healthy individuals without a psychiatric history. Participants filled in the Childhood Trauma Questionnaire. Anatomical T1 MRI scans were acquired at 3T, regional brain morphology was assessed using Freesurfer. Results: In the total sample, trauma-related gray matter reductions were found in the frontal lobe (β = −0.049, p = 0.008; q = 0.048), this effect was driven by the right medial orbitofrontal, paracentral, superior frontal regions and the left precentral region. No trauma-related volume reductions were observed in any other (sub)cortical lobes nor the hippocampus or amygdala, trauma-by-group (i.e. both patient groups and healthy subjects) interaction effects were absent. A categorical approach confirmed a pattern of more pronounced frontal gray matter reductions in individuals reporting multiple forms of trauma and across quartiles of cumulative trauma scores. Similar dose−response patterns were revealed within the bipolar and healthy subgroups, but did not reach significance in schizophrenia-spectrum patients. Conclusions: Findings show that childhood trauma is linked to frontal gray matter reductions, independent of psychiatric morbidity. Our results indicate that childhood trauma importantly contributes to the neurobiological changes commonly observed across psychiatric disorders. Frontal volume alterations may underpin affective and cognitive disturbances observed in trauma-exposed individuals. [ABSTRACT FROM AUTHOR]

Bacterial abortive-infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate1,2. Several RNA-targeting CRISPR–Cas systems (that is, types III and VI) cause abortive-infection phenotypes by activating indiscriminate nucleases3–5. However, a CRISPR-mediated abortive mechanism that leverages indiscriminate DNase activity of an RNA-guided single-effector nuclease has yet to be observed. Here we report that RNA targeting by the type V single-effector nuclease Cas12a2 drives abortive infection through non-specific cleavage of double-stranded DNA (dsDNA). After recognizing an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded RNA (ssRNA), single-stranded DNA (ssDNA) and dsDNA. Within cells, the activation of Cas12a2 induces an SOS DNA-damage response and impairs growth, preventing the dissemination of the invader. Finally, we harnessed the collateral activity of Cas12a2 for direct RNA detection, demonstrating that Cas12a2 can be repurposed as an RNA-guided RNA-targeting tool. These findings expand the known defensive abilities of CRISPR–Cas systems and create additional opportunities for CRISPR technologies.RNA targeting by the Sulfuricurvum type V single-effector nuclease SuCas12a2 drives abortive infection through non-specific cleavage of double-stranded DNA—after recognition of an RNA target through an activating protospacer-flanking sequence, SuCas12a2 efficiently degrades ssRNA, ssDNA and dsDNA. [ABSTRACT FROM AUTHOR]

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Introduction: SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants. Methods: We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8+ T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19. Results: We observed increased CD8+ T cell exhaustion in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8+ effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8+ T cells revealed heterogeneity among CD16+ NK-like CD8+ T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions. Discussion: We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8+ effector T cells, ultimately resulting in the appearance of NK-like CD8+ T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NKlike CD8+ T cells in COVID-19 severity. [ABSTRACT FROM AUTHOR]

Background: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. Methods: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. Results: Combined analysis of the mother's and daughter's duo-exome data and analysis of the mother's and her parents' trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. Conclusion: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult. [ABSTRACT FROM AUTHOR]

We study turbulent emulsions and the emulsification process in homogeneous isotropic turbulence (HIT) using direct numerical simulations (DNS) in combination with the volume of fluid method (VOF). For generating a turbulent flow field, we employ a linear forcing approach augmented by a proportional‐integral‐derivative (PID) controller, which ensures a constant turbulent kinetic energy for two phase flow scenarios and accelerates the emulsification process. For the simulations, the density ratio of dispersed and carrier phases is chosen to be similar to that of oil and water (0.9), representing a typical application. We vary the turbulence intensity and the surface tension coefficient. Thus, we modulate those parameters that directly affect the Hinze scale, which is expected to be the most stable maximum droplet diameter in emulsions in HIT. The considered configurations can be characterized with Taylor Reynolds numbers in the range of 100–140 and Weber numbers, evaluated with the velocity fluctuations and the integral length scale, of 4–70. Using the 3‐D simulation results, we study the emulsification process as well as the emulsions at a statistically stationary state. For the latter, droplet size distributions are evaluated and compared. We observe a Hinze scale similarity of the size distributions considering a fixed integral length scale, that is, similar Hinze scales obtained at different turbulence intensities or for different fluid properties result in similar distributions. [ABSTRACT FROM AUTHOR]

We study the segregation of emulsions in decaying turbulence using direct numerical simulations in combination with the volume of fluid method. To this end, we generate emulsions in forced homogeneous isotropic turbulence and then turn the forcing off and activate the gravitational acceleration. This allows us to study the segregation process in decaying turbulence and under gravity. We consider non-iso-density emulsions, where the dispersed phase is the lighter one. The segregation process is driven by both the minimization of the potential energy achieved by the sinking of the heavier phase as well as the minimization of the surface energy achieved by coalescence. To study these two processes and their impacts on the segregation progress in detail, we consider different buoyancy forces and surface tension coefficients in our investigation, resulting in five different configurations. The surface tension coefficient also alters the droplet size distribution of the emulsion. Using the three-dimensional simulation results and the monitored data, we analyze the driving mechanisms and their impact on the segregation progress in detail. We propose a dimensionless number that reflects the energy release dominating the segregation. Moreover, we evaluate the time required for the rise of the lighter phase and study correlations with the varied parameters: gravitational acceleration and surface tension coefficient. [ABSTRACT FROM AUTHOR]