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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.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as “tightjunctionopathies.”

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.

Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth (MTT assay), effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.

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.

Accumulation of plastic in aquatic environments negatively impacts ecosystems and human livelihood. Urban areas are assumed to 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 is 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 to enter 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 no strong 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 behavioural change geared to reduce plastic pollution in urban environments.

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency.ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders.To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization.The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel Na(V)1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that Na(V)1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower Na(V)1.2 protein levels. In neurons with the frameshift variant, Na(V)1.2 mRNA and protein levels were reduced by similar to 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying Na(V)1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced Na(V)1.2 levels. In contrast, epilepsy neurons displayed no change in Na(V)1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced Na(V)1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to Na(V)1.2 dysfunction and can guide further investigations., Human Molecular Genetics, 32 (13), ISSN:0964-6906, ISSN:1460-2083

Auf dem Weg zur Klimaneutralität stellt die Umstellung der Prozesswärmebereitstellung in der Industrie eine bedeutende Stellschraube dar: 67 % des Endenergiebedarfs der deutschen Industrie und damit fast 20 % des gesamten deutschlandweiten Endenergiebedarfs werden für Prozesswärme benötigt [1]. Ein enormes Potenzial für die Wärmewende und den Klimaschutz, das es zu heben und in sektorenübergreifenden ganzheitlichen Wärmekonzepten mitzudenken gilt.

A knowledge of the morphology of seeds and diaspores is an invaluable resource that has prompted the compilation of descriptions and/or images in a variety of media, including databases with standardized protocols for trait measurement. The pressing need for new solutions to solve environmental crises, together with advances in the application of machine learning and image analysis to solve ecological problems, call for an upgrade of the diaspore morphological datasets. Here, we present DiasMorph, a dataset of morphological traits and images of diaspores from 1,437 taxa in 513 genera, and 96 families from Central Europe, totalling 94,214 records. Moreover, DiasMorph compiles information on quantitative morphological traits extracted from the images following a standardized and reproducible image analysis method, and include not only traditional morphometric measurements, but also colour, and shape features made available for the first time in a large dataset. The quantitative traits records correspond to measurements of individual diaspores, an input currently unavailable in traits databases that will allow for several approaches to be used for a complete exploration of the morphological traits of these species. We also included information on the presence and absence of appendages and structures in the diaspores of the evaluated taxa. 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. Keywords: diaspore appendages, dispersal unit, image dataset, plant traits dataset, seed colour, seed morphology, seed shape, seed size, seed traits.

An online scenario-based experiment to investigate gossip and its short-term affective experiences for the gossip participants

Supplementary Material 1

Drawing on conservation of resources theory, we developed and evaluated a supportive leadership training (SLT) intervention designed to teach leaders ways to be supportive of their employees. Given the important role of supportive leaders in helping employees deal with excessive workloads, we theorized that the beneficial intervention effects on employee well-being would be particularly evident for employees who perceive higher levels of quantitative and qualitative workloads prior to the intervention. Using a cluster randomized controlled field trial, we tested the effects of the SLT on employee social well-being in terms of leader-member exchange (LMX) quality and employee hedonic well-being, including positive affective well-being, emotional exhaustion, and job satisfaction. The participants in the training were directors of childcare centers in Germany. To rigorously evaluate the intervention effects at the employee level, we collected survey data at baseline, 1 month postintervention, and 6 months postintervention, and we used an intent-to-treat approach to analyze the data. A total of 496 employees from 77 childcare centers provided data at baseline, of whom 266 and 226 employees participated in the 1-month and 6-month surveys, respectively. Linear mixed-effects models showed that the effectiveness of the intervention in terms of LMX quality and emotional exhaustion varied depending on the employees' baseline perceptions of quantitative workloads, such that employees with higher quantitative workloads benefited more from the SLT. The findings of this study improve the understanding of the types of outcomes of SLT and contribute to clarifying for whom SLT is effective. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Heterozygous gain-of-function variants inWhole-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.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 theThe report highlights the specific pitfalls of molecular genetic analysis of

Ammonia excretion in fish excretory epithelia is a complex interplay of multiple membrane transport proteins and mechanisms. Using the model system of zebrafish (Danio rerio) larvae, here we identified three paralogues of a novel ammonia transporter, hippocampus-abundant transcript 1 (DrHiat1), also found in most vertebrates. When functionally expressed in Xenopus laevis oocytes, DrHiat1a and DrHiat1b promoted methylamine uptake in a competitive manner with ammonia. In situ hybridization experiments showed that both transporters were expressed as early as the 4-cell stage in zebrafish embryos and could be identified in most tissues 4 days post-fertilization. Larvae experiencing morpholino-mediated knockdown of DrHiat1b exhibited significantly lower whole-body ammonia excretion rates compared with control larvae. Markedly decreased site-specific total ammonia excretion of up to 85% was observed in both the pharyngeal region (site of developing gills) and the yolk sac (region shown to have the highest NH4+ flux). This study is the first to identify DrHiat1b/DrHIAT1 in particular as an important contributor to ammonia excretion in larval zebrafish. Being evolutionarily conserved, these proteins are likely involved in multiple other general ammonia-handling mechanisms, making them worthy candidates for future studies on nitrogen regulation in fishes and across the animal kingdom.

Deforestation and forest degradation remain huge global environmental challenges. Over the last decades, various forest governance initiatives and institutions have evolved in global response to interlinked topics such as climate change mitigation, biodiversity conservation, indigenous rights, and trade impacts – accompanied by various levels of academic attention. Using a Delphi methodology that draws on both policy and academic insights, we assess the currently perceived state of play in global forest governance and identify possible future directions. Results indicate that state actors are seen to be key in providing supportive regulatory frameworks, yet interviewees do not believe these will be established at the global scale. Rather, respondents point to issue-specific, regional and inter-regional coalitions of the willing, involving the private sector, to innovate global forest governance. Linking forest issues with high politics may hold promise, as demonstrated by initiatives regarding illegal logging and timber trade. Confident rule-setting in support of the public good as well as responsible investments are seen as further avenues. New forest governance “hypes”, if used strategically, can provide leverage points and resources to ensure sustainability effects on the ground. At the same time, informal markets are often crucial for governance outcomes and need consideration. As such, clarifying tenure in sovereignty-sensitive ways is important, as are innovative ways for inclusive “glocal” decision-making. Lastly, new technologies, big data and citizens’ capacities are identified as potent innovation opportunities, for making global dependencies between consumption, production and deforestation visible and holding players accountable across the value chains.

Systemic immunoglobulin light chain (AL) amyloidosis is a rare but fatal disease. It results from clonal proliferation of plasma cells with excessive production of insoluble misfolded proteins that aggregate in the extracellular matrix, causing damage to the normal architecture and function of various organs. For decades, treatment for AL amyloidosis was based mainly on therapeutic agents previously studied for its more common counterpart, multiple myeloma. As the prevalence and incidence of AL amyloidosis have increased, ongoing research has been conducted with treatments typically used in myeloma with varying success. In this review, we focus on current treatment strategies and updates to clinical guidelines and therapeutics for AL amyloidosis.

Scientists have developed and deployed successive generations of genome engineering technologies for use in plants, including meganucleases, zinc finger nucleases, TAL effector nucleases, and CRISPR nucleases. Each of these tools has been hailed as potentially revolutionary, capable of providing more efficient and precise ways to modify plant genomes toward improving agronomic traits or making fundamental discoveries. The CRISPR nucleases, in particular, have accelerated the pace of innovation and expanded the boundaries of what is achievable within the plant research space. This review will take care to discuss current plant genome engineering technologies, covering both well-established and up-and-coming tools, as well as describe potential and real-world applications.

A systematic review focusing on the conceptualization, measurement and antecedents of workplace gossip

Based on the promising

Snacking of small quantities of palatable food items throughout the day is common in modern societies and is promoted by 24/7 lifestyles. Long-term mistimed high-caloric food intake disrupts endogenous circadian rhythms and supports the development of obesity and other metabolic disorders. However, less is known about the time-of-day dependent effects of snacking. We hypothesized that already a single snacking episode may affect the circadian regulation of metabolic parameters, in particular when the snack is consumed during the daily rest phase. We performed an acute snack experiment in mice by providing access to chow or chocolate either at day- or nighttime and assessed snack effects on core body temperature, locomotor activity, and gene expression in metabolic tissues. Our results show that daytime chocolate snacking leads to a higher body temperature and locomotor activity increase compared to chow and nighttime intake. This goes along with altered clock and metabolic gene expression in peripheral tissues. Changes in nutrient uptake transporter gene expression in the small intestine suggest increased glucose resorption after daytime snacking. Our results indicate an early mechanism for the adipogenic effect of mistimed high-calorie snacking.

Background:Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in >7000 individuals.Methods:Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher’s exact tests and logistic regression analyses were used.Results:Study of N=7025 subjects (55.8% male; 41±16 years) revealed N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR=1.303; 95% CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) was seen for most AB (e.g. amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR=1.55; 95% CI [1.058-2.271]) and disease likelihood (OR=1.43; 95% CI [1.032-1.985]). APOE4 carriers (∼19%) had lower seropositivity (OR=0.766; 95% CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR=1.599; 95% CI [1.022-2.468]).Conclusions:Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease.

Thorn Apple or Jimson Weed (Datura stramonium) is a tropane alkaloid containing widespread pest plant growing in central Europe. This pest predominantly occurs in millet, buckwheat and maize cultivation. Therefore, sound cleaning of these crops is just as pivotal as reliable analytics. The cleaning of millet at laboratory scale with commercial mechanical cleaning devices, such as sieves, indented separators or table sorters without using colour sorters, reduces the dark coloured Datura seed content by up to 99%. Nevertheless, the few remaining Datura seeds (up to one nut per 30 kg) could lead to an exceedance of the European Union (EU) limit values for tropane alkaloids in baby food. However, plant material other than seeds or even invisible abrasion of Datura seeds can contaminate the millet during harvest, handling, cleaning processes or crop transportation. Contamination originating from adhesive dust can be removed by dehulling the kernels, and a reduction below the EU detection limit could be achieved.

Das stetig zunehmende volatile Marktumfeld verlangt unter anderem nach hoher Effektivität der eigenen Produktion, um international wettbewerbsfähig zu bleiben. Die zur Steigerung der Anlagenverfügbarkeit beitragende Digitalisierung von Produktionsanlagen findet im Maschinen- und Anlagenbau dennoch nur zögerlich Anwendung. Auf Basis einer Unternehmensbefragung wurden die Anforderungen an digitale Nachrüstlösungen analysiert, Diskrepanzen zu bestehenden Systemen abgeleitet und Bedarfe sowie mögliche Lösungen bei der Digitalisierung von Produktionsanlagen aufgezeigt. The continuously increasing volatile market environment calls for a high level of efficiency in a company‘s production system to remain internationally competitive. Although the digitalization of production facilities contributes to an increasing plant availability, it is only hesitantly applied in the mechanical and plant engineering sector. Based on a company survey, the requirements for digital retrofit solutions are analyzed, discrepancies with existing systems derived, and demands as well as possible solutions for the digitalization of production plants presented.

Imprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances. The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements. Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.

Innere, sog. zirkadiane Uhren regulieren zahlreiche Korperfunktionen – darunter unseren Schlaf-Wach-Rhythmus – im 24-h-Takt. Wahrend die Funktion des zirkadianen Systems in der Regulation der Phasenlage des Schlafs (Prozess C) lange bekannt war, zeigen neuere Studien eine weit engere Verknupfung von Uhrensystem und Schlaffunktion auf mehreren Ebenen. Genetische Defekte im molekularen Uhrwerk haben Auswirkungen auf den Schlafhomoostat (Prozess S). Umgekehrt wirken Anderungen im naturlichen Schlafzyklus zuruck auf die Funktion der zirkadianen Uhr – und das nicht nur im zentralen Nervensystem (ZNS), sondern insbesondere auch in peripheren Organen. Dieser Schlaf-Uhr-Crosstalk konnte viele der negativen Effekte von Rhythmus- und Schlafstorungen auf den Energiestoffwechsel erklaren. Gleichzeitig bietet er neue Ansatzpunkte fur die Pravention und Behandlung von schlafassoziierten pathologischen Effekten, z. B. bei Schichtarbeitern. Dieser Ubersichtsartikel beschreibt die Interaktion von Uhrensystem und Schlaf-Regelkreisen im ZNS und deren Effekte auf periphere physiologische Prozesse, insbesondere den Energiestoffwechsel. Er skizziert ein Modell der engen Kopplung von Schlaf und Uhrenfunktion und deren Bedeutung als Angriffspunkt fur die Behandlung von durch Schlafstorungen bedingte Erkrankungen.

Background Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer. Methods To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days. Results Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner. Conclusions Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.

Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. Objective The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. Design, Setting, Patients Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. Results Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. Conclusions Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Background The implementation of quality of life (QoL) concepts in routine care, is still an open matter. We followed the Medical Research Council framework for complex interventions to implement a model of QoL diagnosis and therapeutic options, and investigated its effectiveness in patients with colorectal cancer. Methods This randomised, single-blind, multicentre, clinical trial enrolled patients diagnosed with primary colorectal cancer aged 18 years or older who were surgically treated in one of four recruiting hospitals in Germany. All patients received aftercare from one of 178 coordinating practitioners (CPs) who had access to 75 healthcare professionals providing tailored therapies. QoL was measured (EORTC QLQ-C30, QLQ-CR29) in all patients after surgery (baseline) and during aftercare (3, 6, 12, 18 months). Patients were randomised (1:1) into two groups: a care pathway, including QoL-profiles consisting of 13 QoL scales plus specific therapeutic recommendations forwarded to the patient’s CP or standard postoperative care adhering to the German national guideline for colorectal cancer (control). The primary endpoint was the proportion of patients in each group with a need for QoL therapy 12 months after surgery. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT02321813 and closed to accrual. Findings Between Jan 13, 2014, and Oct 28, 2015, 220 patients were enrolled and randomly assigned (n = 110 per group). At baseline (in hospital after surgery), a need for QoL therapy was diagnosed in 92/103 (89%) of intervention and 86/104 (83%) of control group patients. At 12 months (primary endpoint) the proportion of patients with a need for QoL therapy was 35/83 (42%; 95% CI 31–54%) in the intervention group versus 50/87 (57%; 95% CI: 46–68%) in the control group (p = 0·046, number needed to treat = 7; 95% CI 3–225). Interpretation Patients profited from the diagnosis of QoL deficits and tailored therapeutic options in their treatment of colorectal cancer. This trial confirmed the results of a previous RCT in breast cancer patients. The implementation of QoL concepts should become standard in treatment guidelines on cancer care. Funding Federal Ministry of Education and Research (BMBF; grant no. 01GY1339). Clinical trial information NCT02321813.

Bacterial abortive-infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate

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 (e.g., types III and VI) cause Abi phenotypes by activating indiscriminate RNases3–5. However, a CRISPR-mediated abortive mechanism that relies on indiscriminate DNase activity has yet to be observed. Here we report that RNA targeting by the type V Cas12a2 nuclease drives abortive infection through non-specific cleavage of double-stranded (ds)DNA. Upon recognition of an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded (ss)RNA, ssDNA, and dsDNA. Within cells, the dsDNase activity induces an SOS response and impairs growth, stemming the infection. 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 capabilities of CRISPR-Cas systems and create additional opportunities for CRISPR technologies.