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Recent advances in understanding genetic variants associated with economically important traits in sheep

Song-Song XU, Meng-Hua LI

《农业科学与工程前沿(英文)》 2017年 第4卷 第3期   页码 279-288 doi: 10.15302/J-FASE-2017151

摘要: Sheep are one of the most economically important domesticated animals for human society. However, genetic improvements for the key traits associated with meat, growth, milk, wool, reproduction, horns and tails progress slowly using conventional crossbreeding methods. With the development and utilization of high-throughput screening technologies over the last decade, a list of functional genes and genetic variants associated with these traits has been identified. This review covers recent genome-wide studies on sheep productive traits using high-throughput screening technologies, including those based on single-nucleotide polymorphisms and copy number variants at the whole-genome level (e.g., genome-wide association studies), transcriptome and DNA methylation sequences. Additionally, comprehensive information on functional genes and genetic variants associated with economically important traits in sheep is provided.

关键词: sheep     high-throughput screening     productive traits     genome-wide studies    

Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies

null

《医学前沿(英文)》 2015年 第9卷 第2期   页码 146-161 doi: 10.1007/s11684-014-0373-8

摘要:

Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

关键词: obesity     genetics     genome-wide association studies     body mass index     fat mass- and obesity-associated gene    

A review on the electric vehicle routing problems: Variants and algorithms

Hu QIN , Xinxin SU, Teng REN, Zhixing LUO

《工程管理前沿(英文)》 2021年 第8卷 第3期   页码 370-389 doi: 10.1007/s42524-021-0157-1

摘要: Over the past decade, electric vehicles (EVs) have been considered in a growing number of models and methods for vehicle routing problems (VRPs). This study presents a comprehensive survey of EV routing problems and their many variants. We only consider the problems in which each vehicle may visit multiple vertices and be recharged during the trip. The related literature can be roughly divided into nine classes: Electric traveling salesman problem, green VRP, electric VRP, mixed electric VRP, electric location routing problem, hybrid electric VRP, electric dial-a-ride problem, electric two-echelon VRP, and electric pickup and delivery problem. For each of these nine classes, we focus on reviewing the settings of problem variants and the algorithms used to obtain their solutions.

关键词: electric vehicles     routing     recharging stations     exact algorithms     metaheuristics    

SARS-CoV-2 variants, immune escape, and countermeasures

《医学前沿(英文)》 2022年 第16卷 第2期   页码 196-207 doi: 10.1007/s11684-021-0906-x

摘要: Coronavirus disease 2019 (COVID-19) has become a global pandemic disease. SARS-CoV-2 variants have aroused great concern and are expected to continue spreading. Although many countries have promoted roll-out vaccination, the immune barrier has not yet been fully established, indicating that populations remain susceptible to infection. In this review, we summarize the literature on variants of concern and focus on the changes in their transmissibility, pathogenicity, and resistance to the immunity constructed by current vaccines. Furthermore, we analyzed relationships between variants and breakthrough infections, as well as the paradigm of new variants in countries with high vaccination rates. Terminating transmission, continuing to strengthen variant surveillance, and combining nonpharmaceutical intervention measures and vaccines are necessary to control these variants.

关键词: SARS-CoV-2     COVID-19     vaccine     immune escape     breakthrough     prevention    

Penetrance estimation of variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

《医学前沿(英文)》 2021年 第15卷 第6期   页码 877-886 doi: 10.1007/s11684-021-0863-4

摘要: Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%–80.7%) in relatives and 74.5% (95% CI 70.2%–78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.

关键词: penetrance     PRRT2     paroxysmal kinesigenic dyskinesia     infantile convulsions    

variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants

《医学前沿(英文)》 2024年 第18卷 第1期   页码 81-97 doi: 10.1007/s11684-023-1006-x

摘要: Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine. Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation. Here, a Pakistani family with parental consanguinity was presented, characterized with severe intellectual disability (ID), spastic paraplegia, and deafness. Homozygosity mapping, integrated single nucleotide polymorphism (SNP) array, whole-exome sequencing, and whole-genome sequencing were performed, and homozygous variants in TMEM141 (c.270G>A, p.Trp90*), DDHD2 (c.411+767_c.1249-327del), and LHFPL5 (c.250delC, p.Leu84*) were identified. A Tmem141p.Trp90*/p.Trp90* mouse model was generated. Behavioral studies showed impairments in learning ability and motor coordination. Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells. Transmission electron microscopy showed abnormal mitochondrial morphology. Furthermore, studies on a human in vitro neuronal model (SH-SY5Y cells) with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function, possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model. Conclusively, panoramic variation analysis revealed that multilocus genomic variations of TMEM141, DDHD2, and LHFPL5 together caused variable phenotypes in patient. Notably, the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

关键词: neurodevelopmental disorder     autosomal recessive intellectual disability     consanguinity     spastic paraplegia     hearing loss     TMEM141    

High frequency of alternative splicing variants of the oncogene in neuroendocrine tumors of the pancreas

《医学前沿(英文)》 2023年 第17卷 第5期   页码 907-923 doi: 10.1007/s11684-023-1009-7

摘要: The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK6/7 in cells. These results suggested that FAK6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.

关键词: FAK6/7     SRRM4     neuroendocrine neoplasms     pancreas     breast    

Association of gene variants with juvenile amyotrophic lateral sclerosis

《医学前沿(英文)》 2024年 第18卷 第1期   页码 68-80 doi: 10.1007/s11684-023-1005-y

摘要: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.

关键词: TRMT2B     amyotrophic lateral sclerosis     mitochondrial complex I     tRNA methylation     reactive oxygen species    

Identification of variants associated with sporadic thoracic aortic dissection: a case--control study

《医学前沿(英文)》 2021年 第15卷 第3期   页码 438-447 doi: 10.1007/s11684-020-0826-1

摘要: Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 × 10−6) after 10 000 times permutation test (P = 2.49 × 10−3). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.

关键词: sporadic thoracic aortic dissection     exome sequencing     gene COL3A1     case–control study     extracellular matrix    

R158Q and G212S, novel pathogenic compound heterozygous variants in of Gitelman syndrome

《医学前沿(英文)》 2022年 第16卷 第6期   页码 932-945 doi: 10.1007/s11684-022-0963-9

摘要: The dysfunction of Na+-Cl cotransporter (NCC) caused by mutations in solute carrier family12, member 3 gene (SLC12A3) primarily causes Gitelman syndrome (GS). In identifying the pathogenicity of R158Q and G212S variants of SLC12A3, we evaluated the pathogenicity by bioinformatic, expression, and localization analysis of two variants from a patient in our cohort. The prediction of mutant protein showed that p.R158Q and p.G212S could alter protein’s three-dimensional structure. Western blot showed a decrease of mutant Ncc. Immunofluorescence of the two mutations revealed a diffuse positive staining below the plasma membrane. Meanwhile, we conducted a compound heterozygous model—Ncc R156Q/G210S mice corresponding to human NCC R158Q/G212S. NccR156Q/G210S mice clearly exhibited typical GS features, including hypokalemia, hypomagnesemia, and increased fractional excretion of K+ and Mg2+ with a normal blood pressure level, which made NccR156Q/G210S mice an optimal mouse model for further study of GS. A dramatic decrease and abnormal localization of the mutant Ncc in distal convoluted tubules contributed to the phenotype. The hydrochlorothiazide test showed a loss of function of mutant Ncc in NccR156Q/G210S mice. These findings indicated that R158Q and G212S variants of SLC12A3 were pathogenic variants of GS.

关键词: Gitelman syndrome     mouse model     compound heterozygous     hypokalemia     Slc12a3    

U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population

null

《医学前沿(英文)》 2015年 第9卷 第4期   页码 478-486 doi: 10.1007/s11684-015-0420-0

摘要:

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TL-SNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P<0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P<0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84–3.14), 1.36 (1.03–1.79), 1.01 (0.76–1.35), and 1.37 (1.03–1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

关键词: esophageal squamous cell carcinoma     telomere length     genetic variants     susceptibility     genome-wide association study    

新冠病毒变异株——新型mRNA疫苗能否经受挑战?

Jennifer Welsh

《工程(英文)》 2021年 第7卷 第6期   页码 712-714 doi: 10.1016/j.eng.2021.04.005

Machine learning modeling identifies hypertrophic cardiomyopathy subtypes with genetic signature

《医学前沿(英文)》 2023年 第17卷 第4期   页码 768-780 doi: 10.1007/s11684-023-0982-1

摘要: Previous studies have revealed that patients with hypertrophic cardiomyopathy (HCM) exhibit differences in symptom severity and prognosis, indicating potential HCM subtypes among these patients. Here, 793 patients with HCM were recruited at an average follow-up of 32.78 ± 27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features. Furthermore, we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data. Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings. Consequently, two subtypes characterized by different clinical outcomes were identified in HCM. Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course, while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression. Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities. Furthermore, the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction. By employing echocardiography and genetic screening for the 46 genes, HCM can be classified into two subtypes with distinct clinical outcomes.

关键词: machine learning methods     hypertrophic cardiomyopathy     genetic risk    

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between

Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen

《医学前沿(英文)》 2021年 第15卷 第2期   页码 275-291 doi: 10.1007/s11684-020-0779-4

摘要: Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER=1.95, =0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

关键词: lung cancer     genome-wide association study     function annotation     immune     homologous recombination repair deficiency     genetic heterogeneity    

Neutralization against SARS-CoV-2 Delta/Omicron variants and B cell response after inactivated vaccination

《医学前沿(英文)》 2023年 第17卷 第4期   页码 747-757 doi: 10.1007/s11684-022-0954-x

摘要: Emerging SARS-CoV-2 variants have made COVID-19 convalescents susceptible to re-infection and have raised concern about the efficacy of inactivated vaccination in neutralization against emerging variants and antigen-specific B cell response. To this end, a study on a long-term cohort of 208 participants who have recovered from COVID-19 was conducted, and the participants were followed up at 3.3 (Visit 1), 9.2 (Visit 2), and 18.5 (Visit 3) months after SARS-CoV-2 infection. They were classified into three groups (no-vaccination (n = 54), one-dose (n = 62), and two-dose (n = 92) groups) on the basis of the administration of inactivated vaccination. The neutralizing antibody (NAb) titers against the wild-type virus continued to decrease in the no-vaccination group, but they rose significantly in the one-dose and two-dose groups, with the highest NAb titers being observed in the two-dose group at Visit 3. The NAb titers against the Delta variant for the no-vaccination, one-dose, and two-dose groups decreased by 3.3, 1.9, and 2.3 folds relative to the wild-type virus, respectively, and those against the Omicron variant decreased by 7.0, 4.0, and 3.8 folds, respectively. Similarly, the responses of SARS-CoV-2 RBD-specific B cells and memory B cells were boosted by the second vaccine dose. Results showed that the convalescents benefited from the administration of the inactivated vaccine (one or two doses), which enhanced neutralization against highly mutated SARS-CoV-2 variants and memory B cell responses. Two doses of inactivated vaccine among COVID-19 convalescents are therefore recommended for the prevention of the COVID-19 pandemic, and vaccination guidelines and policies need to be updated.

关键词: COVID-19 convalescent     SARS-CoV-2     inactivated vaccination     neutralizing antibody     B cell response    

标题 作者 时间 类型 操作

Recent advances in understanding genetic variants associated with economically important traits in sheep

Song-Song XU, Meng-Hua LI

期刊论文

Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies

null

期刊论文

A review on the electric vehicle routing problems: Variants and algorithms

Hu QIN , Xinxin SU, Teng REN, Zhixing LUO

期刊论文

SARS-CoV-2 variants, immune escape, and countermeasures

期刊论文

Penetrance estimation of variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

期刊论文

variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants

期刊论文

High frequency of alternative splicing variants of the oncogene in neuroendocrine tumors of the pancreas

期刊论文

Association of gene variants with juvenile amyotrophic lateral sclerosis

期刊论文

Identification of variants associated with sporadic thoracic aortic dissection: a case--control study

期刊论文

R158Q and G212S, novel pathogenic compound heterozygous variants in of Gitelman syndrome

期刊论文

U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population

null

期刊论文

新冠病毒变异株——新型mRNA疫苗能否经受挑战?

Jennifer Welsh

期刊论文

Machine learning modeling identifies hypertrophic cardiomyopathy subtypes with genetic signature

期刊论文

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between

Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen

期刊论文

Neutralization against SARS-CoV-2 Delta/Omicron variants and B cell response after inactivated vaccination

期刊论文