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Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

[Objective] This article discussed the regional differences and spatial convergence of ration security from the perspectives of consumption and demand, in order to provide a scientific basis for each region to better assume the due responsibility of ration safety. [Methods] In order to examine the spatial differentiation characteristics and distribution dynamics of ration self-sufficiency rate in the four main regions of China, this study used the consumption statistics method and measured the self-sufficiency rate of rations based on provincial data from 2000 to 2020. We used the Dagum Gini coefficient and its decomposition method to investigate the degree, source, and trend of change of regional relative differences of ration self-sufficiency in China and its four regions. On this basis, the kernel density estimation method and spatial convergence were further used to describe the dynamic change process of distribution and spatial convergence characteristics of absolute difference. [Results] (1) From 2000 to 2020, the national ration self-sufficiency rate kept rising in three stages and in the four regions it was significantly different. The ration self-sufficiency rate of the four regions in descending order were central China, northeast China, eastern China, and western China. (2) During the study period, the regional differences of the ration self-sufficiency rate increased significantly in eastern and northeastern China, but only slightly in central and western China. However, the average contribution rate of the difference of ration self-sufficiency rate among the four regions to the interregional differences was 47.92%, much higher than the contribution rate of intraregional difference of 20.38% and super-density of 31.71%. (3) Different from the western region, the distribution pattern and polarization trend of the ration self-sufficiency rate in the eastern, central, and northeastern regions were similar, indicating that the absolute differences in the three regions were expanding continuously, and there was a phenomenon of high and low polarization. (4) Considering the spatial spillover effect, the absolute β convergence and conditional β convergence of the ration self-sufficiency rate existed in the whole country and the four main regions. The influencing factors of the ration production played a decisive role in the conditional convergence of the regional ration self-sufficiency rate. [Conclusion] The overall absolute security of China’s ration provision obscured regional insecurity, downplaying the research on regional differences of ration security. But regional differences in ration security are likely to narrow in the future.

BackgroundAlthough survival rates for infants born extremely preterm (gestation

As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At [Formula: see text], we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.

This paper summarized the nursing of sulfonamide-allergic patient with with Pneumocystis carinii infection after liver transplantation. The patient was given Sulfonamide desensitization treatment. Based on the risk analysis, comprehensive interventions such as illness condition observation, medication care, symptoms observation, nebulizer therapy, sputum excretion, effective respiratory function and rehabilitation exercise and psychological care were carried out. Disinfection and isolation measures for carbapenems-resistant Pseudomonas aeruginosa (PA) were developed to improve the recovery of the patient. (本文总结1例磺胺类药物过敏患者肝移植术后肺孢子菌感染的护理经验。针对性进行磺胺脱敏治疗, 从临床危险因素着手, 开展病情观察、脱敏用药护理、过敏症状观察、正确雾化、咳嗽排痰、有效呼吸功能锻炼及康复训练、心理干预等护理干预, 同时针对碳青霉烯类铜绿假单胞菌(CR-PA)做出相应的隔离措施, 帮助患者树立治疗信心, 促使积极配合治疗, 加速疾病恢复。)

BackgroundTo develop a sensitive risk score predicting the risk of mortality in patients with coronavirus disease 2019 (COVID-19) using complete blood count (CBC).MethodsWe performed a retrospective cohort study from a total of 13,138 inpatients with COVID-19 in Hubei, China, and Milan, Italy. Among them, 9,810 patients with ≥2 CBC records from Hubei were assigned to the training cohort. CBC parameters were analyzed as potential predictors for all-cause mortality and were selected by the generalized linear mixed model (GLMM).FindingsFive risk factors were derived to construct a composite score (PAWNN score) using the Cox regression model, including platelet counts, age, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio. The PAWNN score showed good accuracy for predicting mortality in 10-fold cross-validation (AUROCs 0.92-0.93) and subsets with different quartile intervals of follow-up and preexisting diseases. The performance of the score was further validated in 2,949 patients with only 1 CBC record from the Hubei cohort (AUROC 0.97) and 227 patients from the Italian cohort (AUROC 0.80). The latent Markov model (LMM) demonstrated that the PAWNN score has good prediction power for transition probabilities between different latent conditions.ConclusionsThe PAWNN score is a simple and accurate risk assessment tool that can predict the mortality for COVID-19 patients during their entire hospitalization. This tool can assist clinicians in prioritizing medical treatment of COVID-19 patients.FundingThis work was supported by National Key R&D Program of China (2016YFF0101504, 2016YFF0101505, 2020YFC2004702, 2020YFC0845500), the Key R&D Program of Guangdong Province (2020B1111330003), and the medical flight plan of Wuhan University (TFJH2018006).

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.

The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.

Ferroelectric ceramics are highly desired for applications in energy storage devices due to their fast charge-discharge capability. However, electric field-driven gradual degradation of ferroelectric polarization (i.e., fatigue) inevitably results in a decrease in energy efficiency and energy storage density. Therefore, improving fatigue endurance is one challenge for their practical applications in energy storage devices. Here, we provide a strategy to modulate the strain response to the external electric field, and thus, increase the fatigue endurance by employing hybrid improper ferroelectricc Ca3Ti2O7 ceramic that exhibits a negative piezoelectric effect. We synthesized (1 − x) BaTiO 3 − x Ca3Ti2O7 (BT-xCT) ceramics, in which the strain response of ceramics to the electric field gradually decreases with the increasing proportion of Ca3Ti2O7. For BT-0.3CT ceramic, the energy density storage efficiency is improved to 74.95% which is much higher than that of BT-0.1CT (48.07%). The strain response to the external electric field of BT-0.3CT is substantially lowered and almost reaches zero, leading to excellent fatigue endurance ability. This research work paves a route for designing ferroelectric ceramics with smaller strain response and enhanced fatigue endurance ability, which is expected to benefit a wide range of applications of ferroelectric ceramics in various electric capacitors and electric storage devices. [ABSTRACT FROM AUTHOR]

While advances in technology have led to the widespread use of artificial intelligence (AI) in frontline services, the AI empathic effect is often overlooked. Based on emotional contagion theory, this research explores the impacts of AI emotional mimicry and empathic concern in service success and failure via experimental designs, respectively. Results indicate that AI with high emotional mimicry and empathic concern resulted in higher arousal and pleasure, increasing tourists' continuous usage intention. Arousal and pleasure played significant mediating roles in service success. However, while empathic concern significantly affected continuous usage intention through pleasure, arousal did not have a similar effect. The joint effects of extrinsic and intrinsic anthropomorphism (emotional mimicry) were significant in a successful service context, but not in service failure. These results have important implications for the development and promotion of AI and enriches theoretical applications of emotional contagion theory and empathy. [ABSTRACT FROM AUTHOR]

By using the discrete Lax matrices corresponding to Q1(0)$$ Q1(0) $$ and Q1(δ)$$ Q1\left(\delta \right) $$ in the Adler–Bobenko–Suris list of quadrilateral lattice equations, we establish solutions of the (2+1)‐dimensional Schwarzian Korteweg–de Vries (SKdV) equation and its generalizations. According to the structure of integrable Hamiltonian systems provided by one discrete Lax matrix for the Q1(0)$$ Q1(0) $$ lattice, we construct a novel Lax representation for the (2+1)‐dimensional SKdV equation. On the basis of the Riemann surface and elliptic variables, the Hamiltonian phase flows related to the equation are linearized by the Abel–Jacobi coordinates. Consequently, we obtain finite genus solutions to the (2+1)‐dimensional SKdV equation. From the discrete Lax matrix of the Q1(δ)$$ Q1\left(\delta \right) $$ lattice, we study the generalized (2+1)‐dimensional SKdV equation with a parameter δ$$ \delta $$, which can be reduced to a simple case of the Krichever–Novikov equation. Finally, we show that the case of δ=1/2$$ \delta =1/2 $$ can also be solved through a modified version of the other discrete Lax matrix for the Q1(0)$$ Q1(0) $$ equation. [ABSTRACT FROM AUTHOR]