Factors associated with the clinical outcomes of adult cardiac and non-cardiac origin cardiac arrest in emergency departments: a nationwide retrospective cohort study from China

Cardiac arrest(CA)is one of the most common causes of death.[1-3]Despite extensive studies on the management of CA,the global survival rate in adults is only approximately 7%,and 30-day survival is even less than 2%in China.[4]Some studies have shown that CA patients of cardiac and non-cardiac origin may differ in underlying diseases,clinical manifestations,and prognosis,which leads to diff erences in terms of the pathophysiological mechanism and treatment measure.[5,6]However,little is known about the risk factors in relation to the prognosis of CA across arrest etiologies.

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings

The global burden of hepatitis B virus(HBV)and hepatitis C virus(HCV)infections and coinfection represents a major public health concern,particularly in resource-limited settings.Elimination of HCV by 2030 has become foreseeable,with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries(LMICs).However,access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices.Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal.Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection,and with improved access to medications,the most significant barrier remains access to affordable diagnostics and preventive strategies.The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs,albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage.This review underpins the HBV and HCV management challenges in resource-limited settings,highlighting the current status and suggested future elimination strategies in some of these countries.Global efforts should continue to improve awareness and political commitment.Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.

牙龈卟啉单胞菌在消化系统恶性肿瘤中的作用机制的循证评价

目的 口腔菌群与人类健康之间的关系已被学界广泛认识,本研究采用系统评价的方法总结分析牙龈卟啉单胞菌在消化系统恶性肿瘤中的作用。方法 检索PubMed、Embase、MEDLINE、Cochrane图书馆、Scopus和Web of Science数据库,检索时限均从建库至2023年8月25日。由2位评价员独立筛选文献、提取资料并评价纳入文献的偏倚风险。遵循系统评价和荟萃分析的首选报告项目(preferred reporting items for systematic reviews and Meta-analyses,PRISMA)方法对纳入文献进行系统评价,分析牙龈卟啉单胞菌在各消化道恶性肿瘤中的致癌机制。结果 共计28篇文献(包括2项前瞻性队列研究,26项病例对照研究)被纳入本次系统评价,包括胃癌、食管癌、结直肠癌、胰腺癌、肝癌等多种类型。其中研究食管癌的文献有5篇,胃癌有5篇,结直肠癌有9篇(其中1篇同时研究胃癌),胰腺癌有7篇,肝癌有2篇。全部的纳入文献均报道了口腔菌群失调(包括牙龈卟啉单胞菌)与消化系统恶性肿瘤之间的风险关联。结论 本研究系统阐述了牙龈卟啉单胞菌在消化系统恶性肿瘤中的作用,对其可能的致病机制进行分析评价。

白念珠菌ALS3、SSA1基因表达在念珠菌性阴道炎免疫机制中的作用

目的探讨白念珠菌ALS3、SSA1基因缺失对阴道上皮细胞激发免疫反应的作用。方法培养白念珠菌野生株及ALS3、SSA1基因敲除株(SC5314、Δals3、Δssa1),对其进行形态测定。按不同MOI感染人阴道上皮细胞系VK2/E6E7细胞,通过台盼蓝染色观察和乳酸脱氢酶(LDH)活性检测,评价不同MOI白念珠菌对上皮细胞的损伤作用;使用酶联免疫吸附试验(ELISA)评估感染过程中炎性细胞因子及趋化因子在共培养上清中的差异。结果 ALS3基因的缺失对白念珠菌芽管长度影响差异无统计学意义,而SSA1基因的缺失与其他两个菌株相比芽管长度减少约30%～40%(P<0.001)。台盼蓝染色观察及LDH测定发现,3株菌在感染上皮细胞时,其细胞损伤能力均与菌载量成正比;与野生型相比,Δssa1突变体在相同比率感染上皮细胞时,细胞损伤能力明显降低,且差异有统计学意义(P<0.05),Δals3突变株影响较小,甚至略微升高。检测炎性细胞因子及趋化因子发现,突变株在诱导上皮细胞产生促炎因子及趋化因子(GM-CSF、G-CSF、IL-1α、IL-8)的能力上明显减弱,差异均有统计学意义(P<0.05)。结论 ALS3和SSA1基因表达在阴道上皮细胞抗白念珠菌感染的局部免疫应答过程中可能起到重要作用,且SSA1基因表达意义更大。

S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission

Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis.In an analysis of a randomly collected cohort of 124 patients with COVID-19,we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity.By virtual screening of a U.S.FDA approved drug library,we identified an anticoagulation agent dipyridamole(DIP)in silico,which suppressed SARS-CoV-2 replication in vitro.In a proof-of-concept trial involving 31 patients with COVID-19,DIP supplementation was associated with significantly decreased concentrations of D-dimers(P<0.05),increased lymphocyte and platelet recovery in the circulation,and markedly improved clinical outcomes in comparison to the control patients.In particular,all 8 of the DIP-treated severely ill patients showed remarkable improvement:7 patients(87.5%)achieved clinical cure and were discharged from the hospitals while the remaining 1 patient(12.5%)was in clinical remission.

Genomic surveillance of Nevada patients revealed prevalence of unique SARS-CoV-2 variants bearing mutations in the RdRp gene

Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform,which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads,without the need of culture-based amplification.High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak.We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine(F) from proline (P),in the first reported isolate of SARS-CoV-2,Wuhan-Hu-1.This 323F variant was present at a very high frequency in Northern Nevada.Structural modeling determined this mutation in the interface domain,which is important for the association of accessory proteins required for the polymerase.In conclusion,we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations,which is important for understanding the evolution and circulation of SARS-CoV-2variants of public health importance,while it circulates in humans.

A NOVEL VARIANT OF HUMAN INTERFERON α1 GENE

A 520-base pair human IFN-α gene was isolated by PCR method twice from chromosome DNA of a Chinese (Han Nationality) fetal liver. The nucleotide sequences were determined. These two separately amplified DNA fragments shared the completely identical nucleotide sequence but possessed C and G at positions 410 and 541, respectively, which differ from those oflFN-α1 and IFN-αD previously described. Therefore the deduced amino acid sequence would have an Ala at position 114 and a Val at position 158. At all other sites it has the same amino acids as those in IFN-α1 and IFN-αD. We recommend that IFN-αD gene, IFN-αI gene and IFN-αI/158V gene found in our laboratory, be named IFN-αla gene, IFN-αlb gene and IFN-αlc gene.

Biofilm Alterations on the Stepwise Acquisition of Fluconazole-resistant Candida Albicans Isolates

Objectives:By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant Candida albicans isolates,we could find and describe the relationship between drug resistance and biofilm formation ability in a series of clonal strains.Methods:We performed antifungal susceptibility of five drugs(fluconazole,itraconazole,voriconazole,caspofungin and amphotericin B)to further verify the antifungal activity of the six isolates in vitro.Then we combined hyphal formation assay,cell surface hydrophobicity test positively related to adherence ability,and biofilm assays in vitro to observe and compare the phenotypic characteristics of our six clonal strains.Results:Biofilm capability is enhanced for four drug-intermediate strains,whereas the initial susceptible strain and the final resistant strain are both poor in adherence,hyphal growth and biofilm formation.Conclusions:It was suggested that the biofilm formation ability were not absolutely related to the degree of fluconazole resistance.

肿瘤源性外泌体对巨噬细胞极化的调控作用的研究进展

单核巨噬细胞是一种功能多样、对不同的微环境信号应答表现出不同反应的集群。根据受到的不同刺激,巨噬细胞可极化为经典活化型(M1)及替代活化型(M2),是巨噬细胞功能表现的两个极端。核因子-κB、环氧合酶2、乏氧状态、原癌基因MYC、Toll样受体信号通路、Notch信号通路及细胞因子等密切参与肿瘤相关巨噬细胞发生M1-M2型别的转化。其中浸润在肿瘤组织中的巨噬细胞,会受肿瘤产生的细胞因子的影响而表现出M2表型,这些极化的巨噬细胞在促进肿瘤的发生与进展和破坏适应性免疫应答方面作用显著。肿瘤细胞来源的外泌体具有肿瘤细胞本身的特性,可参与多种肿瘤发生、发展的多个过程。本文综述了来源于多种癌细胞的外泌体,详细讨论了在肿瘤免疫微环境中,肿瘤源性外泌体的内容物在调节巨噬细胞极化行为中的作用及其涉及的信号机制。

代谢组学策略评价银杏提取物对高脂诱导动脉粥样硬化金黄地鼠代谢紊乱的药效作用(英文)

目的:研究银杏提取物对高脂诱导动脉粥样硬化金黄地鼠代谢紊乱的纠正作用。方法:基于气相色谱/飞行时间质谱(GC/TOF-MS)检测技术的代谢组学方法,分析比较高脂诱导0、3、6、12周及银杏提取物质干预的金黄地鼠血清中的内源性小分子代谢物,多元统计分析银杏提取物抗动脉粥样硬化相关代谢谱差异及潜在生物标志物。结果:在高脂诱导下,模型动物血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、动脉斑块及血清代谢组均有显著变化。银杏提取物给药后不仅显著降低血清中TC和LDL-C,同时也使高脂诱导偏离的血清代谢谱向正常代谢谱靠近。在动脉粥样硬化的血清生物标志物中,银杏提取物给药后,8个代谢物琥珀酸、甘油酸、亚油酸、花生四烯酸、1-单油酰基甘油、β-生育酚、胆甾-5-烯和赖氨酸回归正常;另外6个代谢物酪氨酸、油酸、2-单油酰基甘油、γ-生育酚、α-生育酚和脱氧胆酸趋向正常。结论:研究结果提示银杏提取物抗动脉粥样硬化效果与其对脂质代谢、胆酸合成及氨基酸代谢的调控密切相关。这将为进一步探讨银杏提取物抗动脉粥样硬化的药效作用机制和特点提供研究基础。

Polydopamine nanoparticle-dotted food gum hydrogel with excellent antibacterial activity and rapid shape adaptability for accelerated bacteria-infected wound healing

Most commonly used wound dressings have severe problems,such as an inability to adapt to wound shape or a lack of antibacterial capacity,affecting their ability to meet the requirements of clinical applications.Here,a nanocomposite hydrogel(XKP)is developed by introducing polydopamine nanoparticles(PDA NPs)into a food gum matrix(XK,consisting of xanthan gum and konjac glucomannan,both FDA-approved food thickening agents)for skin wound healing.In this system,the embedded PDA NPs not only interact with the food gum matrix to form a hydrogel with excellent mechanical strength,but also act as photothermal transduction agents to convert near-infrared laser radiation to heat,thereby triggering bacterial death.Moreover,the XKP hydrogel has high elasticity and tunable water content,enabling it to adapt to the shape of the wound and insulate it,providing a moist environment suitable for healing.In-vivo skin wound healing results clearly demonstrate that XKP can significantly accelerate the healing of wounds by reducing the inflammatory response and promoting vascular reconstruction.In summary,this strategy provides a simple and practical method to overcome the drawbacks of traditional wound dressings,and provides further options when choosing suitable wound healing materials for clinical applications.

Microbiome data analysis with applications to pre-clinical studies using QIIME2: Statistical considerations

Diversity analysis and taxonomic profiles can be generated from marker-gene sequence data with the help of many available computational tools.The Quantitative Insights into Microbial Ecology Version 2(QIIME2)has been widely used for 16S rRNA data analysis.While many articles have demonstrated the use of QIIME2 with suitable datasets,the application to preclinical data has rarely been talked about.The issues involved in the pre-clinical data include the low-quality score and small sample size that should be addressed properly during analysis.In addition,there are few articles that discuss the detailed statistical methods behind those alpha and beta diversity significance tests that researchers are eager to find.Running the program without knowing the logic behind it is extremely risky.In this article,we first provide a guideline for analyzing 16S rRNA data using QIIME2.Then we will talk about issues in pre-clinical data,and how they could impact the outcome.Finally,we provide brief explanations of statistical methods such as group significance tests and sample size calculation.

小檗碱通过挟持药物外排泵Mdr1p逆转白色念珠菌的多药耐药

药物外排泵的过量表达是病原微生物产生多药耐药(MDR)的重要原因之一.逆转药物外排泵的功能有望对抗多药耐药问题.在能危及人类生命的真菌病原菌白色念珠菌中,主要易化子超家族(MFS)类型转运蛋白Mdr1p能非特异性地向细胞外转运很多结构上不相关的抗真菌化合物,从而导致了白色念珠菌的多药耐药.本研究报道了一个有悖过往认知的案例:一个天然产物小檗碱不仅不会被白色念珠菌Mdr1p外排,而且还能特异性地挟持过表达的Mdr1p把自己运输进细胞.进一步研究发现,进入白色念珠菌细胞后的小檗碱能够在线粒体中积累,通过破坏线粒体膜电势和线粒体复合物I引起线粒体功能紊乱,从而杀死Mdr1p过表达的多药耐药白色念珠菌.在用Mdr1p过表达的白色念珠菌小鼠感染模型中,小檗碱治疗组小鼠的平均存活时间(MST)得到了显著延长.本研究提示找寻药物外排泵的逆转剂可能为如何克服多药耐药问题提供了一个新的思路.

Exploring the molecular basis for selective C–H functionalization in plant P450s

Highly prevalent in nature,cytochrome P450 enzymes are powerful biocatalysts for selective C–H functionalization[1].These heme-containing enzymes activate inert C–H bonds within complex molecules for a plethora of transformations with exquisite regio-,chemo-and stereoselectivity.Many plant P450s are of industrial relevance in the production of pharmaceuticals,fragrances,pesticides and vitamins,yet few have been employed commercially[2].Key examples include the P450 CYP71AV1 used for large-scale production of the antimalarial drug artemisinin,and CYP75 enzymes exploited for their differential hydroxylation abilities to manipulate color patterns in top-selling flowers[3].These cases illustrate a minuscule portion of the synthetic potential of P450s.

Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.

Single-chain variable fragment antibody constructs neutralize measles virus infection in vitro and in vivo

Despite the availability of an effective measles virus(MeV)vaccine and efforts to increase vaccine coverage by the WHO,UNICEF,and their partners,MeV has not been eradicated,and the estimated global measles death rose from 89,780 in 2016 to 207,500 in 2019.1 Because there is an effective measles vaccine,antiviral development for measles has not been prioritized,but recent outbreaks have highlighted the need for drugs to prevent transmission in unvaccinated populations and to protect and treat immunocompromised individuals.We identified several neutralizing mouse monoclonal antibodies(mAbs)that target the MeV fusion(F)protein in its prefusion state2 and inhibit fusion and viral infection.We engineered a single-chain variable fragment(scFv)from the most potent anti-MeV F mAb.The scFv retains the ability to inhibit fusion and prevents infection in vitro,and intranasal administration of the scFv antibody construct prevents infection in vivo.