Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of BRCA2 DNA-binding and C-terminal domain in its mobility and conformation in DNA repair

Breast cancer type two susceptibility protein (BRCA2) is an essential protein in genome maintenance, homologous recombination (HR), and replication fork protection. Its function includes multiple interaction partners and requires timely localization to relevant sites in the nucleus. We investigated the importance of the highly conserved DNA-binding domain (DBD) and C-terminal domain (CTD) of BRCA2. We generated BRCA2 variants missing one or both domains in mouse embryonic stem (ES) cells and defined their contribution in HR function and dynamic localization in the nucleus, by single-particle tracking of BRCA2 mobility. Changes in molecular architecture of BRCA2 induced by binding partners of purified BRCA2 were determined by scanning force microscopy. BRCA2 mobility and DNA-damage-induced increase in the immobile fraction were largely unaffected by C-terminal deletions. The purified proteins missing CTD and/or DBD were defective in architectural changes correlating with reduced HR function in cells. These results emphasize BRCA2 activity at sites of damage beyond promoting RAD51 delivery.
Measuring Early Childhood Educators’ Physical Activity and Sedentary Behavior–Related Self-Efficacy: A Systematic Review of Tools

Early childhood educators’ (ECEs) self-efficacy is often predictive of their ability and likelihood of promoting healthy activity behaviors in childcare settings. To date, ECEs’ physical activity and sedentary behavior–related self-efficacy has been measured in a variety of ways in childcare-based research, creating difficulty when comparing across studies. To identify the different approaches ECEs’ self-efficacy is assessed, the current study aimed to compare all existing tools that quantitatively measure physical activity and sedentary behavior–related self-efficacy of pre- and in-service ECEs. Seven online databases were searched for original, peer-reviewed, English-written journal articles. Articles were deemed eligible if they employed a tool which measured physical activity and/or sedentary behavior–related self-efficacy of pre- or in-service ECEs. A total of 16 studies were included in this review, and 13 unique tools were identified. All tools measured task self-efficacy (n = 13), while only 1 tool measured barrier self-efficacy, and approximately half of the tools (n = 7; 54%) reported on the validity and reliability. Great variability existed among the self-efficacy items included in the tools; however, common constructs included: teaching/leading physical activity, fundamental movement skill development, and physical activity programming. Very few tools mentioned sedentary behavior (n = 2) and outdoor/risky play (n = 2). Given the low number of studies that tested validity and reliability of their self-efficacy tools, the lack of consideration for barrier self-efficacy, and the paucity of tools that fully encompassed physical activity, sedentary behavior, and outdoor play considerations for ECEs, future research is needed to validate a new, reliable tool.
Strawberry fruit (Fragaria x ananassa Romina) juice attenuates oxidative imbalance with concomitant modulation of metabolic indices linked to male infertility in testicular oxidative injury

This study investigated the protective properties of strawberry fruit on testicular oxidative injury. Oxidative injury was induced in vitro in testicular tissue homogenates by incubation with ferrous sulphate (FeSO4) in the presence and absence of strawberry fruit extract (SFE) for 30 min at 37˚C, with gallic acid serving as the standard antioxidant drug. Induction of oxidative injury significantly reduced glutathione, cholesterol and triglyceride levels; and inhibited SOD, catalase and ENTPDase activities when compared to normal control. It also led to exacerbated nitric oxide, malondialdehyde, LDL‐cholesterol levels, acetylcholinesterase, ATPase and lipase activities. These effects were, however, reversed following treatment with SFE when compared to the untreated control, except for cholesterol and triglyceride levels. Additionally, the induction of the oxidative injury led to alterations in testicular lipid metabolites that were accompanied by the activation of α‐linolenic acid and linoleic acid metabolic pathways. While SFE treatment had no significant impact on the altered metabolites, it repressed pathways for mitochondrial beta‐oxidation of long‐chain saturated fatty acids and plasmalogen synthesis. High‐performance liquid chromatography analysis of SFE revealed the presence of rutin, caffeic acid, p‐coumarin and cinnamic acid. These data imply the protective potentials of strawberry fruits against testicular oxidative injury.
Overcoming Intrinsic Resistance of Cancer Cells to CAR T-Cell Killing

In the past few years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for cancers that failed standard treatments. Such therapies have already been approved in several blood cancers, such as B-cell leukemia and lymphoma. Despite this progress, a significant proportion of patients experience primary or secondary resistance to CAR T-cell therapy. Here, we review the mechanisms by which CAR T cells eliminate their target and how cancer cells may be insensitive to such killing (here referred to as intrinsic resistance). Recent studies suggest that the activation of apoptosis through death receptor signaling is responsible for a major part of CAR T-cell cytotoxicity in vivo. Indeed, cancer cells harboring aberrant apoptotic machinery may be insensitive to CAR T-cell killing. This intrinsic resistance of cancer cells to CAR T-cell killing could be responsible for a significant portion of treatment failure. Finally, we discuss strategies that may be envisioned to overcome such resistance to enhance CAR T-cell efficacy.
D-MANOVA: fast distance-based multivariate analysis of variance for large-scale microbiome association studies

SUMMARY PERMANOVA (permutational multivariate analysis of variance based on distances) has been widely used for testing the association between the microbiome and a covariate of interest. Statistical significance is established by permutation, which is computationally intensive for large sample sizes. As large-scale microbiome studies such as American Gut Project (AGP) become increasingly popular, a computationally efficient version of PERMANOVA is much needed. To achieve this end, we derive the asymptotic distribution of the PERMANOVA pseudo-F statistic and provide analytical p-value calculation based on chi-square approximation. We show that the asymptotic p-value is close to the PERMANOVA p-value even under a moderate sample size. Moreover, it is more accurate and an order-of-magnitude faster than the permutation-free method MDMR. We demonstrated the use of our procedure D-MANOVA on the AGP dataset. AVAILABILITY D-MANOVA is implemented by the dmanova function in the CRAN package GUniFrac. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Integration of sleep homeostasis and navigation in Drosophila

During sleep, the brain undergoes dynamic and structural changes. In Drosophila, such changes have been observed in the central complex, a brain area important for sleep control and navigation. The connectivity of the central complex raises the question about how navigation, and specifically the head direction system, can operate in the face of sleep related plasticity. To address this question, we develop a model that integrates sleep homeostasis and head direction. We show that by introducing plasticity, the head direction system can function in a stable way by balancing plasticity in connected circuits that encode sleep pressure. With increasing sleep pressure, the head direction system nevertheless becomes unstable and a sleep phase with a different plasticity mechanism is introduced to reset network connectivity. The proposed integration of sleep homeostasis and head direction circuits captures features of their neural dynamics observed in flies and mice.
Metagenome-Wide Analysis of Rural and Urban Surface Waters and Sediments in Bangladesh Identifies Human Waste as a Driver of Antibiotic Resistance

Low- and middle-income countries (LMICs) have higher burdens of multidrug-resistant infections than high-income countries, and there is thus an urgent need to elucidate the drivers of the spread of antibiotic-resistant bacteria in LMICs. Here, we study the diversity and abundance of antibiotic resistance genes in surface water and sediments from rural and urban settings in Bangladesh. ABSTRACT In many low- and middle-income countries, antibiotic-resistant bacteria spread in the environment due to inadequate treatment of wastewater and the poorly regulated use of antibiotics in agri- and aquaculture. Here, we characterized the abundance and diversity of antibiotic-resistant bacteria and antibiotic resistance genes in surface waters and sediments in Bangladesh through quantitative culture of extended-spectrum beta-lactamase (ESBL)-producing coliforms and shotgun metagenomics. Samples were collected from highly urbanized settings (n = 7), rural ponds with a history of aquaculture-related antibiotic use (n = 11), and rural ponds with no history of antibiotic use (n = 6). ESBL-producing coliforms were found to be more prevalent in urban samples than in rural samples. Shotgun sequencing showed that sediment samples were dominated by the phylum Proteobacteria (on average, 73.8% of assigned reads), while in the water samples, Cyanobacteria were the predominant phylum (on average, 60.9% of assigned reads). Antibiotic resistance genes were detected in all samples, but their abundance varied 1,525-fold between sites, with the highest levels of antibiotic resistance genes being present in urban surface water samples. The abundance of antibiotic resistance genes was significantly correlated (R2 = 0.73; P = 8.9 × 10−15) with the abundance of bacteria originating from the human gut, which suggests that the release of untreated sewage is a driver for the spread of environmental antibiotic resistance genes in Bangladesh, particularly in highly urbanized settings. IMPORTANCE Low- and middle-income countries (LMICs) have higher burdens of multidrug-resistant infections than high-income countries, and there is thus an urgent need to elucidate the drivers of the spread of antibiotic-resistant bacteria in LMICs. Here, we study the diversity and abundance of antibiotic resistance genes in surface water and sediments from rural and urban settings in Bangladesh. We found that urban surface waters are particularly rich in antibiotic resistance genes, with a higher number of them associated with plasmids, indicating that they are more likely to spread horizontally. The abundance of antibiotic resistance genes was strongly correlated with the abundance of bacteria that originate from the human gut, suggesting that uncontrolled release of human waste is a major driver for the spread of antibiotic resistance in the urban environment. Improvements in sanitation in LMICs may thus be a key intervention to reduce the dissemination of antibiotic-resistant bacteria.
Liver‐specific decrease in Tff3 gene expression in infant mice perinatally exposed to 2,3,7,8‐tetrabromodibenzofuran or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

Polybrominated dibenzo‐p‐dioxins and dibenzofurans (PBDD/DFs) are byproducts of brominated flame retardants and can cause adverse health effects. Although exposure to polychlorinated (PC) DD/DFs induces toxic effects, including liver injury and neurobehavioral disorder, little is known about toxicities associated with PBDD/DF exposure. Thus, we examined effects of perinatal exposure to brominated congener on the infant mouse. Gene expression in several organs, such as the liver and brain, was analyzed in mouse offspring born to dams administered 2,3,7,8‐tetrabromodibenzofuran (TBDF; 9 or 45 μg/kg body weight) or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD; 3 μg/kg body weight) on gestational day 12.5. An increase in liver size was observed in TBDF‐ or TCDD‐exposed offspring in infancy. Gene microarray analysis revealed that 163 and 36 genes were markedly upregulated and downregulated, respectively, in the liver of TBDF‐exposed mice compared with those in vehicle‐treated mice on postnatal day (PND) 5. Significant increases in Cyp1a1, Cyp1a2, Fmo3, and Pnliprp1 and decreases in Tff3, Ocstamp, Kcnk16, and Lgals2 mRNA levels in TBDF‐exposed offspring on PNDs 5 and 12 were confirmed by quantitative PCR. In particular, a significant reduction in Tff3 mRNA in the liver, but not in the brain, small intestine, colon, and kidney, was observed in offspring perinatally exposed to TBDF or TCDD. Ultrasonic calls of TBDF‐ or TCDD‐exposed offspring on PNDs 3–5 were impaired. Taken together, perinatal exposure to polyhalogenated dioxin/furan congeners disrupts gene expression patterns in the liver and ultrasonic calling during infancy. These results suggest that liver injury may contribute to neurobehavioral disorder.
Acute kidney injury and its progression in hospitalized patients—Results from a retrospective multicentre cohort study with a digital decision support system

In this retrospective multicentric cohort study, we evaluate the potential benefits of a clinical decision support system (CDSS) for the automated detection of Acute kidney injury (AKI). A total of 80,389 cases, hospitalized from 2017 to 2019 at a tertiary care hospital (University of Leipzig Medical Center (ULMC)) and two primary care hospitals (Muldentalkliniken (MTL)) in Germany, were enrolled. AKI was defined and staged according to the Kidney disease: improving global outcomes (KDIGO) guidelines. Clinical and laboratory data was automatically collected from electronic patient records using the frameworks of the CDSS. In our cohort, we found an overall AKI incidence proportion of 12.1%. We identified 6,393/1,703/1,604 cases as AKI stage 1/2/3 (8.0%/2.1%/2.0%, respectively). Administrative coding with N17 (ICD-10-GM) was missing in 55.8% of all AKI cases with the potential for additional diagnosis related groups (DRG) reimbursement of 1,204,200 € in our study. AKI was associated with higher hospital mortality, increased length of hospitalisation and more frequent need of renal replacement therapy. A total of 19.1% of AKI cases (n = 1,848) showed progression to higher AKI stages (progressive AKI) during hospitalization. These cases presented with considerably longer hospitalization, higher rates of renal replacement therapy and increased mortality (p<0.001, respectively). Furthermore, progressive AKI was significantly associated with sepsis, shock, liver cirrhosis, myocardial infarction, and cardiac insufficiency. AKI, and especially its progression during hospitalization, is strongly associated with adverse outcomes. Our automated CDSS enables timely detection and bears potential to improve AKI outcomes, notably in cases of progressive AKI.
The onset of COVID-19, common identity, and intergroup prejudice

ABSTRACT The research presented here examined the relationship between the onset of the COVID-19 pandemic, social group identity, intergroup contact, and prejudice. Utilizing a common ingroup identity approach, two datasets, which were composed of data from university students collected via online questionnaires before and after the onset of COVID-19, were combined (N = 511). Participants identified as either one of two subordinate student identities: domestic (i.e. U.S. citizen or permanent resident) or international (i.e. non-U.S. citizen or foreign resident), then reported on the strength of their subordinate and superordinate identity (university identity). Participants also reported on their contact experiences with outgroup members, outgroup stereotypes, and completed a novel intergroup bias task. Results indicated that after the onset of the pandemic, participants more strongly identified with the superordinate group, which predicted greater perceived intergroup contact and lower intergroup bias. Theoretical implications and future directions are discussed.
Access to fertility preservation for trans and non-binary people in Aotearoa New Zealand

Abstract There is a growing need for healthcare professionals to discuss fertility preservation options with trans and non-binary people before commencing medical transition as part of informed consent-based models of care. In this article, we adapt the Five-A framework of healthcare access to examine fertility preservation information and services. To do so, we present an analysis of data from Counting Ourselves, the first comprehensive national survey in Aotearoa New Zealand of trans and non-binary people’s health and the first study exploring their access to cryopreservation information and services. Among 419 participants who had received gender-affirming hormones or surgery, 33.7% received information about options for fertility preservation and 15.8% accessed fertility preservation services. Findings from the study indicate the need for greater understanding of trans and non-binary people’s desire for genetically related children, and what type of information and form of delivery would be most helpful to ensure equitable outcomes in relation to decision-making around fertility and future family-building.
Mass spectrometry imaging reveals in situ behaviors of multiple components in aerosol particles.

The inhalation of atmospheric particles is toxicological to human health. However, as a complex mixture, tracing the behaviors of multiple components from real aerosol particles is crucial but unachievable by the existing methods. Here, taking advantage of the intrinsic fingerprints of elemental carbon (EC) and organic carbon (OC) in carbonaceous aerosol (CA) upon laser irradiation, we proposed a label-free mass spectrometry imaging method to visualize and quantify the deposition, translocation and component variation of CA in organs. With this method, the heterogeneous deposition, clearance and release behavior of CA in lung, that more OC was released in parenchyma and OC was cleared faster than EC, was observed. The translocation of CA to extrapulmonary organs including kidney, liver, spleen and even brain was also verified and quantified. By comparing the ratio of OC to EC, an organ-specific release behavior of OC from CA during circulation was revealed. In orthotopic lung and liver tumor, OC was found to penetrate more into tumor foci than EC. This technique provides deeper information for understanding the systemic health effects of aerosol particles.
Relationship between sex and cardiovascular mortality in chronic kidney disease: A systematic review and meta-analysis

Chronic kidney disease (CKD) is a significant health challenge associated with high cardiovascular mortality risk. Historically, cardiovascular mortality risk has been found to higher in men than women in the general population. However, recent research has highlighted that this risk may be similar or even higher in women than men in the CKD population. To address the inconclusive and inconsistent evidence regarding this relationship between sex and cardiovascular mortality within CKD patients, a systematic review and meta-analysis of articles published between January 2004 and October 2020 using PubMed/Medline, EMBASE, Scopus and Cochrane databases was performed. Forty-eight studies were included that reported cardiovascular mortality among adult men relative to women with 95% confidence intervals (CI) or provided sufficient data to calculate risk estimates (RE). Random effects meta-analysis of reported and calculated estimates revealed that male sex was associated with elevated cardiovascular mortality in CKD patients (RE 1.13, CI 1.03–1.25). Subsequent subgroup analyses indicated higher risk in men in studies based in the USA and in men receiving haemodialysis or with non-dialysis-dependent CKD. Though men showed overall higher cardiovascular mortality risk than women, the increased risk was marginal, and appropriate risk awareness is necessary for both sexes with CKD. Further research is needed to understand the impact of treatment modality and geographical distribution on sex differences in cardiovascular mortality in CKD.
miR-30a-5p suppresses lung squamous cell carcinoma via ATG5 - mediated autophagy

Propose: Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism. Method: TCGA database of lung squamous cell carcinoma was analyzed to explore the differentially expressed miRNAs and mRNAs and relative prognosis. RT-PCR and Western blot were performed to evaluate autophagy relative gene expression level in human lung squamous cell carcinoma cell Lines. Autophagy flux was observed using transmission electron microscopy and immunofluorescence. Meanwhile, binding relationship of potential target miRNA and mRNAs were also confirmed using Dual-luciferase reporter gene assay. Lung metastatic model was established to evaluated the effect of targeting protein and miRNA. Result: High level expression of ATG5 was detected in LUSC patients. Relative experiments confirmed that ATG5 silencing could decrease the autophagy flux in LUSC. In addition, our research revealed that there is a binding sites between hsa-mir-30a-5p and 3′-UTR of ATG5. Mimic miR-30a-5p suppresses ATG5-mediated autophagy in lung squamous cell carcinoma cells. The in vivo experiments confirmed that miR-30a-5p could attenuate lung squamous cell carcinoma progression through the autophagy pathway. Conclusion: Accordingly, the in vivo and in vitro study in our research have demonstrated that miR-30a-5p inhibits lung squamous cell carcinoma progression via ATG5-mediated autophagy.
The role of CCR2 in prognosis of patients with endometrial cancer and tumor microenvironment remodeling

ABSTRACT Tumor microenvironment (TME) plays a core role in the genesis and progress of endometrial carcinoma (EC). The immune system, a crucial element of TME, functions in various immune cells. In this paper, we have tried to evaluate the prognosis in EC patients by the status of TME. The ESTIMATE algorithm was implemented to computer the number of immune and stromal components in EC tissues from the Cancer Genome Atlas dataset. The CIBERSORT algorithm was employed to assess the proportion of tumor-infiltrating immune cells in EC tissues, which were quantified as Stromal score and Immune score. After the construction of protein–protein interaction network, cell–cell chemokine receptor 2 (CCR2) was identified as a potential predictive element for EC. Further analysis indicated that a higher expression of CCR2 in EC patients was correlated with a better prognosis and a prolonged disease-free survival. According to the transcript level of CCR2, samples were separated into low- and high-expression groups. Gene Set Enrichment Analysis unveiled that metabolism-related pathways were mostly abundant in groups with high-expression, the other one was primarily correlated to immune-related activities. We figured out that some immune cells were positively related to CCR2, suggesting that CCR2 might serve as the immune-dominant status of TME, which was verified by qRT-PCR and HPA analysis in transcriptome and protein level, respectively. Also, CCR2 showed high correlation with immune modulators and chemokine signaling pathway. Thus, the level of CCR2 might have a prognostic value for EC patients, which provides a novel insight for therapeutic strategies of EC. Graphical abstract