Sex differences orchestrated by androgens at single-cell resolution.

Sex differences in mammalian complex traits are prevalent and are intimately associated with androgens1-7. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking. Here we constructed a high-dimensional single-cell transcriptomic atlas comprising over 2.3 million cells from 17 tissues in Mus musculus and explored the effects of sex and androgens on the molecular programs and cellular populations. In particular, we found that sex-biased immune gene expression and immune cell populations, such as group 2 innate lymphoid cells, were modulated by androgens. Integration with the UK Biobank dataset revealed potential cellular targets and risk gene enrichment in antigen presentation for sex-biased diseases. This study lays the groundwork for understanding the sex differences orchestrated by androgens and provides important evidence for targeting the androgen pathway as a broad therapeutic strategy for sex-biased diseases.

Research on the Reliability of Threshold Voltage Based on GaN High-Electron-Mobility Transistors.

With the development of high-voltage and high-frequency switching circuits, GaN high-electron-mobility transistor (HEMT) devices with high bandwidth, high electron mobility, and high breakdown voltage have become an important research topic in this field. It has been found that GaN HEMT devices have a drift in threshold voltage under the conditions of temperature and gate stress changes. Under high-temperature conditions, the difference in gate contact also causes the threshold voltage to shift. The variation in the threshold voltage affects the stability of the device as well as the overall circuit performance. Therefore, in this paper, a review of previous work is presented. Temperature variation, gate stress variation, and gate contact variation are investigated to analyze the physical mechanisms that generate the threshold voltage (VTH) drift phenomenon in GaN HEMT devices. Finally, improvement methods suitable for GaN HEMT devices under high-temperature and high-voltage conditions are summarized.

C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.

Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.

Examining the linkage between economic policy uncertainty, coal price, and carbon pricing in China: Evidence from pilot carbon markets.

Economic policies affect companies' production decisions. And the energy consumption volume is an intuitive reflection of the enterprise's production decisions. In China, coal is the main source of carbon emissions and the most important energy source. Therefore, the coal market and the uncertainty of economic policies are both directly tied to the carbon market. This study explores both the direct impact of economic policy uncertainty and coal price on carbon prices as well as the indirect impact of economic policy uncertainty on carbon prices through coal prices by utilizing the DCC-GARCH model and the NARDL model. The findings indicate that the dynamic correlations between coal prices and the CEPU are always negative and that those between the price of carbon and the CEPU vary by area. Meanwhile, the dynamic correlations between coal and carbon prices are only positive in Shenzhen and Beijing. Both coal prices and economic policy uncertainty produce asymmetrical impacts on carbon prices. Some policy implications are provided for developing the carbon markets in light of the results drawn from the study.

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer.

In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

Antimicrobial resistance, molecular characteristics, virulence and pathogenicity of bla NDM-1-positive Enterobacter cloacae.

Introduction. The bla NDM-1 -positive Enterobacter cloacae has led to limited therapeutic options for clinical treatment.Hypothesis/Gap Statement. Analysing the antimicrobial resistance and molecular typing of bla NDM-1-positive E. cloacae is of great significance. Meanwhile, the effect of the bla NDM-1 gene on the virulence and pathogenicity of E. cloacae remains unclear and should be assessed.Aim. To understand bla NDM-1-positive E. cloacae from different perspectives.Methodology. The PCR was used to screen bla NDM-1-positive E. cloacae, then, antimicrobial susceptibility tests and multilocus sequence typing (MLST) were performed on them; sixty-nine strains of bla NDM-1-negative E. cloacae were collected as the controls, 28 pairs of virulence-related genes' carriage and biofilm-forming ability were detected for preliminary evaluation of the virulence phenotype of the strains; to gain insight into the effect of the bla NDM-1 gene on the virulence and pathogenicity of E. cloacae, the bla NDM-1-positive E. cloacae T2 (NDM-1), the T2 bla NDM-1 knockout strain (ΔNDM-1) and ATCC13047 (ST) were studied, compared the motility, anti-serum killing ability, and virulence to cells. Then, the mice intraperitoneal infection model was established, the survival curve, histopathological characteristics, bacterial load in spleen and the contents of cytokines were compared.Results. (1) Thirty-five bla NDM-1-positive E. cloacae exhibited multidrug resistance. MLST distinguished 12 STs, ST74 was the most common clonal type (11/35), followed by ST114 (10/35). (2) The detection rates of virulence genes clpB, icmf, VasD/Lip and acrA in the bla NDM-1-positive E. cloacae were significantly higher than those in bla NDM-1-negative E. cloacae (P<0.05), while there was no significant difference in the amount of biofilm formation between two groups. (3) The presence of bla NDM-1 gene attenuated the motility diameter of E. cloacae, but had no significant effect on their ability to resist serum killing, and the virulence to cells. The survival rate, histopathological changes, bacterial load in spleen and inflammatory cytokines were not significantly affected.Conclusions. (1) The bla NDM-1-positive E. cloacae exhibited multidrug resistance, and the MLST typing was mainly ST74 and ST114, with a small-scale clonal spread of the ST114 strain in the hospital NICU ward. (2) The bla NDM-1 gene did not affect the virulence and pathogenicity of E. cloacae.

Genomic alterations dissection revealed MUC4 mutation as a potential driver in lung adenocarcinoma local recurrence.

Background: Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, of which genomic alterations play a major role in tumorigenesis. The prognosis of LUAD has been improved these years but nearly half of the patients still develop recurrence even after radical resection. The underlying mechanism driving LUAD recurrence especially genomic alterations is complicated and worth exploring. Methods: Forty-one primary tumors and 43 recurrent tumors were collected from 41 LUAD patients who received surgery resection after recurrence. Whole exon sequencing (WES) was performed to make genomic landscapes. WES data were aligned to genome and further analyzed for somatic mutation, copy number variation and structure variation. MutsigCV was used to identify significantly mutated genes and recurrence specific genes. Results: Significantly mutated genes including EGFR, MUC4 and TP53 were identified in primary and recurrent tumors. Some were found to be more specifically mutated in recurrent tumors, such as the MUC17, KRAS and ZNF families. In recurrent tumors, ErbB signaling pathway, MAPK pathway and cell cycle pathway were highly activated, which maybe the mechanism driving recurrence. The adjuvant therapy would affect tumor evolution and molecular features during recurrence. MUC4 was highly mutated in this study cohort, and it was a potential driver gene in LUAD recurrence by activating ErbB signaling pathway as a ligand of ERBB2. Conclusions: Genomic alteration landscape was changing during LUAD recurrence to construct a more suitable environment for the survival of tumor cells. Several potential driver mutations and targets during LUAD recurrence were identified, such as MUC4, and more investigation was needed to verify the specific functions and roles.

Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation.

Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.

DNA repair mechanisms that promote insertion-deletion events during immunoglobulin gene diversification.

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase-dependent ±1-base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.

Perceived professional benefits and associated factors among nurses during the COVID-19 pandemic: A cross-sectional study.

AIMS: To examine the perceived professional benefits (PPB) and associated factors among nurses during the coronavirus disease 2019 (COVID-19) pandemic in China. DESIGN: Cross-sectional study. METHODS: Using the snowball sampling method, 492 nurses (478 females, 14 males) were recruited. Data were collected using an online survey, including participants' socio-demographic and working characteristics, psychological distress related to the COVID-19 pandemic, dealing with professional frustration, professional self-reflection and PPB from 1-30 April 2020. RESULTS: Nurses experienced high levels of PPB. In linear regression analysis, self-perceived concerns about COVID-19, emotional shock caused by it, risk perception towards their occupations, dealing with professional frustration and professional self-reflection were positively associated with PPB among nurses. These factors explained 84% variance in PPB. CONCLUSIONS: This study highlighted that although the nurses experienced psychological distress, they gained high PPB during the COVID-19 pandemic. Additionally, to facilitate nurses' efforts to achieve professional growth, more educational resources and opportunities for engaging in reflective practices could be provided.

FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer.

Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted therapeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigate the dynamics of cellular heterogeneity, transcriptome regulation, and microenvironmental factors in 107,201 cells from genetically engineered mouse prostate cancer samples with complete time series of tumor evolution seen in patients. We identify that FOXA2 orchestrates prostate cancer adeno-to-neuroendocrine lineage transition and that Foxa2 expression is significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induces the reversal of adeno-to-neuroendocrine transition. The KIT pathway is directly regulated by FOXA2 and specifically activated in neuroendocrine prostate cancer (NEPC). Pharmacologic inhibition of KIT pathway significantly suppresses mouse and human NEPC tumor growth. These findings reveal that FOXA2 drives adeno-to-neuroendocrine lineage plasticity in prostate cancer and provides a potential pharmacological strategy for castration-resistant NEPC.

Effects of Different Roughages on Growth Performance, Nutrient Digestibility, Ruminal Fermentation, and Microbial Community in Weaned Holstein Calves.

This study aimed to assess the effects of feeding with different forage sources and starter concentrations on growth performance, nutrient digestibility, ruminal fermentation, and the microbial community in weaned Holstein calves. A total of 54 Holstein calves (body weight (BW) = 77.50 ± 5.07 kg; age = 70 ± 2.54 days) were assigned to 1 of 3 treatment groups (n = 18/group) that were offered diets with different forages: (1) peanut vine (PV), (2) oat hay (OH), or (3) an alfalfa hay + oat hay combination (alfalfa hay:oat hay =1:1, AO). Starter and forage intakes were recorded daily, while BW and growth parameters were assessed at 15-day intervals. The apparent digestibility of nutrients was determined. Ruminal fluid samples were collected and used to detect relevant indicators. A difference was observed for the forage × age interaction for all feed, nutrient intake, BW, ADG, and body structure parameters (P < 0.05). The final BW, average daily feed intake (ADFI), and average daily gain of the PV calves were higher than those of calves from the other groups (P < 0.05). The ruminal propionate concentration evidently increased in calves of the AO group (P < 0.05). The abundances of Rikenellaceae_RC9_gut_group and Shuttleworthia showed distinct responses to feeding with different forages (P < 0.05) at the genus level. The relative abundance of Shuttleworthia was negatively related to rumen pH and acid detergent fiber digestibility (P < 0.05) and strongly positively related to propionate concentration (P < 0.01). A positive correlation was found between Ruminococcus_1 abundance and butyrate concentration and neutral detergent fiber digestibility (P < 0.05). The relative abundances of Succiniclasticum and Prevotella_7 were negatively related to butyrate concentration (P < 0.05). In conclusion, there was an interaction between the factors (forage × age). The peanut vine used as a forage source promoted a higher starter concentrate intake compared to other diets and increased with the calves' age. The growth performance and rumen bacterial community of the calves were further improved. These results indicate that peanut vine can be used as the main source of forage in the diets of weaned calves.

Associations of walking impairment with visual impairment, depression, and cognitive function in U.S. older adults: NHANES 2013-2014.

BACKGROUND: Walking impairment, a common health problem among older adults, has been linked to poor vision and mental health. This study aimed to investigate the associations of walking impairment with visual impairment, depression, and cognitive function in older adults. METHODS: A total of 1,489 adults aged 60 years and older who had participated in the National Health and Examination Survey (NHANES) 2013-2014 in the United States were included. Multivariate logistic regression models were used to examine the associations of walking impairment with visual impairment, depression, and four subdomains of cognitive function. Sample weights were used to ensure the generalizability of the results. RESULTS: Among all the participants (median age = 68 years; 53.7% women), 17.5% reported walking impairment. Walking impairment was significantly associated with visual impairment (adjusted odds ratio [aOR] = 2.76; 95% CI: 1.47-5.20) and depression (aOR = 4.66; 95% CI: 3.11-6.99). Walking impairment was only associated with the Digit Symbol Substitution (DSST) subdomain of cognitive function in total participants (aOR = 0.97; 95% CI: 0.95-0.99) and in non-Hispanic white adults (aOR = 0.96; 95% CI: 0.94-0.98). Participants with two or three impairment indicators had a higher OR of walking impairment (aOR = 3.64, 95% CI = 2.46-5.38) than those with 0-1 (reference group) impairment indicator. CONCLUSIONS: Walking impairment was associated with visual impairment, depression, and cognitive impairment in American older adults and also positively associated with the number of impairment indicators. The association between walking impairment and cognitive impairment varied according to race. Evaluations of vision, cognition, and depression should be conducted among older adults with walking impairment, and the needs of older adults should be provided in the evaluations alongside information on the biological aspects of their particular race.

New Chromatin Run-On Reaction Enables Global Mapping of Active RNA Polymerase Locations in an Enrichment-free Manner.

The development of a simple and cost-effective method to map the distribution of RNA polymerase II (RNPII) genome-wide at a high resolution is highly beneficial to study cellular transcriptional activity. Here we report a mutation-based and enrichment-free global chromatin run-on sequencing (mGRO-seq) technique to locate active RNPII sites genome-wide at near-base resolution. An adenosine triphosphate (ATP) analog named N6-allyladenosine triphosphate (a6ATP) was designed and could be incorporated into nascent RNAs at RNPII-located positions during a chromatin run-on reaction. By treatment of the run-on RNAs with a mild iodination reaction and subjection of the products to reverse transcription into complementary DNA (cDNA), base mismatch occurs at the original a6A incorporation sites, thus making the RNPII locations detected in the high-throughput cDNA sequencing. The mGRO-seq yields both the map of RNPII sites and the chromatin RNA abundance and holds great promise for the study of single-cell transcriptional activity.

tert-Butyl Nitrite as a Twofold Hydrogen Abstractor for Dehydrogenative Coupling of Aldehydes with N-Hydroxyimides.

A synthetically practical transition metal/catalyst/halogen-free dehydrogenative coupling of aldehydes with N-hydroxyimides promoted solely by tert-butyl nitrite under mild conditions was developed. tert-Butyl nitrite generates two radicals (tBuO and NO) and thus works as a twofold hydrogen abstractor. A diverse array of N-hydroxyimide esters were prepared from either aliphatic or aromatic aldehydes. Benzoyl-substituted aldehydes such as 2-oxo-2-phenylacetaldehyde are also suitable.

The impact of COVID-19 on the stock market crash risk in China.

This study investigates the impact of the COVID-19 pandemic on the stock market crash risk in China. For this purpose, we first estimated the conditional skewness of the return distribution from a GARCH with skewness (GARCH-S) model as the proxy for the equity market crash risk of the Shanghai Stock Exchange. We then constructed a fear index for COVID-19 using data from the Baidu Index. Based on the findings, conditional skewness reacts negatively to daily growth in total confirmed cases, indicating that the pandemic increases stock market crash risk. Moreover, the fear sentiment exacerbates such risk, especially with regard to the impact of COVID-19. In other words, when the fear sentiment is high, the stock market crash risk is more strongly affected by the pandemic. Our evidence is robust for the number of daily deaths and global cases.

Is the cross-correlation of EU carbon market price with policy uncertainty really being? A multiscale multifractal perspective.

This paper aims to examine the cross-correlation relationship between EU carbon market price and the economic policy uncertainty. The United Kingdom and the United State of America are chosen as the representative countries. We first conduct the linear analysis to explore the correlation of EU carbon market futures return with the economic policy uncertainty of the two countries. Our findings show that there is no linear correlation between EU carbon market return and economic policy uncertainty. Then, we apply the multifractal detrended cross-correlation analysis to examine the cross-correlation between the return of EU carbon market futures and economic policy uncertainty. The empirical results indicate that the cross-correlations really exist, and the cross-correlation behavior structure over different carbon trading phases are not the same. Moreover, the empirical results show that the anti-persistence between the EU carbon futures return and economic policy uncertainty changes from the UK and the USA are both relatively strong. The findings provide deeper insights and management implications for the carbon market from a new perspective.

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

Preventing crash in stock market: The role of economic policy uncertainty during COVID-19.

This paper investigates the impact of economic policy uncertainty (EPU) on the crash risk of US stock market during the COVID-19 pandemic. To this end, we use the GARCH-S (GARCH with skewness) model to estimate daily skewness as a proxy for the stock market crash risk. The empirical results show the significantly negative correlation between EPU and stock market crash risk, indicating the aggravation of EPU increase the crash risk. Moreover, the negative correlation gets stronger after the global COVID-19 outbreak, which shows the crash risk of the US stock market will be more affected by EPU during the epidemic.