bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer
Authors: Chen Li , Kong Xiangyi , Fang Yi , Paunikar Shishir , Wang Xiangyu , Brown James A. L. , Bourke Emer , Li Xingrui , Wang Jing
Published: November 2021

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.
Immune Cell Infiltration Landscape of Ovarian Cancer to Identify Prognosis and Immunotherapy-Related Genes to Aid Immunotherapy
Authors: Li Xiushen , Liang Weizheng , Zhao Huanyi , Jin Zheng , Shi Guoqi , Xie Wanhua , Wang Hao , Wu Xueqing
Published: November 2021

Ovarian cancer (OC) is the second leading cause of death in gynecological cancer. Multiple study have shown that the efficacy of tumor immunotherapy is related to tumor immune cell infiltration (ICI). However, so far, the Immune infiltration landscape of tumor microenvironment (TME) in OC has not been elucidated. In this study, We organized the transcriptome data of OC in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, evaluated the patient’s TME information, and constructed the ICI scores to predict the clinical benefits of patients undergoing immunotherapy. Immune-related genes were further used to construct the prognostic model. After clustering analysis of ICI genes, we found that patients in ICI gene cluster C had the best prognosis, and their tumor microenvironment had the highest proportion of macrophage M1 and T cell follicular helper cells. This result was consistent with that of multivariate cox (multi-cox) analysis. The prognostic model constructed by immune-related genes had good predictive performance. By estimating Tumor mutation burden (TMB), we also found that there were multiple genes with statistically different mutation frequencies in the high and low ICI score groups. The model based on the ICI score may help to screen out patients who would benefit from immunotherapy. The immune-related genes screened may be used as biomarkers and therapeutic targets.
The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis
Authors: Pangou Evanthia , Sumara Izabela
Published: November 2021

Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease.
Prevalence of Chronic Diseases and Alterations of Gut Microbiome in People of Ningxia China During Urbanization: An Epidemiological Survey
Authors: Du Yong , Ding Lu , Na Li , Sun Ting , Sun Xian , Wang Liqun , He Shulan , Wang Zhizhong , Lu Zhenhui , Li Feng , Guo Xiaofei , Zhang Yanhong , Tian Jin , Wang Bo , Zhai Sifan , Yang Chao , Liu Xiao
Published: November 2021

The continuous development of urbanization has dramatically changed people’s living environment and lifestyle, accompanied by the increased prevalence of chronic diseases. However, there is little research on the effect of urbanization on gut microbiome in residents. Here we investigated the relation between living environment and gut microbiota in a homogenous population along an urban-rural gradient in Ningxia China. According to the degree of urbanization, the population is divided into four groups: mountainous rural (MR) represents non-urbanized areas, mountainous urban (MU) and plain rural (PR) represent preliminary urbanization, and plain urban (PU) is a representative of complete urbanization. Studies have found that with the deepening of urbanization, the prevalence of chronic diseases, such as diabetes, dyslipidemia, fatty liver, gallstones, and renal cysts, have gradually increased. The intestinal richness and diversity of the microbial community were significantly reduced in the PR and the PU groups compared with the MR and the MU groups. Based on linear discriminant analysis selection, the significantly enriched genera Faecalibacterium, Prevotella, and Pseudobutyrivibrio in the MR group gradually decreased in the MU, the PR, and the PU groups. Effect size results revealed that both residence and diet had an effect on intestinal microbiota. Our results suggested that the disparate patterns of gut microbiota composition were revealed at different levels of urbanization, providing an opportunity to understand the pathogenesis of chronic diseases and the contribution of the “rural microbiome” in potential protection against the occurrence of chronic diseases.
Vitality of Proteinase K in rRTPCR Detection of SARS-CoV2 Bypassing RNA Extraction
Authors: Shukla Alka , Gangwar Mayank , Sharma Gaurav , Prakash Pradyot , Nath Gopal
Published: November 2021

This study aimed to detect the SARS-COV2 viral component directly from inoculated VTM without RNA extraction. Inoculated VTMs of already tested 50 positive and 50 negative samples were divided into three groups. Group I was treated with Proteinase K (PK) followed by 3-step-heat treatment at different temperatures (25°C, 60°C, and 98°C) and stored at 4°C. Group II was directly subjected to 3-step-heat treatment without PK exposure and stored at 4°C. And group III was set-up as standard group; it was processed using Qiagen’s column based QIAamp Nucleic Acid kit and the obtained nucleic acids were stored at 4°C. These stored samples were used as a template to execute real-time polymerase chain reaction, and results were noted. Group I demonstrated 96% and 88% sensitivity for N and ORF1ab genes respectively, whereas group II demonstrated 78% and 60% when compared to the results of standard group III. Overall group I showed better results than group II when compared to group III. Thus, in situations where gold-standard reagents are not available, PK exposure and heat treatment can be employed to carry out molecular detection of SARS-CoV2 viral component.
Proteome Profiling of RNF213 Depleted Cells Reveals Nitric Oxide Regulator DDAH1 Antilisterial Activity
Authors: Martina Lia , Asselman Caroline , Thery Fabien , Boucher Katie , Delhaye Louis , Maia Teresa M. , Dermaut Bart , Eyckerman Sven , Impens Francis
Published: November 2021

RNF213 is a large, poorly characterized interferon-induced protein. Mutations in RNF213 are associated with predisposition for Moyamoya disease (MMD), a rare cerebrovascular disorder. Recently, RNF213 was found to have broad antimicrobial activity in vitro and in vivo, yet the molecular mechanisms behind this function remain unclear. Using mass spectrometry-based proteomics and validation by real-time PCR we report here that knockdown of RNF213 leads to transcriptional upregulation of MVP and downregulation of CYR61, in line with reported pro- and anti-bacterial activities of these proteins. Knockdown of RNF213 also results in downregulation of DDAH1, which we discover to exert antimicrobial activity against Listeria monocytogenes infection. DDAH1 regulates production of nitric oxide (NO), a molecule with both vascular and antimicrobial effects. We show that NO production is reduced in macrophages from RNF213 KO mice, suggesting that RNF213 controls Listeria infection through regulation of DDAH1 transcription and production of NO. Our findings propose a potential mechanism for the antilisterial activity of RNF213 and highlight NO as a potential link between RNF213-mediated immune responses and the development of MMD.
Changes in Vaginal Microbiome Diversity in Women With Polycystic Ovary Syndrome
Authors: Lu Chaoyi , Wang Hui , Yang Jihong , Zhang Xinyue , Chen Yao , Feng Ruizhi , Qian Yun
Published: November 2021

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that affects women. It can be accompanied by many clinical manifestations that can vary between individuals. Previous studies have found that there are specific changes in the intestinal flora of PCOS patients, and interventions to modify the intestinal flora can significantly improve the symptoms of PCOS. Women with PCOS have a higher incidence of vaginitis compared to healthy women. Few studies to-date have focused on investigating vaginal flora. Here, we aimed to explore distribution changes of the vaginal microbiome in PCOS patients. We recruited 42 PCOS patients (T-PCOS) and 24 healthy controls (T-control). 16s rRNA gene sequencing was used to sequence their vaginal microbiome. Normally, Lactobacillus was dominated in vaginal. Lactobacillus-dominated-type vaginal microbiome in T-PCOS and T-control (L-PCOS and L-control) and non-Lactobacillus-dominated-type vaginal microbiome in T-PCOS and T-control (N-PCOS and N-control) were analyzed separately. A total of 655 operational taxonomic units were detected in this sequencing, including 306 unique to T-PCOS, 202 unique to T-control, and 147 common between the two groups. At the genus level, Lactobacillus accounted for more than 70% of the total microbiome. Observed species (P = 0.021), Chao1 index (P = 0.020), and ACE index (P = 0.023) decreased significantly in L-PCOS. Principal component analysis showed no statistically significant differences among the subgroups. There were significant statistical differences in principal coordinate analysis in the Jaccard distance between the T-PCOS and T-control groups and between the L-PCOS and L-control groups. Linear discriminant analysis effect size found that Enterococcus and Actinomycetes were significantly different in the T-PCOS group. Atopobium and Actinomyces were statistically significantly different in patients with L-PCOS and N-PCOS group, respectively. Environmental factor analysis found that Ezakiella was significantly negatively correlated with age, while Streptococcus was significantly negatively correlated with follicle stimulating hormone. There were statistically significant differences between PCOS patients and healthy women in the vaginal microbiome, regardless of the abundance of Lactobacillus. Alpha diversity of vaginal microbiome decreased markedly in PCOS patients when it was dominated by Lactobacillus spp. Actinomyces could be a potential biomarker to identify PCOS. Streptococcus may have an impact on the pathological changes in PCOS by affecting the female reproductive endocrine environment.
The Origin of Patterns
Authors: Duin Robert P. W.
Published: November 2021

The question is discussed from where the patterns arise that are recognized in the world. Are they elements of the outside world, or do they originate from the concepts that live in the mind of the observer? It is argued that they are created during observation, due to the knowledge on which the observation ability is based. For an experienced observer this may result in a direct recognition of an object or phenomenon without any reasoning. Afterwards and using conscious effort he may be able to supply features or arguments that he might have used for his recognition. The discussion is phrased in the philosophical debate between monism, in which the observer is an element of the observed world, and dualism, in which these two are fully separated. Direct recognition can be understood from a monistic point of view. After the definition of features and the formulation of a reasoning, dualism may arise. An artificial pattern recognition system based on these specifications thereby creates a clear dualistic situation. It fully separates the two worlds by physical sensors and mechanical reasoning. This dualistic position can be solved by a responsible integration of artificially intelligent systems in human controlled applications. A set of simple experiments based on the classification of histopathological slides is presented to illustrate the discussion.
Colliding Identities During COVID-19: Identifying and Addressing the Challenges of Being an Academic Mother During a Global Pandemic
Authors: Harrop Gill
Published: November 2021

Academic workloads require a careful balance of teaching, research, supervision, and administrative responsibilities. Being an academic parent adds an additional level of responsibility to this, which has traditionally been successfully managed with organisation, careful planning and support. For many academic parents the Covid-19 pandemic disrupted this carefully curated balance, forcing them to work from home while also dealing with the loss of childcare and the requirement to provide homeschooling. The pre-existing gender disparity in childcare and housework was exacerbated by lockdown, with a disproportionate impact on academic mothers who were often forced to take on additional childcare and housework responsibilities, alongside remote schooling. The gender disparity further affected job stability, with women losing a greater number of paid working hours during the pandemic and having greater employment instability. This article reflects upon the impact of gender disparity in academic parents during the Covid-19 pandemic, and considers potential barriers to productivity and progression, including the role of interruptions, delivering sensitive materials in a workspace shared with children and technological challenges.
The Clinical Values of Afamin, Triglyceride and PLR in Predicting Risk of Gestational Diabetes During Early Pregnancy
Authors: Wang Xuechun , Zheng Xiuqiong , Yan Jianying , Xu Rongli , Xu Mu , Zheng Lin , Xu Liangpu , Lin Zhi
Published: November 2021

Objective

To establish a model to predict gestational diabetes mellitus (GDM) based on the clinical characteristics, early pregnancy (10-12 weeks gestation) peripheral blood routine, and biochemical indicators, and to explore its predictive efficiencies.

Methods

Data from 607 pregnant women with GDM were compared to the data from 833 pregnant women without GDM admitted to the Obstetrics Department of Fujian Maternity and Child Health Hospital (affiliated to Fujian Medical University) from May 2018 to December 2018 were retrospectively included. The ages of the pregnant women, paternal ages, number of pregnancies, number of deliveries, pre-pregnancy heights/weights, and the calculated body mass indexes (BMI) were recorded. In all participants, 10-12 weeks of pregnancy, afamin concentration, routine blood work, prenatal aneuploidy screening, and biochemical testing were performed. At weeks 24-28 of gestation, patients underwent oral glucose tolerance test (OGTT) for GDM screening.

Results

Multivariate logistic regression analysis showed that maternal age, early pregnancy afamin level, triglycerides, and platelet/lymphocyte ratio (PLR) were independent risk factors for gestational diabetes. The formula for predicting GDM probability was as follows: P = 1/1 + exp( − 6.054 + 0.774 × triglycerides + 0.002 × afamin + 0.155 × age − 0.012 × PLR)]. From the established ROC curve, the area under the curve (AUC) was 0.748, indicating that the model has a good degree of discrimination. When the predictive probability cut-off value was set on 0.358, sensitivity, specificity, positive predictive value, and negative predictive value were 69.2%, 68.3%, 42.5%, and 86.2%, respectively, and the accuracy rate was 70.2%. The Hosmer-Lemeshow test results showed that the goodness of the model fit has a good calibration ability (χ2 = 12.269, df=8, P=0.140).

Conclusions

Maternal age, early pregnancy afamin level, triglycerides, and PLR are independent risk factors for gestational diabetes. When combined, the above indicators are helpful for prediction, early diagnosis, and intervention of gestational diabetes.
A Network Biology Approach to Understanding the Tissue-Specific Roles of Non-Coding RNAs in Arthritis
Authors: Ali Shabana Amanda , Pastrello Chiara , Kaur Navdeep , Peffers Mandy J. , Ormseth Michelle J. , Jurisica Igor
Published: November 2021

Discovery of non-coding RNAs continues to provide new insights into some of the key molecular drivers of musculoskeletal diseases. Among these, microRNAs have received widespread attention for their roles in osteoarthritis and rheumatoid arthritis. With evidence to suggest that long non-coding RNAs and circular RNAs function as competing endogenous RNAs to sponge microRNAs, the net effect on gene expression in specific disease contexts can be elusive. Studies to date have focused on elucidating individual long non-coding-microRNA-gene target axes and circular RNA-microRNA-gene target axes, with a paucity of data integrating experimentally validated effects of non-coding RNAs. To address this gap, we curated recent studies reporting non-coding RNA axes in chondrocytes from human osteoarthritis and in fibroblast-like synoviocytes from human rheumatoid arthritis. Using an integrative computational biology approach, we then combined the findings into cell- and disease-specific networks for in-depth interpretation. We highlight some challenges to data integration, including non-existent naming conventions and out-of-date databases for non-coding RNAs, and some successes exemplified by the International Molecular Exchange Consortium for protein interactions. In this perspective article, we suggest that data integration is a useful in silico approach for creating non-coding RNA networks in arthritis and prioritizing interactions for further in vitro and in vivo experimentation in translational research.
Reproductive Regulation of PrRPs in Teleost: The Link Between Feeding and Reproduction
Authors: Xia Chuanhui , Qin Xiangfeng , Zhou Lingling , Shi Xuetao , Cai Tianyi , Xie Yunyi , Li Wei , Du Ruixin , OuYang Yu , Yin Zhan , Hu Guangfu
Published: November 2021

Prolactin-releasing peptide (PrRP), a sort of vital hypothalamic neuropeptide, has been found to exert an enormous function on the food intake of mammals. However, little is known about the functional role of PrRP in teleost. In the present study, two PrRP isoforms and four PrRP receptors were isolated from grass carp. Ligand-receptor selectivity displayed that PrRP1 preferentially binds with PrRP-R1a and PrRP-R1b, while PrRP-R2a and PrRP-R2b were special receptors for PrRP2. Tissue distribution indicated that both PrRPs and PrRP-Rs were highly expressed in the hypothalamus-pituitary-gonad axis and intestine, suggesting a latent function on food intake and reproduction. Using grass carp as a model, we found that food intake could significantly induce hypothalamus PrRP mRNA expression, which suggested that PrRP should be also an anorexigenic peptide in teleost. Interestingly, intraperitoneal (IP) injection of PrRPs could significantly induce serum luteinizing hormone (LH) secretion and pituitary LHβ and GtHα mRNA expression in grass carp. Moreover, using primary culture grass carp pituitary cells as a model, we further found that PrRPs could directly induce pituitary LH secretion and synthesis mediated by AC/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, estrogen treatment of prepubertal fish elicited increases in PrRPs and PrPR receptors expression in primary cultured grass carp hypothalamus cells, which further confirmed that the PrRP/PrRPR system may participate in the neuroendocrine control of fish reproduction. These results, taken together, suggest that PrRPs might act as a coupling factor in feeding metabolism and reproductive activities in teleost.
Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment
Authors: Batoon Lena , McCauley Laurie K.
Published: November 2021

The skeleton is a common site for cancer metastases with the bone microenvironment providing the appropriate conditions for cancer cell colonization. Once in bone, cancer cells effectively manipulate their microenvironment to support their growth and survival. Despite previous efforts to improve treatment modalities, skeletal metastases remain with poor prognoses. This warrants an improved understanding of the mechanisms leading to bone metastasis that will aid development of effective treatments. Macrophages in the tumor microenvironment are termed tumor associated macrophages (TAMs) and their crosstalk with cancer cells is critical in regulating tumorigenicity in multiple cancers. In bone metastases, this crosstalk is also being increasingly implicated but the specific signaling pathways remain incompletely understood. Here, we summarize the reported functions, interactions, and signaling of macrophages with cancer cells during the metastatic cascade to bone. Specifically, we review and discuss how these specific interactions impact macrophages and their profiles to promote tumor development. We also discuss the potential of targeting this crosstalk to inhibit disease progression. Finally, we identify the remaining knowledge gaps that will need to be addressed in order to fully consider therapeutic targeting to improve clinical outcomes in cancer patients.
Multi-Objective Optimization Method for the Shape of Large-Space Buildings Dominated by Solar Energy Gain in the Early Design Stage
Authors: Zhang Longwei , Wang Chao , Chen Yu , Zhang Lingling
Published: November 2021

Large-space buildings feature a sizable interface for receiving solar radiation, and optimizing their shape in the early design stage can effectively increase their solar energy harvest while considering both energy efficiency and space utilization. A large-space building shape optimization method was developed based on the “modeling-calculation-optimization” process to transform the “black box” mode in traditional design into a “white box” mode. First, a two-level node control system containing core space variables and envelope variables is employed to construct a parametric model of the shape of a large-space building. Second, three key indicators, i.e., annual solar radiation, surface coefficient, and space efficiency, are used to representatively quantify the performance in terms of sunlight capture, energy efficiency, and space utilization. Finally, a multi-objective genetic algorithm is applied to iteratively optimize the building shape, and the Pareto Frontier formed by the optimization results provides the designer with sufficient alternatives and can be used to assess the performance of different shapes. Further comparative analysis of the optimization results can reveal the typical shape characteristics of the optimized solutions and potentially determine the key variables affecting building performance. In a case study of six large-space buildings with typical shapes, the solar radiation of the optimized building shape solutions was 13.58–39.74% higher than that of reference buildings 1 and 3; compared with reference buildings 2 and 4, the optimized solutions also achieved an optimal balance of the three key indicators. The results show that the optimization method can effectively improve the comprehensive performance of buildings.
Short-Term Effects of Low-Head Barrier Removals on Fish Communities and Habitats
Authors: Bubb Damian H. , Birnie-Gauvin Kim , Tummers Jeroen S. , Aarestrup Kim , Jepsen Niels , Lucas Martyn C.
Published: November 2021

Barrier removal is increasingly being seen as the optimal solution to restore lotic habitat and fish communities, however, evidence of its efficacy is often limited to single sites or catchments. This study used a before–after methodology to examine the short-term (average, 541 days) effects of low-head (0.1–2.9 m) barrier removal at 22 sites distributed across Denmark and northern England on fish density, community, and river habitat responses. Following barrier removal, changes in the aquatic habitat were observed, such that the area immediately upstream of the former barrier location became shallower, with larger substrate and faster flow conditions. The reinstatement of this habitat was especially valuable in Danish streams, where these habitat features are rare, due to the naturally low gradients. Across all 22 sites fish species richness and diversity was similar before and after removal of barriers, likely because of the short study timescale (1–2 years). Across all sites combined, there was an increase in total fish density following barrier removal. A large increase in salmonid (Salmo trutta and Salmo salar) densities following barrier removal occurred at 7 out of 12 Danish sites. No similar response in salmonid density was observed at any of the UK sites which were mostly characterized by high channel gradients and short ponded zones. Two UK barrier removal sites showed marked increases in density of non-salmonid fish species. This study suggests that the removal of low-head barriers can be an effective method of restoring lotic habitats, and can lead to positive changes in fish density in the former ponded zone. The short-term effect of small barrier removal on the fish community is more variable and its effectiveness is likely to be determined by wider riverine processes.
Towards a Cost-Effective Implementation of Genomic Prediction Based on Low Coverage Whole Genome Sequencing in Dezhou Donkey
Authors: Zhao Changheng , Teng Jun , Zhang Xinhao , Wang Dan , Zhang Xinyi , Li Shiyin , Jiang Xin , Li Haijing , Ning Chao , Zhang Qin
Published: November 2021

Low-coverage whole genome sequencing is a low-cost genotyping technology. Combined with genotype imputation approaches, it is likely to become a critical component of cost-effective genomic selection programs in agricultural livestock. Here, we used the low-coverage sequence data of 617 Dezhou donkeys to investigate the performance of genotype imputation for low-coverage whole genome sequence data and genomic prediction based on the imputed genotype data. The specific aims were as follows: 1) to measure the accuracy of genotype imputation under different sequencing depths, sample sizes, minor allele frequency (MAF), and imputation pipelines and 2) to assess the accuracy of genomic prediction under different marker densities derived from the imputed sequence data, different strategies for constructing the genomic relationship matrixes, and single-vs. multi-trait models. We found that a high imputation accuracy (>0.95) can be achieved for sequence data with a sequencing depth as low as 1x and the number of sequenced individuals ≥400. For genomic prediction, the best performance was obtained by using a marker density of 410K and a G matrix constructed using expected marker dosages. Multi-trait genomic best linear unbiased prediction (GBLUP) performed better than single-trait GBLUP. Our study demonstrates that low-coverage whole genome sequencing would be a cost-effective approach for genomic prediction in Dezhou donkey.
Identification of Potential Key Genes in the Pathogenesis of Chronic Obstructive Pulmonary Disease Through Bioinformatics Analysis
Authors: Guan Qingzhou , Tian Yange , Zhang Zhenzhen , Zhang Lanxi , Zhao Peng , Li Jiansheng
Published: November 2021

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality. The etiology of COPD is complex, and the pathogenesis mechanisms remain unclear. In this study, we used rat and human COPD gene expression data from our laboratory and the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between individuals with COPD and healthy individuals. Then, protein–protein interaction (PPI) networks were constructed, and hub genes were identified. Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks. A total of 198 DEGs were identified, and a PPI network with 144 nodes and 355 edges was constructed. Twelve hub genes were identified by the cytoHubba plugin in Cytoscape. Of these genes, CCR3, CCL2, COL4A2, VWF, IL1RN, IL2RA, and CCL13 were related to inflammation or immunity, or tissue-specific expression in lung tissue, and their messenger RNA (mRNA) levels were validated by qRT-PCR. COL4A2, VWF, and IL1RN were further verified by the GEO dataset GSE76925, and the ceRNA network was constructed with Cytoscape. These three genes were consistent with COPD rat model data compared with control data, and their dysregulation direction was reversed when the COPD rat model was treated with effective-component compatibility of Bufei Yishen formula III. This bioinformatics analysis strategy may be useful for elucidating novel mechanisms underlying COPD. We pinpointed three key genes that may play a role in COPD pathogenesis and therapy, which deserved to be further studied.
Prognostic Values and Clinical Significance of S100 Family Member’s Individualized mRNA Expression in Pancreatic Adenocarcinoma
Authors: Li Xiaomin , Qiu Ning , Li Qijuan
Published: November 2021

Objective: Pancreatic adenocarcinoma (PAAD) is a common malignant tumor worldwide. S100 family (S100s) is wildly involved in regulating the occurrence, development, invasion, metastasis, apoptosis, and drug resistance of many malignant tumors. However, the expression pattern, prognostic value, and oncological role of individual S100s members in PAAD need to be elucidated.

Methods: The transcriptional expression levels of S100s were analyzed through the Oncomine and GEPIA, respectively. The protein levels of S100s members in PAAD were studied by Human Protein Atlas. The correlation between S100 mRNA expression and overall survival and tumor stage in PAAD patients was studied by GEPIA. The transcriptional expression correlation and gene mutation rate of S100s members in PAAD patients were explored by cBioPortal. The co-expression networks of S100s are identified using STRING and Gene MANIA to predict their potential functions. The correlation of S100s expression and tumor-infiltrating immune cells was tested by TIMER. Pathway activity and drug target analyzed by GSCALite.

Results: 13 S100s members were upregulated in PAAD tissues. 15 S100s members were associated with TP53 mutation. Expression levels of S100A3/A5/A6/A10/A11/A14/A16/B/P/Z were significantly correlated with the pathological stage. Prognosis analysis demonstrated that PAAD patients with low mRNA levels of S100A1/B/Z or high levels of S100A2/A3/A5/A10/A11/A14/A16 had a poor prognosis. Immuno-infiltration analysis showed that the mRNA levels of S100A10/A11/A14/A16 were correlated with the infiltration degree of macrophages in PAAD. Drug sensitivity analysis showed that PAAD expressing high levels of S100A2/A6/A10/A11/A13/A14/A16 maybe resistant to small molecule drugs.

Conclusion: This study identifies the clinical significance and biological functions of the S100s in PAAD, which may provide novel insights for the selection of prognostic biomarkers.
Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures
Authors: Ringheim Garth E. , Wampole Matthew , Oberoi Kinsi
Published: November 2021

Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren’s disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.
Prenatal Maternal Stress Exacerbates Experimental Colitis of Offspring in Adulthood
Authors: Sun Yue , Xie Runxiang , Li Lu , Jin Ge , Zhou Bingqian , Huang Huan , Li Mengfan , Yang Yunwei , Liu Xiang , Cao Xiaocang , Wang Bangmao , Liu Wentian , Jiang Kui , Cao Hailong
Published: November 2021

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide and correlates with dysregulated immune response because of gut microbiota dysbiosis. Some adverse early life events influence the establishment of the gut microbiota and act as risk factors for IBD. Prenatal maternal stress (PNMS) induces gut dysbiosis and perturbs the neuroimmune network of offspring. In this study, we aimed to investigate whether PNMS increases the susceptibility of offspring to colitis in adulthood. The related index was assessed during the weaning period and adulthood. We found that PNMS impaired the intestinal epithelial cell proliferation, goblet cell and Paneth cell differentiation, and mucosal barrier function in 3-week-old offspring. PNMS induced low-grade intestinal inflammation, but no signs of microscopic inflammatory changes were observed. Although there was no pronounced difference between the PNMS and control offspring in terms of their overall measures of alpha diversity for the gut microbiota, distinct microbial community changes characterized by increases in Desulfovibrio, Streptococcus, and Enterococcus and decreases in Bifidobacterium and Blautia were induced in the 3-week-old PNMS offspring. Notably, the overgrowth of Desulfovibrio persisted from the weaning period to adulthood, consistent with the results observed using fluorescence in situ hybridization in the colon mucosa. Mechanistically, the fecal microbiota transplantation experiment showed that the gut microbiota from the PNMS group impaired the intestinal barrier function and induced low-grade inflammation. The fecal bacterial solution from the PNMS group was more potent than that from the control group in inducing inflammation and gut barrier disruption in CaCo-2 cells. After treatment with a TNF-α inhibitor (adalimumab), no statistical difference in the indicators of inflammation and intestinal barrier function was observed between the two groups. Finally, exposure to PNMS remarkably increased the values of the histopathological parameters and the inflammatory cytokine production in a mouse model of experimental colitis in adulthood. These findings suggest that PNMS can inhibit intestinal development, impair the barrier function, and cause gut dysbiosis characterized by the persistent overgrowth of Desulfovibrio in the offspring, resulting in exacerbated experimental colitis in adulthood.
COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge
Authors: Furlan Anna , Forner Gabriella , Cipriani Ludovica , Vian Elisa , Rigoli Roberto , Gherlinzoni Filippo , Scotton Piergiorgio
Published: November 2021

B cell-targeting strategies such as rituximab are widely used in B cell hematologic malignancies, rheumatologic and musculoskeletal diseases and a variety of autoimmune disorders. The purpose of this paper is to illustrate how exposure to anti-CD20 treatment profoundly affects B cell functions involved in anti-SARS-CoV-2 immunity and significantly impacts on the clinical and serological course of SARS-CoV-2 infection, long term immunity and vaccine responses. The data presented here suggest that the effects of B cell-depleting agents on adaptive immunity should be taken into account for the proper selection and interpretation of SARS-CoV-2 diagnostics and to guide appropriate therapeutic approaches and protective measures. Combination therapeutic strategies including immunotherapy in association with prolonged antiviral treatment may play a decisive role in the setting of B cell immune deficiencies.
Comparative Transcriptome Profiling Reveals Insights Into the Mechanisms Related to Explosive Growth of Alexandrium pacificum
Authors: Liu Yuan , Zhu Zhimei , Qi Juan , Sui Zhenghong , Shang Erlei , Zhang Shu , Niaz Zeeshan
Published: November 2021

Alexandrium pacificum is an organism that has an important impact on the aquaculture industry and human health. In this study, the digital gene expression approach was used to conduct a comparative analysis of differentially expressed genes (DEGs) that influence the explosive growth of A. pacificum following five treatment conditions: normal culture (C), high phosphorus and manganese (M), high irradiance (G), low phosphorus (P), and low nitrogen (N). Compared with the C conditions, a total of 265, 320, 185, and 150 DEGs were detected in the M, G, P, and N treatment groups, respectively. Clustering analysis suggested that A. pacificum acclimated to explosive growth using similar mechanisms in the M and G conditions. Analysis of DEGs showed that upregulation of genes associated with the pentose phosphate pathway and photosynthesis may contribute to explosive growth. Unigenes involved in the cell cycle were also found to be upregulated to promote cell division. The DEGs identified in this study may allow for the elucidation of molecular mechanisms responsible for the explosive growth of A. pacificum.
Case Report: Venoarterial Extracorporeal Membrane Oxygenation Support for Caowu-Induced Cardiac Arrest
Authors: Ren Binbin , Wang Liming , Chen Kun , Chen Lin , Wang Huabin
Published: November 2021

Introduction: Caowu, the main root of the Aconitum plant, is widely used in China. Aconitine is the main toxic component of Aconitum, which can cause a variety of malignant arrhythmias and lead to death. Four patients who developed malignant arrhythmia after drinking medicinal wine containing Caowu were reported in this study. Cardiac arrest occurred soon after symptom onset. All patients received venoarterial extracorporeal membrane oxygenation (VA-ECMO) support after conservative medical treatment had failed. Patients who were directly transferred to our hospital received VA-ECMO support earlier than patients who were first treated at a local hospital. One patient received hemoperfusion in the emergency room before VA-ECMO support; the other three patients began hemoperfusion after VA-ECMO treatment. Surviving patients who received VA-ECMO earlier after symptom onset showed no obvious neurological complications. The patient who received a longer cardiopulmonary resuscitation time but received hemoperfusion before VA-ECMO had mild neurological complications. The mortality rate was 25% (1 of 4 patients). Two patients had thrombotic complications in venous vessels.

Conclusions: Cardiogenic shock due to refractory ventricular tachycardia caused by aconitine is lethal. Conservative supportive treatment did not provide a short-term antiarrhythmic effect and the cardiogenic shock was not well controlled. VA-ECMO treatment combined with hemoperfusion is promising temporary support to successfully treat aconitine-induced cardiogenic shock caused by refractory ventricular tachycardia.
Association Between a History of Dengue Fever and the Risk of Systemic Autoimmune Rheumatic Diseases: A Nationwide, Population-Based Case-Control Study
Authors: Chen Yun-Wen , Hsieh Tsu-Yi , Lin Ching-Heng , Chen Hsian-Min , Lin Chi-Chien , Chen Hsin-Hua
Published: November 2021

Purpose: To determine the association between a history of clinically diagnosed dengue infection and the risk of systemic autoimmune rheumatic diseases (SARDs).

Methods: Using claims data from the 1997–2013 Taiwanese National Health Insurance Research Database, we included 74,422 patients who were diagnosed with SARDs and 297,688 patients without SARDs who were matched (in a 1:4 ratio) for age, sex, year of SARDs index date, and city of residence. The associations between the development of SARDs and a history of dengue infection (International Classification of Diseases, Ninth Revision, Clinical Modification code 061) were investigated using conditional logistic regression analysis shown as odds ratios (ORs) with 95% confidence intervals (CIs) after adjusting for potential confounders.

Results: We included 17,126 patients with systemic lupus erythematosus (SLE), 15,531 patients with Sjogren's syndrome (SS), 37,685 patients with rheumatoid arthritis (RA), 1,911 patients with systemic sclerosis (SSc), 1,277 patients with dermatomyositis (DM), and 892 patients with polymyositis (PM). SLE (OR, 4.55; 95% CI, 2.77–7.46; p <0.001) risk was significantly associated with a history of dengue infection. However, no statistically significant association was found between dengue infection and SS (OR, 1.41; 95% CI, 0.88–2.26; p = 0.155), RA (OR, 1.03; 95% CI, 0.70–1.50; p = 0.888), SSc (OR, 1.97; 95% CI, 0.38–10.29; p = 0.420), DM (OR, 0.54; 95% CI, 0.04–7.27; p = 0.641), or PM (OR, 2.08; 95% CI, 0.23–18.79; p = 0.513).

Conclusion: This study revealed that a history of dengue infection was significantly associated with the risk of SLE, but not SS, RA, SSc, DM, or PM.
Prevalence and Impact Factors of COVID-19 Vaccination Hesitancy Among Breast Cancer Survivors: A Multicenter Cross-Sectional Study in China
Authors: Peng Xin , Gao Ping , Wang Qiong , Wu Hong-ge , Yan Yun-li , Xia Ying , Wang Jian-ying , Lu Fang , Pan Hong , Yang Yi , Liang Fan , Zhao Lei , Cheng Jing
Published: November 2021

Cancer patients are at a high risk of being infected with COVID-19 and have a poor prognosis after infection. Breast cancer is one of the most common cancers. Since vaccination is an effective measure to prevent the spread of COVID-19, we studied the vaccination rate among breast cancer survivors and analyzed their characteristics to provide evidence for boosting the vaccination rate. The researchers conducted a multicenter, cross-sectional study on 747 breast cancer survivors from six hospitals in Wuhan city between June 5, 2021, and June 12, 2021. The self-administrated questionnaires based on relevant studies were distributed. The researchers then compared differences in characteristics among vaccinated patients, hesitant patients, and non-vaccinated patients. Moreover, they performed univariable and multivariable logistic regression analyses to identify potential factors associated with vaccination hesitancy. The researchers assessed a total of 744 breast cancer survivors −94 cases in the vaccinated group, 103 in the planning group, 295 in the hesitancy group, and 252 in the refusal group. The vaccination rate was 12.63% (95% CI 10.25–15.02%) and 37.23% (95% CI 27.48–47.82%) patients reported adverse reactions. The vaccination hesitancy/refusal rate was 73.52% (95% CI 70.19–76.66%), which was independently associated with current endocrine or targeted therapy (odds ratio [OR] = 1.52, 95% CI 1.03–2.24), no notification from communities or units (OR = 2.46, 95% CI 1.69–3.59) and self-perceived feel (general vs. good, OR = 1.46, 95% CI 1.01–2.13; bad vs. good, OR = 4.75, 95% CI 1.85–12.16). In the hesitancy/refusal group, the primary reason was “I did not know who to ask whether I can get vaccinated” (46.07%), the person who would most influence decisions of patients was the doctor in charge of treatment (35.83%). Effective interaction between doctors and patients, simple and consistent practical guidelines on vaccination, and timely and positive information from authoritative media could combat misinformation and greatly reduce vaccine hesitancy among breast cancer survivors.
Antifungal Activity of Siderophore Isolated From Escherichia coli Against Aspergillus nidulans via Iron-Mediated Oxidative Stress
Authors: Khan Azmi , Singh Pratika , Kumar Ravinsh , Das Sujit , Singh Rakesh Kumar , Mina Usha , Agrawal Ganesh Kumar , Rakwal Randeep , Sarkar Abhijit , Srivastava Amrita
Published: November 2021

Microorganisms produce various secondary metabolites for growth and survival. During iron stress, they produce secondary metabolites termed siderophores. In the current investigation, antifungal activity of catecholate siderophore produced by Escherichia coli has been assessed against Aspergillus nidulans. Exogenous application of the bacterial siderophore to fungal cultures resulted in decreased colony size, increased filament length, and changes in hyphal branching pattern. Growth inhibition was accompanied with increased intracellular iron content. Scanning electron microscopy revealed dose-dependent alteration in fungal morphology. Fluorescent staining by propidium iodide revealed cell death in concert with growth inhibition with increasing siderophore concentration. Antioxidative enzyme activity was also compromised with significant increase in catalase activity and decrease in ascorbate peroxidase activity. Siderophore-treated cultures showed increased accumulation of reactive oxygen species as observed by fluorescence microscopy and enhanced membrane damage in terms of malondialdehyde content. Antifungal property might thus be attributed to xenosiderophore-mediated iron uptake leading to cell death. STRING analysis showed interaction of MirB (involved in transport of hydroxamate siderophore) and MirA (involved in transport of catecholate siderophore), confirming the possibility of uptake of iron–xenosiderophore complex through fungal transporters. MirA structure was modeled and validated with 95% residues occurring in the allowed region. In silico analysis revealed MirA–Enterobactin–Fe3+ complex formation. Thus, the present study reveals a promising antifungal agent in the form of catecholate siderophore and supports involvement of MirA fungal receptors in xenosiderophore uptake.