bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative transcriptomics of high-altitude Vulpes and their low-altitude relatives
Authors: Lyu Tianshu , Yang Xiufeng , Zhao Chao , Wang Lidong , Zhou Shengyang , Shi Lupeng , Dong Yuehuan , Dou Huashan , Zhang Honghai
Published: September 2022

The harsh environment of Qinghai-Tibet Plateau (QTP) imposes strong selective stresses (e.g., hypoxia, high UV-radiation, and extreme temperature) to the native species, which have driven striking phenotypic and genetic adaptations. Although the mechanisms of high-altitude adaptation have been explored for many plateau species, how the phylogenetic background contributes to genetic adaption to high-altitude of Vulpes is largely unknown. In this study, we sequenced transcriptomic data across multiple tissues of two high-altitude Vulpes (Vulpes vulpes montana and Vulpes ferrilata) and their low-altitude relatives (Vulpes corsac and Vulpes lagopus) to search the genetic and gene expression changes caused by high-altitude environment. The results indicated that the positive selection genes (PSGs) identified by both high-altitude Vulpes are related to angiogenesis, suggesting that angiogenesis may be the result of convergent evolution of Vulpes in the face of hypoxic selection pressure. In addition, more PSGs were detected in V. ferrilata than in V. v. montana, which may be related to the longer adaptation time of V. ferrilata to plateau environment and thus more genetic changes. Besides, more PSGs associated with high-altitude adaptation were identified in V. ferrilata compared with V. v. montana, indicating that the longer the adaptation time to the high-altitude environment, the more genetic alterations of the species. Furthermore, the result of expression profiles revealed a tissue-specific pattern between Vulpes. We also observed that differential expressed genes in the high-altitude group exhibited species-specific expression patterns, revealed a convergent expression pattern of Vulpes in high-altitude environment. In general, our research provides a valuable transcriptomic resource for further studies, and expands our understanding of high-altitude adaptation within a phylogenetic context.
Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China
Authors: Xia Zhongmin , Wang Xudong , Ye Huiming , Gao Chunliu , Zhou Xiaoman , Chen Jing , Ge Yunsheng , Li Juan , Zhou Yulin , Guo Qiwei
Published: September 2022

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is caused by pathogenic variants of G6PD that result in decreased G6PD activity, is an X-linked inherited inborn error of metabolism that occurs worldwide. Individuals with G6PD deficiency and heterozygous females with normal G6PD activity (i.e., all individuals with pathogenic G6PD variants) are at risk of developing hemolytic anemia under increased oxidative challenge. However, this risk can be minimized by timely diagnosis. Currently, two assays are used to diagnose G6PD deficiency in China: evaluation of enzymatic activity and targeted genotyping. In terms of identification of all individuals with pathogenic G6PD variants, the performance and cost of different diagnostic strategies (isolated or combined evaluation of G6PD activity and G6PD genotyping) can vary, and these factors should be comprehensively evaluated. In this study, we examined 555 infants (437 males and 118 females) who were positive for the newborn screening of G6PD deficiency. We first evaluated the diagnostic performances of enzymatic testing and targeted genotyping. Both assays attained 100% specificities and positive predictive values for both male and female infants. In contrast, the sensitivities and negative predictive values (NPVs) of the diagnostic tests were different for male and female infants. For male infants, the sensitivities were 99.8 and 98.3%, and the NPVs were 94.1% and 69.6%, for enzymatic testing and targeted genotyping, respectively. For female infants, the sensitivities were 62.5% and 97.9%, and the NPVs were 37.9% and 91.7%, for enzymatic testing and targeted genotyping, respectively. We also evaluated the cost of the five different diagnostic strategies. The combination of G6PD activity testing of all infants, followed by genotyping of female infants with normal G6PD activity, attained high diagnostic sensitivity (99.8%) at a low cost (8.60 USD per diagnosed case). In the future, simultaneous examination of G6PD activity and whole-exon or whole-gene G6PD sequencing could become a standard clinical practice. Our data provide references for clinical practice on the standardization of current and future interventions for G6PD deficiency in China.
Evaluation of GENESIS, SAIGE, REGENIE and fastGWA-GLMM for genome-wide association studies of binary traits in correlated data
Authors: Gurinovich Anastasia , Li Mengze , Leshchyk Anastasia , Bae Harold , Song Zeyuan , Arbeev Konstantin G. , Nygaard Marianne , Feitosa Mary F , Perls Thomas T , Sebastiani Paola
Published: September 2022

Performing a genome-wide association study (GWAS) with a binary phenotype using family data is a challenging task. Using linear mixed effects models is typically unsuitable for binary traits, and numerical approximations of the likelihood function may not work well with rare genetic variants with small counts. Additionally, imbalance in the case-control ratios poses challenges as traditional statistical methods such as the Score test or Wald test perform poorly in this setting. In the last couple of years, several methods have been proposed to better approximate the likelihood function of a mixed effects logistic regression model that uses Saddle Point Approximation (SPA). SPA adjustment has recently been implemented in multiple software, including GENESIS, SAIGE, REGENIE and fastGWA-GLMM: four increasingly popular tools to perform GWAS of binary traits. We compare Score and SPA tests using real family data to evaluate computational efficiency and the agreement of the results. Additionally, we compare various ways to adjust for family relatedness, such as sparse and full genetic relationship matrices (GRM) and polygenic effect estimates. We use the New England Centenarian Study imputed genotype data and the Long Life Family Study whole-genome sequencing data and the binary phenotype of human extreme longevity to compare the agreement of the results and tools’ computational performance. The evaluation suggests that REGENIE might not be a good choice when analyzing correlated data of a small size. fastGWA-GLMM is the most computationally efficient compared to the other three tools, but it appears to be overly conservative when applied to family-based data. GENESIS, SAIGE and fastGWA-GLMM produced similar, although not identical, results, with SPA adjustment performing better than Score tests. Our evaluation also demonstrates the importance of adjusting by full GRM in highly correlated datasets when using GENESIS or SAIGE.
Case Report: A novel desmoplakin mutation in a taiwanese woman with familial dilated cardiomyopathy that necessitated heart transplantation
Authors: Chang Yi-Han , Lin Pei , Lin Jia-Ling , Huang Hsin-Yu , Hsu Chao-Kai , Hsu Chih-Hsin
Published: September 2022

Around one-third of patients diagnosed with idiopathic dilated cardiomyopathy (DCM) turn out to be familial cases, in only a few of which the identification of a pathogenic/likely pathogenic variant could be achieved. Cardiomyopathy caused by desmoplakin gene mutations represents a distinct form with a high prevalence of left ventricle involvement. We report a novel desmoplakin mutation carried by two individuals in a Taiwanese family, in which the proband recovered well after heart transplantation and under medical control, while her son had received an implantable cardioverter defibrillator and has been under guideline-directed medical therapy. The present study broadens the genetic spectrum of this disease entity and strengthens the notion that a detailed family history with genetic study contributes to the early detection and treatment of inherited diseases.
YgiM may act as a trigger in the sepsis caused by Klebsiella pneumoniae through the membrane-associated ceRNA network
Authors: Han Mingxiao , Chen Zhihao , He Ping , Li Ziyuan , Chen Qi , Tong Zelei , Wang Min , Du Hong , Zhang Haifang
Published: September 2022

Sepsis is one of the diseases that can cause serious mortality. In E. coli, an inner membrane protein YgiM encoded by gene ygiM can target the eukaryotic peroxisome. Peroxisome is a membrane-enclosed organelle associated with the ROS metabolism and was reported to play the key role in immune responses and inflammation during the development of sepsis. Klebsiella pneumoniae (K. pneumoniae) is one of the important pathogens causing sepsis. However, the function of gene vk055_4013 which is highly homologous to ygiM of E. coli has not been demonstrated in K. pneumoniae. In this study, we prepared ΔygiM of K. pneumoniae ATCC43816, and found that the deletion of ygiM did not affect bacterial growth and mouse mortality in the mouse infection model. Interestingly, ΔygiM not only resulted in reduced bacterial resistance to macrophages, but also attenuated pathological manifestations in mouse organs. Furthermore, based on the data of Gene Expression Omnibus, the expression profiles of micro RNAs (miRNAs) and messenger RNAs (mRNAs) in the serum of 44 sepsis patients caused by K. pneumoniae infection were analyzed, and 11 differently expressed miRNAs and 8 DEmRNAs associated with the membrane function were found. Finally, the membrane-associated competing endogenous RNAs (ceRNAs) network was constructed. In this ceRNAs network, DEmiRNAs (hsa-miR-7108-5p, hsa-miR-6780a-5p, hsa-miR-6756-5p, hsa-miR-4433b-3p, hsa-miR-3652, hsa-miR-342-3p, hsa-miR-32-5p) and their potential downstream target DEmRNAs (VNN1, CEACAM8, PGLYRP1) were verified in the cell model infected by wild type and ΔygiM of K. pneumoniae, respectively. Taken together, YgiM may trigger the sepsis caused by K. pneumoniae via membrane-associated ceRNAs. This study provided new insights into the role of YgiM in the process of K. pneumoniae induced sepsis.
Construction of ceRNA network and identification of hub genes in aniridia-associated keratopathy using bioinformatics analysis
Authors: Wu Jiawen , Zhang Daowei , Wu Jihong , Zhang Shenghai
Published: September 2022

Aniridia-associated keratopathy (AAK) is characteristic at ocular surface of aniridia caused by haploinsufficiency of PAX6. Competing endogenous RNA (ceRNA) has been reported to play an important role in various diseases, whereas its function on AAK is unclear. The microarray data of 20 AAK patients and 20 healthy people were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed lncRNAs, miRNAs, and mRNAs were analyzed using “limma” packages and weighted gene co-expression network analysis (WGCNA). A ceRNA network was constructed by Cytoscape 3.9.1, and miR-224-5p, miR-30a-5p, and miR-204-5p were at the center of the network. CIBERSORTx algorithm and ssGSEA analyses revealed that AAK was associated with immune cell infiltration, showing that activated Mast cells increased while resting Mast cells decreased and NK cells decreased in AAK. Type II INF Response, CCR, parainflammation, T cell co-stimulation, and APC co-stimulation of AAK patients differed from healthy individuals. Additionally, the ROC curve of five genes, MITF(AUC = 0.988), RHOB(AUC = 0.973), JUN(AUC = 0.953), PLAUR (AUC = 0.925), and ARG2 (AUC = 0.915) with high confidence in predicting AAK were identified. Gene set enrichment analysis (GSEA) analysis of hub genes enriched in the IL-17 signaling pathway.
The impact of COVID-19 on safe abortion access in Africa: An analysis through a framework of reproductive justice and lens of structural violence
Authors: Tiew Amanda , Berro Pizzarossa Lucía , Jastaniah Ibtehal , Jayaweera Ruvani T.
Published: September 2022

The SARS-CoV-2 virus causing the coronavirus disease (COVID-19) global pandemic heightened restrictions on sexual and reproductive health and rights (SRHR), especially concerning safe abortion access. The African region has been particularly susceptible to the impact of COVID-19 on sexual and reproductive health services. Using a framework of reproductive justice, we interviewed key informants from the Mobilizing Action around Medication Abortion (MAMA) Network regarding the impacts of structural violence and COVID-19 on SRHR programming in Africa, particularly programming on self-managed abortion. We identified themes of lacking infrastructures of support, emergent marginality, and neocolonial funding environments as facets of structural violence within the context of the MAMA Network, as heightened by the COVID-19 global pandemic.
Mannose inhibits Plasmodium parasite growth and cerebral malaria development via regulation of host immune responses
Authors: Lv Li , Xu Zihao , Zhao Meichen , Gao Jian , Jiang Rumeng , Wang Qian , Shi Xiaoyu
Published: September 2022

D-mannose can be transported into a variety of cells via glucose transporter (GLUT), and supraphysiological levels of D-mannose impairs tumor growth and modulates immune cell function through mechanisms such as interference with glycolysis and induction of oxidative stress. Blood-stage Plasmodium mainly depends on glycolysis for energy supply and pathological immune response plays a vital role in cerebral malaria. However, it is not clear whether mannose affects malaria blood-stage infection. Here, we fed D-mannose to Plasmodium berghei-infected mice and found weight loss and reduced parasitemia without apparent side effects. Compromised parasitemia in C57BL/6 mice was accompanied by an increase in splenic macrophages compared to an untreated group. When mannose was applied to a rodent experimental cerebral malaria (ECM) model, the incidence of ECM decreased. Expression of activation marker CD69 on T cells in peripheral blood and the brain were reduced, and cerebral migration of activated T cells was prevented by decreased expression of CXCR3. These findings suggest that mannose inhibits Plasmodium infection by regulating multiple host immune responses and could serve as a potential strategy for facilitating malaria treatment.
Molecular Characteristics of T Cell-Mediated Tumor Killing in Hepatocellular Carcinoma
Authors: Hong Wei-feng , Liu Mou-yuan , Liang Li , Zhang Yang , Li Zong-juan , Han Keqi , Du Shi-suo , Chen Yan-jie , Ma Li-heng
Published: September 2022

Background

Although checkpoint blockade is a promising approach for the treatment of hepatocellular carcinoma (HCC), subsets of patients expected to show a response have not been established. As T cell-mediated tumor killing (TTK) is the fundamental principle of immune checkpoint inhibitor therapy, we established subtypes based on genes related to the sensitivity to TKK and evaluated their prognostic value for HCC immunotherapies.

Methods

Genes regulating the sensitivity of tumor cells to T cell-mediated killing (referred to as GSTTKs) showing differential expression in HCC and correlations with prognosis were identified by high-throughput screening assays. Unsupervised clustering was applied to classify patients with HCC into subtypes based on the GSTTKs. The tumor microenvironment, metabolic properties, and genetic variation were compared among the subgroups. A scoring algorithm based on the prognostic GSTTKs, referred to as the TCscore, was developed, and its clinical and predictive value for the response to immunotherapy were evaluated.

Results

In total, 18 out of 641 GSTTKs simultaneously showed differential expression in HCC and were correlated with prognosis. Based on the 18 GSTTKs, patients were clustered into two subgroups, which reflected distinct TTK patterns in HCC. Tumor-infiltrating immune cells, immune-related gene expression, glycolipid metabolism, somatic mutations, and signaling pathways differed between the two subgroups. The TCscore effectively distinguished between populations with different responses to chemotherapeutics or immunotherapy and overall survival.

Conclusions

TTK patterns played a nonnegligible role in formation of TME diversity and metabolic complexity. Evaluating the TTK patterns of individual tumor will contribute to enhancing our cognition of TME characterization, reflects differences in the functionality of T cells in HCC and guiding more effective therapy strategies.
The emerging roles of interstitial macrophages in pulmonary fibrosis: A perspective from scRNA-seq analyses
Authors: Gu Yanrong , Lawrence Toby , Mohamed Rafeezul , Liang Yinming , Yahaya Badrul Hisham
Published: September 2022

Pulmonary fibrosis is an irreversible and progressive disease affecting the lungs, and the etiology remains poorly understood. This disease can be lethal and currently has no specific clinical therapeutic regimen. Macrophages, the most common type of immune cell in the lungs, have been reported to play a key role in the pathogenesis of fibrotic disease. The lung macrophage population is mostly composed of alveolar macrophages and interstitial macrophages, both of which have not been thoroughly studied in the pathogenesis of lung fibrosis. Interstitial macrophages have recently been recognised for their participation in lung fibrosis due to new technology arising from a combination of bioinformatics and single-cell RNA sequencing analysis. This paper reviews recent developments regarding lung macrophage classification and summarizes the origin and replenishment of interstitial macrophages and their function in pulmonary fibrosis.
Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis
Authors: Koch Clarissa M. , Prigge Andrew D. , Setar Leah , Anekalla Kishore R. , Do-Umehara Hahn Chi , Abdala-Valencia Hiam , Politanska Yuliya , Shukla Avani , Chavez Jairo , Hahn Grant R. , Coates Bria M.
Published: September 2022

Background

Respiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.

Methods

Nasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS (</= 3 days), prolonged NIS (> 3 days), and IMV was compared.

Findings

Increased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for </= 3 days, despite both groups requiring an equal degree of respiratory support at the time of sampling. Infants who required invasive mechanical ventilation had increased expression of genes involved in neutrophil activation and cell death.

Interpretation

Increased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.
Validation of the X-ray microtomography in the assessment of duodenal morphometry and surface area in celiac disease
Authors: Virta Johannes , Hannula Markus , Lindfors Katri , Tamminen Ilmari , Taavela Juha , Huhtala Heini , Kaukinen Katri , Saavalainen Päivi , Hyttinen Jari , Kurppa Kalle
Published: September 2022

Background

Duodenal histology remains the diagnostic reference standard in celiac disease. However, traditional methods have suboptimal sensitivity and reproducibility for early mucosal changes and research purposes. We validated a recently introduced micro-CT imaging method for an accurate digital evaluation of duodenal histomorphometry and mucosal surface areas.

Methods

Endoscopic biopsies from 58 individuals were utilized for the micro-CT imaging, selecting histological changes ranging from normal to severely damaged mucosa. The imaging protocol was optimized for practicability and resolution. The Bland–Altman method was applied to test intra- and interobserver variations in the blinded measurements.

Results

The 3D micro-CT reconstructions enabled easy and precise digital cutting with optimal orientation and computer-assisted measurement of the surface area. Intraobserver analysis of morphological measurements showed a mean difference of 0.011 with limits of agreement (LA) from -0.397 to 0.375 and a standard deviation (SD) of 0.197. The corresponding figures for interobserver analysis were 0.080, from -0.719 to 0.537 and 0.320, respectively. The intraclass correlation coefficients (ICC) for the intraobserver and interobserver variations were 0.981 and 0.954, respectively. Intraobserver surface area analysis yielded a mean difference of 0.010, LA from -0.764 to 0.785 and an SD of 0.395, and an interobserver analysis mean difference of 0.028, LA from -0.642 to 0.698 and SD of 0.342. The respective ICCs for the intra- and interobserver variations were 0.963 and 0.972.

Conclusions

Micro-CT showed excellent accuracy and reproducibility in the evaluation of mucosal morphometry and surface areas. The improved sensitivity for histological changes is a powerful tool for the diagnosis of celiac disease and for clinical and pharmacological studies.
Lymphocyte–C-reactive protein ratio can differentiate disease severity of COVID-19 patients and serve as an assistant screening tool for hospital and ICU admission
Authors: Zhang Jian-Nan , Gao Yang , Wang Xin-Tong , Li Na-Na , Du Xue , Tang Yu-Jia , Lai Qi-Qi , Chen Peng-Fei , Yue Chuang-Shi , Wu Ji-Han , Kang Kai , Zhao Ming-Yan
Published: September 2022

In this study, we aimed to explore whether lymphocyte–C-reactive protein ratio (LCR) can differentiate disease severity of coronavirus disease 2019 (COVID-19) patients and its value as an assistant screening tool for admission to hospital and intensive care unit (ICU). A total of 184 adult COVID-19 patients from the COVID-19 Treatment Center in Heilongjiang Province at the First Affiliated Hospital of Harbin Medical University between January 2020 and March 2021 were included in this study. Patients were divided into asymptomatic infection group, mild group, moderate group, severe group, and critical group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (ninth edition). Demographic and clinical data including gender, age, comorbidities, severity of COVID-19, white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), red blood cell distribution width (RDW), platelet (PLT), C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), albumin (ALB), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL), and D-dimer were obtained and collated from medical records at admission, from which sequential organ failure assessment (SOFA) score and LCR were calculated, and all the above indicators were compared among the groups. Multiple clinical parameters, including LYMPH, CRP, and LCR, showed significant differences among the groups. The related factors to classify COVID-19 patients into moderate, severe, and critical groups included age, number of comorbidities, WBC, LCR, and AST. Among these factors, the number of comorbidities showed the greatest effect, and only WBC and LCR were protective factors. The area under the receiver operating characteristic (ROC) curve of LCR to classify COVID-19 patients into moderate, severe, and critical groups was 0.176. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 1,780.7050 and 84.6% and 66.2%, respectively. The related factors to classify COVID-19 patients into severe and critical groups included the number of comorbidities, PLT, LCR, and SOFA score. Among these factors, SOFA score showed the greatest effect, and LCR was the only protective factor. The area under the ROC curve of LCR to classify COVID-19 patients into severe and critical groups was 0.106. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 571.2200 and 81.3% and 90.0%, respectively. In summary, LCR can differentiate disease severity of COVID-19 patients and serve as a simple and objective assistant screening tool for hospital and ICU admission.
A real-time GPU-accelerated parallelized image processor for large-scale multiplexed fluorescence microscopy data
Authors: Lu Guolan , Baertsch Marc A. , Hickey John W. , Goltsev Yury , Rech Andrew J. , Mani Lucas , Forgó Erna , Kong Christina , Jiang Sizun , Nolan Garry P. , Rosenthal Eben L.
Published: September 2022

Highly multiplexed, single-cell imaging has revolutionized our understanding of spatial cellular interactions associated with health and disease. With ever-increasing numbers of antigens, region sizes, and sample sizes, multiplexed fluorescence imaging experiments routinely produce terabytes of data. Fast and accurate processing of these large-scale, high-dimensional imaging data is essential to ensure reliable segmentation and identification of cell types and for characterization of cellular neighborhoods and inference of mechanistic insights. Here, we describe RAPID, a Real-time, GPU-Accelerated Parallelized Image processing software for large-scale multiplexed fluorescence microscopy Data. RAPID deconvolves large-scale, high-dimensional fluorescence imaging data, stitches and registers images with axial and lateral drift correction, and minimizes tissue autofluorescence such as that introduced by erythrocytes. Incorporation of an open source CUDA-driven, GPU-assisted deconvolution produced results similar to fee-based commercial software. RAPID reduces data processing time and artifacts and improves image contrast and signal-to-noise compared to our previous image processing pipeline, thus providing a useful tool for accurate and robust analysis of large-scale, multiplexed, fluorescence imaging data.
Impact of vaccination on hospitalization and mortality from COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience
Authors: Shields Adrian M. , Tadros Susan , Al-Hakim Adam , Nell Jeremy M. , Lin Me Me Nay , Chan Michele , Goddard Sarah , Dempster John , Dziadzio Magdalena , Patel Smita Y. , Elkalifa Shuayb , Huissoon Aarnoud , Duncan Christopher J. A. , Herwadkar Archana , Khan Sujoy , Bethune Claire , Elcombe Suzanne , Thaventhiran James , Klenerman Paul , Lowe David M. , Savic Sinisa , Burns Siobhan O. , Richter Alex G.
Published: September 2022

Background

Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients.

Objectives

To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern.

Methods

The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022.

Results

22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave.

Conclusions

Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts.
Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia
Authors: Liang Taotao , Wang Xiaojiao , Liu Yanyan , Ai Hao , Wang Qian , Wang Xianwei , Wei Xudong , Song Yongping , Yin Qingsong
Published: September 2022

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.
CD56-negative NK cells: Frequency in peripheral blood, expansion during HIV-1 infection, functional capacity, and KIR expression
Authors: Cocker Alexander T. H. , Liu Fuguo , Djaoud Zakia , Guethlein Lisbeth A. , Parham Peter
Published: September 2022

Human NK cells are usually defined as CD3-CD56+lymphocytes. However, a CD56-CD16+(CD56neg) lymphocyte population that displays NK-associated markers expands during chronic viral infections such as HIV-1 and HCV, and, to lesser extent, in herpesvirus infections. This CD56neg NK cell subset has been understudied because it requires the exclusion of other lymphocytes to accurately identify its presence. Many questions remain regarding the origin, development, phenotype, and function of the CD56neg NK cell population. Our objective was to determine the frequency of this NK subset in healthy controls and its alteration in viral infections by performing a meta-analysis. In addition to this, we analyzed deposited CyTOF and scRNAseq datasets to define the phenotype and subsets of the CD56neg NK cell population, as well as their functional variation. We found in 757 individuals, from a combined 28 studies and 6 datasets, that the CD56neg subset constitutes 5.67% of NK cells in healthy peripheral blood, while HIV-1 infection increases this population by a mean difference of 10.69%. Meta-analysis of surface marker expression between NK subsets showed no evidence of increased exhaustion or decreased proliferation within the CD56neg subset. CD56neg NK cells have a distinctive pattern of KIR expression, implying they have a unique potential for KIR-mediated education. A perforin-CD94-NKG2C-NKp30-CD56neg population exhibited different gene expression and degranulation responses against K562 cells compared to other CD56neg cells. This analysis distinguishes two functionally distinct subsets of CD56neg NK cells. They are phenotypically diverse and have differing capacity for education by HLA class-I interactions with KIRs.
A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
Authors: Tian Xiao-Mao , Xiang Bin , Yu Yi-Hang , Li Qi , Zhang Zhao-Xia , Zhanghuang Chenghao , Jin Li-Ming , Wang Jin-Kui , Mi Tao , Chen Mei-Lin , Liu Feng , Wei Guang-Hui
Published: September 2022

Background

Neuroblastoma (NB) is the most frequent solid tumor in pediatrics, which accounts for roughly 15% of cancer-related mortality in children. NB exhibited genetic, morphologic, and clinical heterogeneity, which limited the efficacy of available therapeutic approaches. Recently, a new term ‘cuproptosis’ has been used to denote a unique biological process triggered by the action of copper. In this instance, selectively inducing copper death is likely to successfully overcome the limitations of conventional anticancer drugs. However, there is still a gap regarding the role of cuproptosis in cancer, especially in pediatric neuroblastoma.

Methods

We characterized the specific expression of cuproptosis-related genes (CRGs) in NB samples based on publicly available mRNA expression profile data. Consensus clustering and Lasso-Cox regression analysis were applied for CRGs in three independent cohorts. ESTIMATE and Xcell algorithm was utilized to visualize TME score and immune cell subpopulations’ relative abundances. Tumor Immune Dysfunction and Exclusion (TIDE) score was used to predict tumor response to immune checkpoint inhibitors. To decipher the underlying mechanism, GSVA was applied to explore enriched pathways associated with cuproptosis signature and Connectivity map (CMap) analysis for drug exploration. Finally, qPCR verified the expression levels of risk-genes in NB cell lines. In addition, PDHA1 was screened and further validated by immunofluorescence in human clinical samples and loss-of-function assays.

Results

We initially classified NB patients according to CRGs and identified two cuproptosis-related subtypes that were associated with prognosis and immunophenotype. After this, a cuproptosis-related prognostic model was constructed and validated by LASSO regression in three independent cohorts. This model can accurately predict prognosis, immune infiltration, and immunotherapy responses. These genes also showed differential expression in various characteristic groups of all three datasets and NB cell lines. Loss-of-function experiments indicated that PDHA1 silencing significantly suppressed the proliferation, migration, and invasion, in turn, promoted cell cycle arrest at the S phase and apoptosis of NB cells.

Conclusions

Taken together, this study may shed light on new research areas for NB patients from the cuproptosis perspective.
The vectoring competence of the mite Varroa destructor for deformed wing virus of honey bees is dynamic and affects survival of the mite
Authors: Ryabov Eugene V. , Posada-Florez Francisco , Rogers Curtis , Lamas Zachary S. , Evans Jay D. , Chen Yanping , Cook Steven C.
Published: September 2022

The ectoparasitic mite, Varroa destructor and the viruses it vectors, including types A and B of Deformed wing virus (DWV), pose a major threat to honey bees, Apis mellifera. Analysis of 256 mites collected from the same set of field colonies on five occasions from May to October 2021 showed that less than a half of them, 39.8% (95% confidence interval (CI): 34.0 - 46.0%), were able to induce a high (overt) level DWV infection with more than 109 viral genomes per bee in the pupa after 6 days of feeding, with both DWV-A and DWV-B being vectored at similar rates. To investigate the effect of the phoretic (or dispersal) stage on adult bees on the mites’ ability to vector DWV, the mites from two collection events were divided into two groups, one of which was tested immediately for their infectiveness, and the other was kept with adult worker bees in cages for 12 days prior to testing their infectiveness. We found that while 39.2% (95% CI: 30.0 – 49.1%) of the immediately tested mites induced overt-level infections, 12-day passage on adult bees significantly increased the infectiousness to 89.8% (95% CI: 79.2 – 95.6%). It is likely that Varroa mites that survive brood interruptions in field colonies are increasingly infectious. The mite lifespan was affected by the DWV type it transmitted to pupae. The mites, which induced high DWV-B but not DWV-A infection had an average lifespan of 15.5 days (95% CI: 11.8 - 19.2 days), which was significantly shorter than those of the mites which induced high DWV-A but not DWV-B infection, with an average lifespan of 24.3 days (95% CI: 20.2 - 28.5), or the mites which did not induce high levels of DWV-A or DWV-B, with an average survival of 21.2 days (95% CI: 19.0 - 23.5 days). The mites which transmitted high levels of both DWV-A and DWV-B had an intermediate average survival of 20.5 days (95% CI: 15.1 - 25.9 days). The negative impact of DWV-B on mite survival could be a consequence of the ability of DWV-B, but not DWV-A to replicate in Varroa.
A typology of responsibility for coastal flood risk adaptation
Authors: van der Plank Sien , Brown Sally , Tompkins Emma L. , Nicholls Robert J.
Published: September 2022

The management of coastal flood risk is adapting to meet the challenges and increased risks posed by population change as well as by climate change, especially sea level rise. Protection is being targeted to areas where the benefits are highest, while elsewhere there is a shift towards more localized “living with floods” and “resilience” approaches. Such decentralized approaches to flood risk management (FRM) require a diverse range of stakeholder groups to be engaged as “flood risk citizens”. Engagement of households in FRM is central to this process. Despite significant research on stakeholder engagement in coastal and flood risk management, there is less focus on the nature of responsibility in coastal adaptation. There is no framework by which to assess the different types of responsibility in hazard management and adaptation, and little research on the implications of expecting these responsibilities of stakeholder groups. In this paper, we identify five types of responsibility that are embedded throughout the disaster risk reduction cycle of managing coastal flooding. We build this “typology of responsibility” on existing work on the evolution of stakeholder engagement and stakeholder responsibility relationships in risk management processes, and a dataset of institutional stakeholder interviews and households surveys conducted across three case studies in England, the United Kingdom, in 2018 and 2019. We analyze the interviews using thematic analysis to explore institutional stakeholder perceptions of responsibility in coastal FRM, and analyze the household survey through descriptive and inferential statistics. By developing the first disaster risk reduction focused typology of responsibility for coastal flooding, we provide researchers and decision-makers with a tool to guide their planning and allocation of responsibilities in risk management for floods and other climate-driven hazards.
An evaluation method for determining the optimal structure of artificial reefs based on their flow field effects
Authors: Ma Qiaofeng , Ding Jian , Xi Yanbin , Song Jun , Liang Shuxiu , Zhang Ruijin
Published: September 2022

To design artificial reef (ARs) structures that can provide better habitats for fish, extensive research has been conducted on the flow field effects of ARs with different structures. The evaluation indices of the flow field effects include upwelling and back vortex flow. However, there has been little quantitative analysis of these two indices. In addition, several studies have suggested that other flow field characteristics of ARs can aid in providing habitats for fish. To evaluate the flow field effects of ARs more comprehensively, the following work was conducted in this study. First, the flow field of the solid cubic AR was simulated using a computational fluid dynamics (CFD)-based software (Fluent), and based on the particle image velocimetry (PIV) approach, these simulation results were verified by flume experiments. Next, the flow fields of ARs with other structures (hollow cube, solid triangular pyramid, hollow triangular pyramid, solid truncated rectangular pyramid, and hollow truncated rectangular pyramid) were simulated using the verified numerical model. Subsequently, based on the analytic hierarchy process (AHP) approach, an evaluation model with six evaluation indices of the flow field effect of ARs (upwelling region, wake region, surface area of ARs, upper slow-flowing area, lateral slow-flowing area, and internal velocity of ARs) was established, and the weights of the evaluation indices were determined using the entropy weight method (EWM). Finally, to determine the structure of ARs with optimal flow field effects, the evaluation model was used for evaluating the flow field effects of all ARs. The superiority and ranking of the flow field effects of all ARs were calculated using the fuzzy comprehensive evaluation (FCE) method. This study provides a theoretical basis and reference for the optimization of AR structures.
Numerical and experimental investigation on hydrodynamic performance of the stick-held dip net in Pacific saury fishery
Authors: Li Fei , Song Liming , Hua Chuanxiang , Zhu Qingcheng
Published: September 2022

Stick-held dip (SHD) net is an effective fishing gear target for catching the Pacific saury. In this study, the hydrodynamic performance of an SHD net in current was investigated by means of numerical simulation and experimental test, and a mathematical model based on the lumped-mass method and principle of rigid body kinematics was developed to predict the net shape and tension of the cable. A series of physical model tests based on Tauti’s law and full-scale measurements at sea were conducted to evaluate the applicability of the numerical model. The results showed that the prediction performance of the numerical model was good, with a mean relative error of approximately 20% among the numerical, experimental, and field measured data. The dynamic shooting behavior of the SHD net at different current velocities and the effects of the length of the hauling rope and the mesh size on the net shape and tension of the cable were analyzed using the numerical simulation approach. When the current velocity increased from 0.12 to 0.46 m/s, the enclosed volume of the SHD net decreased by 62.9%. The height of net opening increased by 9.29% to 13.53% for every 10% increase in the length of the hauling rope from 0.96 to 1.44 m. With the increase in mesh size from 24 to 30 and 35 mm, the sinking depth and speed of the net increased, and the tension force of the cables decreased by 9.02% and 12.10%, respectively. The results suggested that (1) the numerical model could realistically represent the hydrodynamic characteristics of the SHD net; (2) the suitable operation current velocity is below 0.60 m/s; (3) the reasonable length of the hauling rope is about 30 m; and (4) the mesh size of the main netting could be increased to 30 mm.
Spatial and seasonal characteristics of dissolved heavy metals in the seawater of Beibu Gulf, the Northern South China Sea
Authors: Zhu Zuhao , Wei Huihua , Guan Yao , Zhang Li , Sun Pengfei , Zhang Qiufeng
Published: September 2022

Heavy metal contaminations in the marine environment are of considerable attention because of their high potential ecological effects and public concern for human health. However, the influencing factors for the large-scale distributions of heavy metals in Beibu Gulf, a newly developing industry and port in South China, are still unclear due to the lack of large-scale investigation. Here, a total of 871 samples in the 127 stations in the seawater of Beibu Gulf during spring, summer, fall and winter in 2020-2021 were analyzed for dissolved heavy metal concentrations and physicochemical parameters. The concentrations of heavy metals in the Beibu Gulf ranked following the order of Zn > Cu > Cr > As > Pb > Hg > Cd. Compared to other regions, the concentrations of Hg were at relatively higher levels, which were mainly influenced by the input of the transportation of water masses from the local and other regions; whereas the other heavy metals were at relatively lower levels. Seasonally variations in the concentrations of heavy metals were observed in the gulf, which is mainly influenced by human activities (i.e., shipping and mariculture activities) and seasonally hydrological conditions. Seasonal changes in the spatial distribution of heavy metals have been found in the gulf. The higher concentrations of heavy metals mainly occurred in the coastal bays or areas in summer whereas the higher concentrations were observed in the offshore areas during the other three seasons. This is mainly related to the seasonal changes of the water masses that affect the seawater of Beibu Gulf, which exhibits the dominant contribution of coastal current from the northern Beibu Gulf in summer, and the dominant contribution of west-Guangdong coastal current and SCS water during the other three seasons. The potential ecological risk index revealed that Hg is the main ecological risk factor in the gulf, and the heavy metal contamination in the gulf seems to be noticeable. This study highlights the seasonal changes of the water masses that affect the seawater of Beibu Gulf greatly affecting the large-scale distributions of heavy metals in the gulf.
Experimental research and application of old combined bridge barriers with non-standard sections
Authors: He Guomeng , Ren Yanhong , Sun Chun , Deng Yong , Tan Yan , Deng Qichuan , Wang Chenghu , Bu Qianmiao
Published: September 2022

To improve the protective performance of old combined bridge barriers with non-standard sections, this article has improved the guardrail scheme. The newly improved guardrail is evaluated by finite element simulation, yield line theory calculation, and a crash test to see whether it reaches class SA protection. The results show that the blocking, redirecting, and buffering functions of the improved scheme meet the Standard for Safety Performance Evaluation of Highway Barriers (JTG B05-01-2013), and its protection class reaches class SA. The bridge barrier with strict deformation control cannot be evaluated by the yield line theory calculation alone. Thus, the evaluation should be assisted with finite element simulation and a crash test. The improved scheme has been successfully applied to engineering practice. With simple construction, safety, and reliability, the scheme effectively reduces engineering costs and improves the protective performance of old combined bridge barriers with non-standard sections.