汪贻广团队发展程序调控肿瘤及淋巴结免疫微环境的纳米递释新策略

近日,学术期刊《Nano Letters》在线发表了北京大学药学院天然药物及仿生药物国家重点实验室汪贻广研究团队的最新研究成果"Cooperative Self-Assembled Nanoparticle Induces Sequential Immunogenic Cell Death and Toll-Like ...     

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses are enveloped, positive-sense, and single-stranded RNA viruses, many of which are zoonotic pathogens that crossed over into humans. Seven coronavirus species, including SARS-CoV-2, have been discovered that, depending on the virus and host physiological condition, may cause mild or lethal respiratory disease. There is considerable variation in disease prevalence and severity across populations and communities. Importantly, minority populations in the United States appear to have been disproportionally affected by COVID-19 (1, 2). For example, in Chicago, more than 50% of COVID-19 cases and nearly 70% of COVID-19 deaths are in African Americans (who make up 30% of the population of Chicago) (1). While social and economic factors are largely responsible for driving COVID-19 health disparities, investigating genetic diversity at host genes related to SARS-CoV-2 infection could help identify functionally important variation, which may play a role in individual risk for severe COVID-19 infection.In this study, we focused on four key genes playing a role in SARS-CoV-2 infection (3). The ACE2 gene, encoding the angiotensin-converting enzyme-2 protein, was reported to be a main binding site for severe acute respiratory syndrome coronavirus (SARS-CoV) during an outbreak in 2003, and evidence showed stronger binding affinity to SARS-CoV-2, which enters the target cells via ACE2 receptors (3, 4). The ACE2 gene is located on the X chromosome (chrX); its expression level varies among populations (5); and it is ubiquitously expressed in the lung, blood vessels, gut, kidney, testis, and brain, all organs that appear to be affected as part of the COVID-19 clinical spectrum (6). SARS-CoV-2 infects cells through a membrane fusion mechanism, which in the case of SARS-CoV, is known to induce down-regulation of ACE2 (7). Such down-regulation has been shown to cause inefficient counteraction of angiotensin II effects, leading to enhanced pulmonary inflammation and intravascular coagulation (7). Additionally, altered expression of ACE2 has been associated with cardiovascular and cerebrovascular disease, which is highly relevant to COVID-19 as several cardiovascular conditions are associated with severe disease. TMPRSS2, located on the outer membrane of host target cells, binds to and cleaves ACE2, resulting in activation of spike proteins on the viral envelope and facilitating membrane fusion and endocytosis (8). Two additional genes, DPP4 and LY6E, have been shown to play an important role in the entry of SARS-CoV-2 virus into host cells. DPP4 is a known functional receptor for the Middle East respiratory syndrome coronavirus (MERS-CoV), causing a severe respiratory illness with high mortality (9, 10). LY6E encodes a glycosylphosphatidylinositol-anchored cell surface protein, which is a critical antiviral immune effector that controls coronavirus infection and pathogenesis (11). Mice lacking LY6E in hematopoietic cells were susceptible to murine coronavirus infection (11).Previous studies of genetic diversity at ACE2 and TMPRSS2 in global human populations did not include an extensive set of African populations (5, 12–14). No common coding variants (defined here as minor allele frequency [MAF] > 0.05) at ACE2 were identified in any prior population studies. However, few studies included diverse indigenous African populations whose genomes harbor the greatest diversity among humans. This leads to a substantial disparity in the representation of African ancestries in human genetic studies of COVID-19, impeding health equity as the transferability of findings based on non-African ancestries to African populations can be low (15). Including more African populations in studying the genetic diversity of genes involved in SARS-CoV-2 infection is extremely necessary. Additionally, the evolutionary forces underlying global patterns of genetic diversity at host genes related to SARS-CoV-2 infection are not well understood. Using methods to detect natural selection signatures at host genes related to viral infections helps identify putatively functional variants that could play a role in disease risk.We characterized genetic variation and studied natural selection signatures at ACE2, TMPRSS2, DPP4, and LY6E in ethnically diverse human populations by analyzing 2,012 genomes from ethnically diverse Africans (referred to as the “African diversity” dataset), 2,504 genomes from the 1000 Genomes Project (1KG), and whole-exome sequencing of 15,977 individuals of European ancestry (EA) and African ancestry from the Penn Medicine BioBank (PMBB) dataset (SI Appendix, Fig. S1). The African diversity dataset includes populations with diverse subsistence patterns (hunter-gatherers, pastoralists, agriculturalists) and speaking languages belonging to the four major language families in Africa (Khoesan; Niger–Congo, of which Bantu is the largest subfamily; Afroasiatic; and Nilo-Saharan). We identify functionally relevant variation, compare the patterns of variation across global populations, and provide insight into the evolutionary forces underlying these patterns of genetic variation. In addition, we perform an association study using the variants identified from whole-exome sequencing at the four genes and clinical traits derived from electronic health record (EHR) data linked to the subjects enrolled in the PMBB. The EHR data include diseases related to organ dysfunctions associated with severe COVID-19, such as respiratory, cardiovascular, liver, and renal complications. Our study of genetic variation in genes involved in SARS-CoV-2 infection provides data to investigate infection susceptibility within and between populations and indicates that variants in these genes may play a role in comorbidities relevant to COVID-19 severity.     

宝鸡市2000—2007年乙型肝炎流行病学特征和控制策略分析

目的了解宝鸡市乙型肝炎发病情况及流行病学特征，为制定控制策略和措施提供科学依据。方法采用描述流行病学方法，对2000-2007年宝鸡市乙型肝炎疫情资料进行统计分析。结果2000～2004年各年龄组发病率呈上升趋势，2005年起各年龄组发病率均有所下降，特别是14岁以下儿童发病率下降比较明显。农村发病明显高于城区。发病构成中农民所占比例最高，占乙型肝炎发病总数的51．85％，幼托儿童和散居儿童发病构成呈下降趋势。结论14岁以下儿童乙肝免疫防治策略已初见成效。应在加强新生儿及儿童乙型肝炎免疫接种工作的同时，加大对中青年及农村劳动人口乙型肝炎疫苗的免疫接种工作。     

影响医院业务收入因素的灰色关联分析

本文对影响医院业务收入的固定资产总值、专业设备资金、每门诊人次收费等八项主要因素运用灰色系统的理论加以分析,主要目的是找出对业务收入影响强弱的因素,分析原因,提出建议,旨在为领导制定计划、安排人员、分配物资等方面提供可靠的信息和依据。     

不同浓度含钠电解质溶液复苏对烧伤小儿机体内环境的影响

目的观察两种不同含钠浓度的电解质溶液对小儿烧伤液体复苏后机体内环境的影响。方法选择40例年龄6个月至两岁的小儿烧伤病例,烧伤面积从25%～54%,随机分成俩组,每组20例,A组采用平衡盐溶液(A组含钠量130mmol/L),B组采用高钠复方乳酸钠溶液(含钠量174mmol/L),两种不同的电解质溶液行液体复苏。并分别于伤后1～4天抽取血标本检测K 、Na 、Cl-和HCO3-四种电解质,记录各时段液体输入量和尿量以及血浆晶体渗透压等。结果A组伤后第一天的补液量明显高于B组,且A组血清Na 、HCO3-浓度明显下降,伤后第二天逐步回升。A、B两组K 浓度于伤后第三、第四天明显下降。结论电解质溶液中钠离子浓度的不同对小儿烧伤机体内环境的影响较大,含钠量高的溶液可能更有利于烧伤小儿机体内环境保持稳定。     

The remedial effect of soluble interleukin-1 receptor type Ⅱ on endometriosis in the nude mouse model

Objective： Recent studies have shown that the local expression of soluble interleukin （IL） -1 receptor type Ⅱ （slL-1 R Ⅱ ） in endometrial tissue of women with endometriosis is decreased, and the depression of IL-1 R Ⅱ was more significant in infertile women than that in fertile women with endometriosis. In this research, we investigated the remedial effect of slL-1-R Ⅱ administration on endometriosis in the nude mouse model. Methods： Nineteen nude model mice with endometriosis were randomly divided into three groups： group A was treated by intraperitoneal administration with only slL-1 R Ⅱ for two weeks, group B was similarly treated with only IL- 1, and group C （control） was administered saline. After 2 weeks, the size of the ectopic endometrial lesions was calculated, and the expression of vascular endothelial growth factor （VEGF） and B-cell lymphoma leukemia-2 （Bcl- 2） were detected by immunohistochemistry. The IL-8 and VEGF levels in the peritoneal fluid （PF） and serum were also measured by enzyme-linked immunosorbent assay （ELISA）. Results： The mean size of ectopic endometrial lesion did not differ between the three groups （P 〉 0.05）. Compared with the control, the expression of VEGF and Bcl-2 was significantly lower in group A, and higher in group B. In the three groups, the levels of IL-8 in the PF and serum were highest in group A, and lowest in group B. Conclusion： slL-1 R Ⅱ may suppresse hyperplasia of ectopic endometriosis, perhaps by reducing the expression of certain cytokines, such as VEGF, IL-8, and Bcl-2, which could provide a new clinical strategy for the treatment of endometriosis.     

肾转移瘤的CT诊断特征

目的：探讨肾转移瘤的CT诊断特征．方法：回顾性分析12例肾转移瘤及12例原发性肾癌的CT表现．结果：12例肾转移瘤共检出42个病灶,4例单发,8例为双侧、多灶性;9个病灶位于肾髓质内呈楔形,33个病灶累及肾皮髓质、呈类圆形;41个病灶平扫呈等密度,所有病灶增强后均呈轻度强化,均未见包膜;8个病灶引起肾轮廓改变;7例肾转移瘤同时伴有其它部位及脏器的转移．12例肾原发癌均为单发,同时累及肾皮髓质,呈类圆形或不规则形;10例病灶平扫呈等、低密度;1例增强后轻度强化,11例增强后呈中、重度不均匀强化,3例可见假包膜;10例引起肾轮廓改变;2例伴有肾静脉癌栓,1例伴有肾周淋巴结转移．结论：肾转移瘤具有典型的影像学特点,了解这一特点有助于肾转移瘤的诊断．     

趋势季节模型在菌痢发病预测中的应用

目的探讨趋势季节模型是否适用于细菌性痢疾(简称菌痢)的发病预测。方法利用我中心疾病监测信息系统2001-2006年鹤壁市菌痢发病资料,用趋势季节模型的方法预测2007-2009年鹤壁市各季度的菌痢发病率,观察预测发病率与实际发病率是否一致。结果用趋势季节模型的方法预测,2007年各季度预测发病率分别为0.32‰、1.55‰、4.08‰、0.96‰,实际发病率分别为0.37‰、1.31‰、3.77‰、0.94‰;2008年各季度预测发病率分别为0.29‰、1.41‰、3.96‰、0.36‰,实际发病率分别为0.44‰、0.91‰、4.04‰、0.52‰;2009年1、2、3、4季度预测发病率分别为0.26‰、1.27‰、3.31‰、0.56‰,实际发病率分别为0.17‰、1.20‰、2.67‰、0.43‰,利用趋势季节模型计算出的预测发病率与实际发病率均相接近。结论利用趋势季节模型预测我市菌痢的发病率是适用的,其它地区、其它疾病的发病只要符合趋势季节变化,均可使用该模型进行预测。     

高频部分液体通气对吸入伤犬呼吸循环功能的影响

目的　观察高频部分液体通气 (highfrequencypartialliquidventilation ,HFPLV)对吸入性损伤犬肺力学、氧合和血流动力学参数的影响。　方法　 16条犬经吸入蒸气 ,造成重度吸入性损伤模型 ,并随机分为对照组和治疗组。两组动物致伤后均行高频喷射通气 (highfrequencyjetventila tiot,HFJV) ,治疗组同时经气管导管缓慢注入氟碳液体 (3ml/kg体重 ) ,行HFPLV治疗 ,于通气后3 0、60和 90min时测定两组动物血气、肺顺应性、气道阻力及血流动力学参数。　结果　治疗组PaO2 呈进行性上升 ,在各时相点与致伤后比较差异有显著性意义 (P <0 .0 5 ) ,而对照组各时相点与致伤后比较差异无显著性意义 (P >0 .0 5 ) ;治疗组PaCO2 也逐渐增高 ,于 60、90min显著高于致伤后水平 (P <0 .0 5 )。与对照组比较 ,治疗组各时相点的PaO2 稍有升高 (P >0 .0 5 ) ,PaCO2 于 90min显著增高 (P <0 .0 5 ) ,而两组动 /静态气道阻力、肺顺应性和血流动力学参数比较 ,差异均无显著性意义 (P >0 .0 5 )。　结论　HFPLV与单纯HFJV相比 ,更有利于吸入性损伤的动脉氧合 ,对血流动力学参数无明显不利影响     

盐酸去甲万古霉素纯度控制方法的改进

目的：改进盐酸去甲万古霉素质量控制的方法。方法：在中国药典与美国药典方法的基础上,优化了两种不同的流动相系统(三乙胺-乙腈-四氢呋喃系统和磷酸氢二铵-甲醇系统),用梯度洗脱对盐酸去甲万古霉素及其有关物质进行分离。结果：与中国药典方法相比,分离效果显著提高,两种方法在2．5～40μg范围内,峰面积与进样量线性关系良好,检测限10ng。结论：改进后的RP-HPLC方法能更加真实的反映去甲万古霉素及其有关物质的含量。