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Abstract We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Abstract Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phlebovirus genus in the phenuviridae family. Its genome is trisegmented with small (S), medium (M) and large (L) fragments. In nature, the virus exists as a single serotype that is responsible for outbreaks of Rift Valley fever (RVF), a zoonotic disease that often occurs in Africa and the Middle East. RVFV genomes are thought to undergo both recombination and reassortment and investigations of these events is important for monitoring the emergence of virulent strains and understanding the evolutionary characteristics of this virus. The aim of this study was to characterize the genomes of RVFV isolates from cattle, sheep, and goats collected during an interepidemic period in Kenya between June 2016 and November 2021. A total of 691 serum samples from cattle (n = 144), goats (n = 185) and sheep (n = 362) were analysed at the Central Veterinary Laboratories. The competitive IgM-capture ELISA, was used to screen the samples; 205 samples (29.67%) tested positive for RVFV. Of the 205 positive samples, 42 (20.5%) were from cattle, 57 (27.8%) from goats, and 106 (51.7%) from sheep. All the IgM-positive samples were further analyzed by qPCR, and 24 (11.71%) tested positive with Ct values ranging from 14.788 to 38.286. Two samples, 201808HABDVS from sheep and 201810CML3DVS from cattle, had Ct values of less than 20.0 and yielded whole genome sequences with 96.8 and 96.4 coverage, respectively. There was no statistically significant evidence of recombination in any of the three segments and also phylogenetic analysis showed no evidence of reassortment in the two isolated RVFV segments when compared with other isolates of different lineages from previous outbreaks whose genomes are deposited in the GenBank. No evidence of reassortment leaves room for other factors to be the most probable contributors of change in virulence, pathogenicity and emergence of highly virulent strains of the RVFV.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9  GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36  GeV/c^{2}, rejecting cross sections above 9.2×10^{-48}  cm at the 90% confidence level.

Dedifferentiated endometrial carcinoma is a rare, highly aggressive subtype of endometrial cancer associated with poor survival outcomes. Current guidelines recommend treatment of advanced-stage disease with surgical staging or cytoreduction and platinum/taxane-based chemotherapy. Despite these approaches, the achievement of long-term remission or prolonged survival is challenging. Recent Phase III studies demonstrate that the addition of PD-1 inhibitors to standard chemotherapy significantly improves progression-free survival in patients with measurable, mismatch repair deficient (dMMR) and proficient (pMMR) advanced-stage or recurrent endometrial carcinoma. However, the role of PD-1 blockade in the treatment of undifferentiated and dedifferentiated endometrial carcinoma remains unclear, as very few patients with these cancer subtypes were included in the trials. In this case report, we present a patient with dMMR dedifferentiated endometrial carcinoma, treated with primary surgery to no gross residual disease, followed by carboplatin/paclitaxel chemotherapy and a short course of maintenance pembrolizumab. To date, the patient remains with a prolonged disease-free survival of 61 months, supporting the potential use of PD-1 inhibitors in the upfront treatment of unmeasurable, advanced-stage, dMMR dedifferentiated endometrial carcinoma.

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of the kidney following its physiological functions and link cell subtypes to genes, proteins, metabolites, and pathways. They further show that messenger RNA levels along the nephron are congruent with the subsegmental physiological activity. This reference atlas provides a framework for the classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

The reference to the article is Manuscript ID EPJC-20-06-042 from the internal review perspective. The reference to the article as published, is: (Table presented.).

Cystic fibrosis (CF) is the most common inherited, life‐limiting disorder in Caucasian populations. It is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to an impairment of protein expression and/or function. CFTR is a chloride/bicarbonate channel expressed at the apical surface of epithelial cells of different organs. Nowadays, more than 2100 CFTR genetic variants have been described, but not all of them cause CF. However, around 80–85% of the patients worldwide are characterized by the presence, at least in one allele, of the mutation F508del. CFTR mutations cause aberrant hydration and secretion of mucus in hollow organs. In the lungs, this condition favors bacterial colonization, allowing the development of chronic infections that lead to the onset of the CF lung disease, which is the main cause of death in patients. In recent years, evidence has reported that CFTR loss of function is responsible for alterations in a particular class of bioactive lipids, called sphingolipids (SL). SL are ubiquitously present in eukaryotic cells and are mainly asymmetrically located within the external leaflet of the plasma membrane, where they organize specific platforms capable of segregating a selected number of proteins. CFTR is associated with these platforms that are fundamental for its functioning. Considering the importance of SL in CFTR homeostasis, we attempt here to provide a critical overview of the literature to determine the role of these lipids in channel stability and activity, and whether their modulation in CF could be a target for new therapeutic approaches.

Abstract Background Up to 70% of breast cancer patients report symptoms of insomnia during and after treatment. Despite the ubiquity of insomnia symptoms, they are under-screened, under-diagnosed and poorly managed in breast cancer patients. Sleep medications treat symptoms but are ineffective to cure insomnia. Other approaches such as cognitive behavioral therapy for insomnia, relaxation through yoga and mindfulness are often not available for patients and are complex to implement. An aerobic exercise program could be a promising treatment and a feasible option for insomnia management in breast cancer patients, but few studies have investigated the effects of such a program on insomnia. Methods This multicenter, randomized clinical trial evaluate the effectiveness of a moderate to high intensity physical activity program (45 min, 3 times per week), lasting 12 weeks, in minimizing insomnia, sleep disturbances, anxiety/depression, fatigue, and pain, and in enhancing cardiorespiratory fitness. Patients with breast cancer be recruited from six hospitals in France and randomly allocated to either the “training” or the “control” group. Baseline assessments include questionnaires [Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index questionnaire (PSQI), Hospital Anxiety Depression Scale (HADS), Epworth Sleepiness Scale (ESS)], home polysomnography (PSG), and 7-day actigraphy coupled with completion of a sleep diary. Assessments are repeated at the end of training program and at six-month follow-up. Discussion This clinical trial will provide additional evidence regarding the effectiveness of physical exercise in minimizing insomnia during and after chemotherapy. If shown to be effective, exercise intervention programs will be welcome addition to the standard program of care offered to patients with breast cancer receiving chemotherapy. Trial registration : National Clinical Trials Number (NCT04867096).

This study compares students’ TPACK at the beginning and at the end of their college education according to their involvement and the number of computer science courses. Research was conducted at the Faculty of Education in Osijek, Croatia, with the same generation of students, in 2015 (N=71) and 2020 (N=43). The results showed a statistically significant difference for Technological, Pedagogical and Content Knowledge, for all students in the sample and for students with additional computer science courses. In the case of overall TPACK, there is no difference for the overall sample of students but for students with additional computer science courses, the difference is significant.

Belatacept offers superior long-term outcome relative to calcineurin inhibitor (CNI)-based immunosuppression. However, the higher frequency of early T cell-mediated rejection (TCMR) in belatacept-treated patients hampered the widespread adoption of costimulation blockade. Here, we applied gene expression analysis and whole-slide inflammatory cell quantification to assess the impact of belatacept on intragraft immune signature. We studied formalin-fixed, paraffin-embedded renal biopsies from 92 patients stratified by histopathologic diagnosis (TCMR, borderline changes, or normal) and immunosuppression regimen (belatacept, CNI). An interaction model was built to explore maintenance treatment-dependent expression level changes of immune response-related genes across diagnostic categories of normal, borderline changes, and TCMR. Ninety-one percent of genes overexpressed in TCMR showed significant correlation with whole section inflammatory load. There were 27 genes that had a positive association with belatacept treatment. These were mostly related to myeloid cells and innate immunity. Genes negatively associated with costimulation blockade (n = 14) could be linked to B-cell differentiation and proliferation. We concluded that expression levels of genes characteristic of TCMR are strongly interconnected with quantitative changes of the biopsy inflammatory load. Our results might suggest differential involvement of the innate immune system, and an altered B-cell engagement during TCMR in belatacept-treated patients relative to CNI-treated referents.

LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above 1.4×10-48cm2 for a WIMP mass of 40GeV/c2 and a 1000days exposure. LZ achieves this sensitivity through a combination of a large 5.6t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.

PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4×10-48 cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3×10-43 cm2 (7.1×10-42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020.

We describe the design and assembly of the LUX-ZEPLIN experiment, a direct detection search for cosmic WIMP dark matter particles. The centerpiece of the experiment is a large liquid xenon time projection chamber sensitive to low energy nuclear recoils. Rejection of backgrounds is enhanced by a Xe skin veto detector and by a liquid scintillator Outer Detector loaded with gadolinium for efficient neutron capture and tagging. LZ is located in the Davis Cavern at the 4850’ level of the Sanford Underground Research Facility in Lead, South Dakota, USA. We describe the major subsystems of the experiment and its key design features and requirements.

BackgroundThe role of the soluble urokinase plasminogen activator receptor (suPAR) in focal segmental glomerulosclerosis (FSGS) as the circulating factor or as a predictor of recurrence after transplantation remains controversial. Previously published studies in mice and isolated podocytes produced conflicting results on the effect of suPAR on podocyte injury, effacement of foot processes, and proteinuria. These discordant results were in part due to diverse experimental designs and different strains of mice. The aim of our study was to determine the reasons for the inconsistencies of the previous studies results with suPAR by using uniform methods and studies in different strains of mice.MethodsWe utilized a primary culture of human podocytes and 2 mouse models, the wild type (WT) and the urokinase plasminogen activator receptor (uPAR) KO (uPAR), in an attempt to resolve the reported conflicting results.ResultsIn both WT and uPAR mouse models, injection of recombinant uPAR, even at a high dose (100 μg), did not induce proteinuria, effacement of podocytes, or disruption of the cytoskeleton. Injection of suPAR resulted in its deposition exclusively in the glomerular endothelial cells and not in the podocytes of WT mice and was not detected at the uPAR KO mice. Kidneys from patients with recurrent FSGS had negative immunostaining for uPAR. We also evaluated the effect of recombinant uPAR on primary culture of human podocytes. uPAR did not result in podocytes damage.ConclusionssuPAR by itself is not the cause for direct podocyte injury, in vitro or in vivo. These findings suggest a more complex and still poorly understood role of suPAR in FSGS.

A fuel cell (FC) is one of the most viable solutions to the current energy crisis and environmental pollution problem. It can be applied in power generation, portable power supply, as well as in hybrid vehicles. Due to the versatile nature of this energy source and non-dependency over the environmental conditions, FCs can be a significant source of alternative energy source in the future. Researchers are working on power conversion topologies and control strategies development for FC application for the past decade. However, the latest summary of the progress in this sector is not available in the literature. This article is aimed at discussing the various control techniques and energy management systems reported in the literature. The configurations are categorized according to their nature, application area, and performance. Different energy management strategies used in fuel cell-based systems are considered here for the qualitative analysis. The essential characteristics such as the advantages, disadvantages, and improvement opportunities of various energy management strategies of fuel cell vehicles are discussed from the control system point of view. Finally, the recent trends in the development of fuel cell hybrid energy management systems are presented to improve the performance based on the above qualitative analysis. This article will help the researchers in this field to know the current status, future trend and the future research directions in fuel cell research for power generation.

Abstract Background Concomitant occurrence of anti-GBM disease and anti-PLA2R positive membranous nephropathy have been previously described. However, to the best of our knowledge, this is the first case report that documents the co-occurrence of the diseases proven by both serologic and histologic methods. Case presentation A 51-year-old woman presented to hospital with nausea, bilateral lower extremity edema, dyspnea, dark urine, and then anuria. Symptoms developed one month after an upper respiratory tract infection. Laboratory results showed acute kidney injury, and hypoalbuminemia. Immunologic examination revealed both anti-GBM and anti-PLA2R positivity. Kidney biopsy demonstrated the histological features of Goodpasture’s disease and anti-PLA2R positive membranous nephropathy. Steroid, cyclophosphamide, and plasmapheresis were commenced. Despite the combined immunosuppressive, the patient remained on renal replacement therapy. Conclusions Microbial kidney injury can trigger multiple autoimmune diseases. The simultaneous occurrence of anti-glomerular basement (anti-GBM) disease and membranous nephropathy is extremely rare. Delayed recognition leads to delayed treatment, causing worse renal and patient outcomes, as well as increased financial costs.

Abstract Straightforward and general Passerini and Ugi procedures have been developed to incorporate four‐membered heterocycles into highly functionalized scaffolds. Additionally, toslymethyl isocyanide (TosMIC)‐derived Ugi adducts have been prepared, showcasing the prospect of the multicomponent reaction.

Notre recherche s’inscrit dans le cadre théorique de la textologie sémiotique, visant à appréhender le sens textuel et ses modalités de représentation en élargissant le champ traditionnel de la linguistique textuelle et en utilisant des outils variés. À cette fin, elle introduit le concept de ‘constringence’ parmi les termes classiquement associés à la cohérence textuelle, tels que la connexité grammaticale et la cohésion sémantique. Ce concept, complémentaire aux catégories caractérisant le plan linguistique du texte, vise à décrire le processus mental du récepteur lors de l’interprétation des faits supposés exprimés dans le texte. L’étude poursuit deux objectifs principaux. Elle cherche d’une part à évaluer l’applicabilité de la représentation sémiotique textuelle, notamment la catégorie de la constringence, dans l’analyse du sens des textes français, ainsi que les perspectives nouvelles qu’elle offre en tant que méthode d’analyse. D’autre part, elle examine comment les thésaurus documentaires traitant les schémas conceptuels peuvent contribuer à l’étude de la constringence et à la représentation du sens des textes français.

Background: There is an urgent need to develop and implement low cost, high-throughput standardized methods for routine molecular assessment of transplant biopsies. Given the vast archive of formalin-fixed and paraffin-embedded (FFPE) tissue blocks in transplant centers, a reliable protocol for utilizing this tissue bank for clinical validation of target molecules as predictors of graft outcome over time, would be of great value. Methods: We designed and optimized assays to quantify 19 target genes, including previously reported set of tissue common rejection module (tCRM) genes. We interrogated their performance for their clinical utility for detection of graft rejection and inflammation by analyzing gene expression microarrays analysis of 163 renal allograft biopsies, and subsequently validated in 40 independent FFPE archived kidney transplant biopsies at a single center. Results: A QPCR (Fluidigm) and a barcoded oligo-based (NanoString) gene expression platform were compared for evaluation of amplification of gene expression signal for 19 genes from degraded RNA extracted from FFPE biopsy sections by a set protocol. Increased expression of the selected 19 genes, that reflect a combination of specific cellular infiltrates (8/19 genes) and a graft inflammation score (11/19 genes which computes the tCRM score allowed for segregation of kidney transplant biopsies with stable allograft function and normal histology from those with histologically confirmed acute rejection (AR; p = 0.0022, QPCR; p = 0.0036, barcoded assay) and many cases of histological borderline inflammation (BL). Serial biopsy shaves used for gene expression were also processed for in-situ hybridization (ISH) for a subset of genes. ISH confirmed a high degree of correlation of signal amplification and tissue localization. Conclusions: Target gene expression amplification across a custom set of genes can identify AR independent of histology, and quantify inflammation from archival kidney transplant biopsy tissue, providing a new tool for clinical correlation and outcome analysis of kidney allografts, without the need for prospective kidney biopsy biobanking efforts.