Complete genome sequence of Candidatus Ruthia magnifica

The hydrothermal vent clam Calyptogena magnifica (Bivalvia: Mollusca) is a member of the Vesicomyidae. Species within this family form symbioses with chemosynthetic Gammaproteobacteria. They exist in environments such as hydrothermal vents and cold seeps and have a rudimentary gut and feeding groove, indicating a large dependence on their endosymbionts for nutrition. The C. magnifica symbiont, Candidatus Ruthia magnifica, was the first intracellular sulfur-oxidizing endosymbiont to have its genome sequenced (Newton et al. 2007). Here we expand upon the original report and provide additional details complying with the emerging MIGS/MIMS standards. The complete genome exposed the genetic blueprint of the metabolic capabilities of the symbiont. Genes which were predicted to encode the proteins required for all the metabolic pathways typical of free-living chemoautotrophs were detected in the symbiont genome. These include major pathways including carbon fixation, sulfur oxidation, nitrogen assimilation, as well as amino acid and cofactor/vitamin biosynthesis. This genome sequence is invaluable in the study of these enigmatic associations and provides insights into the origin and evolution of autotrophic endosymbiosis

A tracer study of the Arctic Ocean's liquid freshwater export variability

We present an analysis of the variability of the liquid Arctic freshwater (FW) export, using a simulation from the Community Climate System Model Version 3 (CCSM3) that includes passive tracers for FW from different sources. It is shown that the FW exported through the western Canadian Arctic Archipelago (CAA) comes mainly from the Pacific and from North American runoff. The variability of the FW export from both of these sources is generally in phase, due to the strong influence of variations of the velocity anomaly on the CAA FW export variability. The velocity anomaly in the CAA is in turn mainly governed by variations in the large-scale atmospheric circulation (i.e., the Arctic Oscillation). In Fram Strait, the FW export is mainly composed of Eurasian runoff and FW of Pacific origin. The variability of the Fram Strait FW export is governed both by changes in the velocity and in the FW concentration, and the variability of the FW concentration from the two largest sources is not in phase. The Eurasian runoff export through Fram Strait depends strongly on the release of FW from the Eurasian shelf, which occurs during years with an anticyclonic circulation anomaly (negative Vorticity index) and takes 3 years to reach Fram Strait after leaving the shelf. In contrast, the variability of the Pacific FW export through Fram Strait is mainly controlled by changes in the Pacific FW storage in the Beaufort Gyre, with an increased export during years with a cyclonic circulation anomaly (positive Vorticity index)

Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens

There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression of plasticity-related molecules were examined in the NAc of rats displaying anhedonic behavior (measured in the sucrose-consumption test) in response to chronic mild stress. To demonstrate the relevance of our measurements to depression, we tested whether the observed changes were sensitive to reversal with antidepressants (imipramine and fluoxetine). Data show that animals displaying anhedonic behavior display an hypertrophy of medium spiny neurons in the NAc and, in parallel, have increased expression of the genes encoding for brain-derived neurotrophic factor, neural cell adhesion molecule and synaptic protein synapsin 1. Importantly, the reversal of stress-induced anhedonia by antidepressants is linked to a restoration of gene-expression patterns and dendritic morphology in the NAc. Using an animal model of depression, we show that stress induces anhedonic behavior that is associated with specific changes in the neuronal morphology and in the gene-expression profile of the NAc that are effectively reversed after treatment with antidepressants.The present work was funded by the Portuguese Foundation for Technology (FCT), project PTDC/SAU-NEU/105180/2008. FM and PL are recipients of postdoctoral fellowships and MM is recipient of a doctoral fellowship, all from FCT, Portugal

Oleic Acid Exhibits Anti-Proliferative and Anti-Invasive Activities via the PTEN/AKT/mTOR Pathway in Endometrial Cancer

Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the LKB1fl/flp53fl/fl mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the LKB1fl/flp53fl/fl mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer

Understanding the Interplay Among Regulatory Self-Efficacy, Moral Disengagement, and Academic Cheating Behaviour During Vocational Education: A Three-Wave Study

The literature has suggested that to understand the diffusion of unethical conduct in the workplace, it is important to investigate the underlying processes sustaining engagement in misbehaviour and to study what occurs during vocational education. Drawing on social-cognitive theory, in this study, we longitudinally examined the role of two opposite dimensions of the self-regulatory moral system, regulatory self-efficacy and moral disengagement, in influencing academic cheating behaviour. In addition, in line with the theories highlighting the bidirectional relationship between cognitive processes and behaviour, we aimed to also examine the reciprocal influence of behaviour on these dimensions over time. Overall, no previous studies have examined the longitudinal interplay between these variables. The sample included 866 (62.8% female) nursing students who were assessed three times annually from the beginning of their vocational education. The findings from a cross-lagged model confirmed that regulatory self-efficacy and moral disengagement have opposite influences on cheating behaviour, that regulatory self-efficacy negatively influences not only the engagement in misconduct but also the justification mechanisms that allow the divorce between moral standards and action, and that moral disengagement and cheating behaviour reciprocally support each other over time. Specifically, not only did moral disengagement influence cheating behaviour even when controlling for its prior levels, but also cheating behaviour affected moral disengagement one year later, controlling for its prior levels. These findings suggest that recourse to wrongdoing could gradually lead to further normalising this kind of behaviour and morally desensitising individuals to misconduct

Young carers in Germany: to live on as normal as possible – a grounded theory study

<p>Abstract</p> <p>Background</p> <p>In contrast to a growing body of research on the situation of adult family care givers, in Germany hardly anything is known about the situation of children and teenagers who are involved in the care of their relatives.</p> <p>Methods</p> <p>In this Grounded Theory study 81 semi structured interviews have been carried out with children and their parents in 34 families, in which one member is chronically ill. 41 children and 41 parents participated and the sample is heterogeneous and diverse.</p> <p>Results</p> <p>On the one hand, there is the phenomenon 'keeping the family together", which describes how families themselves cope with the chronic illness and also, which tasks to what extent are being shifted and redistributed within the family in order to manage daily life. Influencing factors, the children's motives as well as the impact on the children also belong to this phenomenon. The second phenomenon 'to live a normal course of life' describes concrete wishes and expectations of support for the family to manage the hindered daily life. These two phenomena linked together constitute the 'model of experience and construction of familial care, in which children take over an active role'.</p> <p>Conclusion</p> <p>It will be discussed, that the more families are in dire need of support, the more their distress becomes invisible, furthermore, that management of chronic illness is a process, in which the entire family is involved, and thus needs to be considered, and finally, that young carer's relief is not possible without relief of their parents.</p

Homologous Recombination Deficiency Should Be Tested for in Patients With Advanced Stage High-Grade Serous Ovarian Cancer Aged 70 Years and Over

OBJECTIVE: Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group. METHODS: From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (\u3c 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed). RESULTS: Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [p \u3c 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [p \u3c 0.001]. gBRCA PVs observed in 24% younger vs 8% of older participants (p \u3c 0.001); sBRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to gBRCA was 35% vs 31% (p = 0.36). CONCLUSIONS: HRD frequency was similar in participants aged \u3c 70 and ≥ 70 years (35% vs 31%) when the contribution of gBRCA was excluded; rates of sBRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications

State of the science and future directions for research on HIV and cancer : Summary of a joint workshop sponsored by IARC and NCI

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice