bluuebunny/crossref_metadata_2025 huggingface dataset:
PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27
Authors: Ng Zhen Long , Siew Jiamin , Li Jia , Ji Guanxu , Huang Min , Liao Xiaohua , Yu Sue , Chew Yuanyuan , Png Chin Wen , Zhang Yongliang , Wen Shijun , Yang Henry , Zhou Yiting , Long Yun Chau , Jiang Zhi Hong , Wu Qiang
Published: February 2021

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.
RBM14 Modulates Tubulin Acetylation and Regulates Spindle Morphology During Meiotic Maturation in Mouse Oocytes
Authors: Qin Hao , Qu Yi , Yuan Yi-Feng , Li Yang-Yang , Qiao Jie
Published: February 2021

RBM14 is an RNA-binding protein that regulates spindle integrity in mitosis; however, its functions during meiosis are still unclear. In this study, we discovered that RBM14 expression was down-regulated in oocytes from old mice. The RBM14 distribution at different stages of meiosis was explored, while it presents overlapped localization patterns with α-tubulin in MI- and MII-stage oocytes. Treatment of MI-stage oocytes with spindle-perturbing agents revealed that RBM14 was co-localized with microtubules. RBM14 knockdown with RBM14-specific morpholino showed that RBM14-depleted oocytes underwent symmetric division compared to the controls. RBM14 knockdown also resulted in spindle defects and chromosome abnormalities during oocyte maturation, presumably due to α-tubulin hyperacetylation. Co-immunoprecipitation analysis demonstrated that RBM14 is interacted with endogenous α-tubulin in mammalian cells. These findings indicate that RBM14 is an essential modulator of oocyte meiotic maturation by regulating α-tubulin acetylation to affect spindle morphology and chromosome alignment. Consequently, RBM14 represents a potential biomarker of oocyte quality and a novel therapeutic target in women with oocyte maturation failure.
Nanostructure Nickel-Based Selenides as Cathode Materials for Hybrid Battery-Supercapacitors
Authors: Sun Haocheng , Wang Chensheng , Qi Zhiqiang , Hu Wenliang , Zhang Zhijie
Published: February 2021

Supercapacitors (SCs) have attracted many attentions and already became part of some high-power derived devices such as Tesla’s electric cars because of their higher power density. Among all types of electrical energy storage devices, battery-supercapacitors are the most promising for superior performance characteristics, including short charging time, high power density, safety, easy fabrication procedures, and long operational life. An SC usually consists of two foremost components, namely electrode materials, and electrolyte. The selection of appropriate electrode materials with rational nanostructured designs have resulted in improved electrochemical properties for high performance and has reduced the cost of SCs. In this review, we mainly spotlight the nickel-based selenides nanostructured which applied as high-performance cathode materials for SCs. Different nickel-based selenides materials are highlighted in various categories, such as nickel-cobalt-based bimetallic chalcogenides and nickel-M based selenides. Also, we mentioned material modification for this material type. Finally, the designing strategy and future improvements on nickel-based selenides materials for the application of SCs are also discussed.
Development and Validation of a Predictive Model for Coronary Artery Disease Using Machine Learning
Authors: Wang Chen , Zhao Yue , Jin Bingyu , Gan Xuedong , Liang Bin , Xiang Yang , Zhang Xiaokang , Lu Zhibing , Zheng Fang
Published: February 2021

Early identification of coronary artery disease (CAD) can prevent the progress of CAD and effectually lower the mortality rate, so we intended to construct and validate a machine learning model to predict the risk of CAD based on conventional risk factors and lab test data. There were 3,112 CAD patients and 3,182 controls enrolled from three centers in China. We compared the baseline and clinical characteristics between two groups. Then, Random Forest algorithm was used to construct a model to predict CAD and the model was assessed by receiver operating characteristic (ROC) curve. In the development cohort, the Random Forest model showed a good AUC 0.948 (95%CI: 0.941–0.954) to identify CAD patients from controls, with a sensitivity of 90%, a specificity of 85.4%, a positive predictive value of 0.863 and a negative predictive value of 0.894. Validation of the model also yielded a favorable discriminatory ability with the AUC, sensitivity, specificity, positive predictive value, and negative predictive value of 0.944 (95%CI: 0.934–0.955), 89.5%, 85.8%, 0.868, and 0.886 in the validation cohort 1, respectively, and 0.940 (95%CI: 0.922–0.960), 79.5%, 94.3%, 0.932, and 0.823 in the validation cohort 2, respectively. An easy-to-use tool that combined 15 indexes to assess the CAD risk was constructed and validated using Random Forest algorithm, which showed favorable predictive capability (http://45.32.120.149:3000/randomforest). Our model is extremely valuable for clinical practice, which will be helpful for the management and primary prevention of CAD patients.
Potential Mechanisms and Effects of Efferocytosis in Atherosclerosis
Authors: Wang Lili , Li Hongxia , Tang Yuhan , Yao Ping
Published: February 2021

Atherosclerosis (AS) is the main pathological basis for the development of cardio-cerebrovascular diseases. Abnormal accumulation of apoptotic and necrotic cells resulted in plaque enlargement, necrotic core formation and plaque rupture in AS. Under physiological conditions, apoptotic cells (ACs) could be effectively phagocytized and cleared by phagocyte-mediated efferocytosis. In contrast, the clearance efficiency of ACs in AS plaque was much lower because of the impaired efferocytosis in AS. Recent findings have made great progress on the molecular mechanisms of efferocytosis process and dynamic regulation, and its dysfunction on organismal health. Yet, there are still few effective treatments for this process. This article reviews the mechanism of efferocytosis and the role of efferocytosis in AS, highlighting a novel therapeutic strategy for AS, which mainly prevents the progression of plaque by targeting efferocytosis.
Integrated Analysis of Key Genes and Pathways Involved in Nonalcoholic Steatohepatitis Improvement After Roux-en-Y Gastric Bypass Surgery
Authors: Chen Fu , Zhou Yong , Wu Zhiyuan , Li Yunze , Zhou Wenlong , Wang Yong
Published: February 2021

Background

As the incidence of nonalcoholic fatty liver disease (NAFLD) increases globally, nonalcoholic steatohepatitis (NASH) has become the second common cause of liver transplantation for liver diseases. Recent evidence shows that Roux-en-Y gastric bypass (RYGB) surgery obviously alleviates NASH. However, the mechanism underlying RYGB induced NASH improvement is still elusive.

Methods

We obtained datasets, including hepatic gene expression data and histologic NASH status, at baseline and 1 year after RYGB surgery. Differentially expressed genes (DEGs) were identified comparing gene expression before and after RYGB surgery in each dataset. Common DEGs were obtained between both datasets and further subjected to functional and pathway enrichment analysis. Protein–protein interaction (PPI) network was constructed, and key modules and hub genes were also identified.

Results

In the present study, GSE106737 and GSE83452 datasets were included. One hundred thirty common DEGs (29 up-regulated and 101 down-regulated) were identified between GSE106737 and GSE83452 datasets. KEGG analysis showed that mineral absorption, IL-17 signaling pathway, osteoclast differentiation, and TNF signaling pathway were significantly enriched. Based on the PPI network,IGF1,JUN,FOS,LDLR,TYROBP,DUSP1,CXCR4,ATF3,CXCL2,EGR1,SAA1,CTSS, andPPARAwere identified as hub genes, and three functional modules were also extracted.

Conclusion

This study identifies the global gene expression change in the liver of NASH patients before and after RYGB surgery in a bioinformatic method. Our findings will contribute to the understanding of molecular biological changes underlying NASH improvement after RYGB surgery.
Transcriptomic Signatures and Functional Network Analysis of Chronic Rhinosinusitis With Nasal Polyps
Authors: Hao Yun , Zhao Yan , Wang Ping , Du Kun , Li Ying , Yang Zhen , Wang Xiangdong , Zhang Luo
Published: February 2021

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic sinonasal inflammatory disease with limited treatment options of corticosteroids, sinus surgery, or both. CRSwNP is frequently associated with allergic rhinitis and asthma, but the molecular mechanisms underlying CRSwNP inflammation are not completely understood. We obtained four gene expression profiles (GSE136825, GSE36830, GSE23552, and GSE72713) from four Gene Expression Omnibus (GEO), which collectively included 65 nasal polyp samples from CRSwNP patients and 54 nasal mucosal samples from healthy controls. Using an integrated analysis approach, we identified 76 co-differentially expressed genes (co-DEGs, including 45 upregulated and 31 downregulated) in CRSwNP patients compared with the healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified the terms including immune effector process, leukocyte migration, regulation of the inflammatory response, Staphylococcus aureus infection, and cytokine-cytokine receptor interaction. protein-protein interaction (PPI) network analysis and real-time quantitative PCR (RT-qPCR) showed that 7 genes might be crucial in CRSwNP pathogenesis. Repurposing drug candidates (Alfadolone, Hydralazine, SC-560, Iopamidol, Iloprost, etc) for CRSwNP treatment were identified from the Connectivity Map (CMap) database. Our results suggest multiple molecular mechanisms, diagnostic biomarkers, potential therapeutic targets, and new repurposing drug candidates for CRSwNP treatment.
Integrative Analysis of Transcriptome-Wide Association Study and mRNA Expression Profiles Identified Candidate Genes and Pathways Associated With Acute Myocardial Infarction
Authors: Chen Guanzhong , Liu Liwei , Li Huanqiang , Lun Zhubin , Mai Ziling , Lai Wenguang , Chen Enzhao , Zhou Chunyun , Yu Sijia , Yang Junqing , Chen Shiqun , Chen Jiyan , Liu Yong
Published: February 2021

Background

Acute myocardial infarction (AMI), characterized by an event of myocardial necrosis, is a common cardiac emergency worldwide. However, the genetic mechanisms of AMI remain largely elusive.

Methods

A genome-wide association study dataset of AMI was obtained from the CARDIoGRAMplusC4D project. A transcriptome-wide association study (TWAS) was conducted using the FUSION tool with gene expression references of the left ventricle and whole blood. Significant genes detected by TWAS were subjected to Gene Ontology (GO) enrichment analysis. Then the TWAS results of AMI were integrated with mRNA expression profiling to identify common genes and biological processes. Finally, the identified common genes were validated by RT-qPCR analysis.

Results

TWAS identified 1,050 genes for the left ventricle and 1,079 genes for whole blood. Upon comparison with the mRNA expression profile, 4 common genes were detected, including HP (PTWAS = 1.22 × 10–3, PGEO = 4.98 × 10–2); CAMP (PTWAS = 2.48 × 10–2, PGEO = 2.36 × 10–5); TNFAIP6 (PTWAS = 1.90 × 10–2, PGEO = 3.46 × 10–2); and ARG1 (PTWAS = 8.35 × 10–3, PGEO = 4.93 × 10–2). Functional enrichment analysis of the genes identified by TWAS detected multiple AMI-associated biological processes, including autophagy of mitochondrion (GO: 0000422) and mitochondrion disassembly (GO: 0061726).

Conclusion

This integrative study of TWAS and mRNA expression profiling identified multiple candidate genes and biological processes for AMI. Our results may provide a fundamental clue for understanding the genetic mechanisms of AMI.
Evolution of Protein-Mediated Biomineralization in Scleractinian Corals
Authors: Zaquin Tal , Malik Assaf , Drake Jeana L. , Putnam Hollie M. , Mass Tali
Published: February 2021

While recent strides have been made in understanding the biological process by which stony corals calcify, much remains to be revealed, including the ubiquity across taxa of specific biomolecules involved. Several proteins associated with this process have been identified through proteomic profiling of the skeletal organic matrix (SOM) extracted from three scleractinian species. However, the evolutionary history of this putative “biomineralization toolkit,” including the appearance of these proteins’ throughout metazoan evolution, remains to be resolved. Here we used a phylogenetic approach to examine the evolution of the known scleractinians’ SOM proteins across the Metazoa. Our analysis reveals an evolutionary process dominated by the co-option of genes that originated before the cnidarian diversification. Each one of the three species appears to express a unique set of the more ancient genes, representing the independent co-option of SOM proteins, as well as a substantial proportion of proteins that evolved independently. In addition, in some instances, the different species expressed multiple orthologous proteins sharing the same evolutionary history. Furthermore, the non-random clustering of multiple SOM proteins within scleractinian-specific branches suggests the conservation of protein function between distinct species for what we posit is part of the scleractinian “core biomineralization toolkit.” This “core set” contains proteins that are likely fundamental to the scleractinian biomineralization mechanism. From this analysis, we infer that the scleractinians’ ability to calcify was achieved primarily through multiple lineage-specific protein expansions, which resulted in a new functional role that was not present in the parent gene.
BLVector: Fast BLAST-Like Algorithm for Manycore CPU With Vectorization
Authors: Gálvez Sergio , Agostini Federico , Caselli Javier , Hernandez Pilar , Dorado Gabriel
Published: February 2021

New High-Performance Computing architectures have been recently developed for commercial central processing unit (CPU). Yet, that has not improved the execution time of widely used bioinformatics applications, like BLAST+. This is due to a lack of optimization between the bases of the existing algorithms and the internals of the hardware that allows taking full advantage of the available CPU cores. To optimize the new architectures, algorithms must be revised and redesigned; usually rewritten from scratch. BLVector adapts the high-level concepts of BLAST+ to the x86 architectures with AVX-512, to harness their capabilities. A deep comprehensive study has been carried out to optimize the approach, with a significant reduction in time execution. BLVector reduces the execution time of BLAST+ when aligning up to mid-size protein sequences (∼750 amino acids). The gain in real scenario cases is 3.2-fold. When applied to longer proteins, BLVector consumes more time than BLAST+, but retrieves a much larger set of results. BLVector and BLAST+ are fine-tuned heuristics. Therefore, the relevant results returned by both are the same, although they behave differently specially when performing alignments with low scores. Hence, they can be considered complementary bioinformatics tools.
Ribosomal Protein SA-Positive Neutrophil Elicits Stronger Phagocytosis and Neutrophil Extracellular Trap Formation and Subdues Pro-Inflammatory Cytokine Secretion Against Streptococcus suis Serotype 2 Infection
Authors: Sun Qiang , Li Na , Jia Li , Guo Wenfei , Jiang Hexiang , Liu Baijun , Bao Chuntong , Liu Mengmeng , Huang Jing , Lei Liancheng
Published: February 2021

Streptococcus suis serotype 2 (SS2), an important zoonotic pathogen that causes septicemia, arthritis, and irreversible meningitis in pigs and humans, can be transmitted to humans from pigs. S. suis causes huge economic losses to the swine industry and poses a serious threat to public health. Previously, we found that the brain tissues of mice with SS2-induced meningitis showed disrupted structural integrity and significantly enhanced polymorphonuclear neutrophil (PMN) infiltration. We showed that the brain tissues of SS2-infected mice had increased ribosomal protein SA (RPSA)-positive PMN counts. However, the inflammatory responses of RPSA+ PMNs to SS2 and their effects on the blood-brain barrier (BBB) remain unclear. Therefore, in studying the pathogenesis of SS2-induced meningitis, it is essential that we explore the functions of RPSA+ PMNs and their effects on the BBB. Herein, using flow cytometry and immunofluorescence microscopy analyses, we found that RPSA expression enhances PMN-induced phagocytosis and PMN-induced formation of neutrophil extracellular traps (NETs), which facilitate further elimination of bacteria. PMN surface expression of RPSA also alleviates local inflammation and tissue injuries by inhibiting secretion of the pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the single-cell BBB model showed that RPSA disrupts BBB integrity by downregulating expression of tight junction-associated membrane proteins on PMNs. Taken together, our data suggest that PMN-surface expression of RPSA is a double-edged sword. RPSA+ PMN owns a stronger ability of bacterial cleaning and weakens inflammatory cytokines release which are useful to anti-infection, but does hurt BBB. Partly, RPSA+ PMN may be extremely useful to control the infection as a therapeutic cellular population, following novel insights into the special PMN population.
O-Linked N-Acetylglucosamine Modification of Mitochondrial Antiviral Signaling Protein Regulates Antiviral Signaling by Modulating Its Activity
Authors: Seo Junghwa , Park Yun Soo , Kweon Tae Hyun , Kang Jingu , Son Seongjin , Kim Han Byeol , Seo Yu Ri , Kang Min Jueng , Yi Eugene C. , Lee Yong-ho , Kim Jin-Hong , Park Boyoun , Yang Won Ho , Cho Jin Won
Published: February 2021

Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. Several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been identified; however, the direct regulatory mechanisms linking O-GlcNAcylation with antiviral RIG-I-like receptor signaling are not fully understood. In this study, we found that cellular levels of O-GlcNAcylation decline in response to infection with Sendai virus. We identified a heavily O-GlcNAcylated serine-rich region between amino acids 249–257 of the mitochondrial antiviral signaling protein (MAVS); modification at this site disrupts MAVS aggregation and prevents MAVS-mediated activation and signaling. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-β. Taken together, these results suggest that O-GlcNAcylation of MAVS may be a master regulatory event that promotes host defense against RNA viruses.
Regulation of Intestinal Inflammation by Dietary Fats
Authors: Basson Abigail R. , Chen Christy , Sagl Filip , Trotter Ashley , Bederman Ilya , Gomez-Nguyen Adrian , Sundrud Mark S. , Ilic Sanja , Cominelli Fabio , Rodriguez-Palacios Alex
Published: February 2021

With the epidemic of human obesity, dietary fats have increasingly become a focal point of biomedical research. Epidemiological studies indicate that high-fat diets (HFDs), especially those rich in long-chain saturated fatty acids (e.g., Western Diet, National Health Examination survey; NHANES ‘What We Eat in America’ report) have multi-organ pro-inflammatory effects. Experimental studies have confirmed some of these disease associations, and have begun to elaborate mechanisms of disease induction. However, many of the observed effects from epidemiological studies appear to be an over-simplification of the mechanistic complexity that depends on dynamic interactions between the host, the particular fatty acid, and the rather personalized genetics and variability of the gut microbiota. Of interest, experimental studies have shown that certain saturated fats (e.g., lauric and myristic fatty acid-rich coconut oil) could exert the opposite effect; that is, desirable anti-inflammatory and protective mechanisms promoting gut health by unanticipated pathways. Owing to the experimental advantages of laboratory animals for the study of mechanisms under well-controlled dietary settings, we focus this review on the current understanding of how dietary fatty acids impact intestinal biology. We center this discussion on studies from mice and rats, with validation in cell culture systems or human studies. We provide a scoping overview of the most studied diseases mechanisms associated with the induction or prevention of Inflammatory Bowel Disease in rodent models relevant to Crohn’s Disease and Ulcerative Colitis after feeding either high-fat diet (HFD) or feed containing specific fatty acid or other target dietary molecule. Finally, we provide a general outlook on areas that have been largely or scarcely studied, and assess the effects of HFDs on acute and chronic forms of intestinal inflammation.
Relationship Between Pregnancy and Acute Disseminated Encephalomyelitis: A Single-Case Study
Authors: Deng Shuwen , Qiu Ke , Tu Ranran , Zheng Haiping , Lu Wei
Published: February 2021

The relationship between pregnancy and autoimmune diseases is unclear. This study investigated the possible role of local immune changes and the activation state of the HMGB1/TLR4/Nf-κB/IL-6 pathway at the maternal–fetal interface during pregnancy in the pathogenesis of acute disseminated encephalomyelitis (ADEM). Clinical data and blood samples of a patient with ADEM were collected to observe the dynamic changes in lymphocyte populations after an abortion. The expression of HMGB1, TLR4, Nf-κB, AQP4, IL-2, IL-4, IL-6, and TNF-α in the fetal membrane and placenta was compared between the patient with pregnancy-related ADEM and a woman with a normal pregnancy using Real-time qPCR and western blotting (WB). The patient was diagnosed with ADEM in the early stage of pregnancy after showing limb weakness symptoms. In the third month of gestation, the symptoms worsened, with a disturbance of consciousness and breathing. After the abortion, the patient relapsed with vertigo and visual rotation. Analysis of lymphocyte subsets by flow cytometry showed that B lymphocytes increased, while natural killer T lymphocytes decreased. WB and Real-time qPCR showed that the expression levels of HMGB1, TLR4, Nf-κB, AQP4, and IL-6 in the fetal membrane and placenta were higher in the patient with pregnancy-related ADEM than in the woman with a normal pregnancy, while those of IL-2 were lower in the patient than in the woman with a normal pregnancy. The local immune changes and the activation of the HMGB1/TLR4/Nf-κB/IL-6 pathway at the maternal–fetal interface may be related to the pathogenesis of ADEM.
The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes
Authors: Clark Matthew , Kroger Charles J. , Ke Qi , Tisch Roland M.
Published: February 2021

T cell receptor (TCR) signaling influences multiple aspects of CD4+and CD8+T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.
Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF
Authors: Sun Hong-Wei , Wu Wen-Chao , Chen Hai-Tian , Xu Yi-Tuo , Yang Yan-Yan , Chen Jing , Yu Xing-Juan , Wang Zilian , Shuang Ze-Yu , Zheng Limin
Published: February 2021

Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.
Impaired Cellular Immunity to SARS-CoV-2 in Severe COVID-19 Patients
Authors: Ni Ling , Cheng Meng-Li , Feng Yu , Zhao Hui , Liu Jingyuan , Ye Fang , Ye Qing , Zhu Gengzhen , Li Xiaoli , Wang Pengzhi , Shao Jing , Deng Yong-Qiang , Wei Peng , Chen Fang , Qin Cheng-Feng , Wang Guoqing , Li Fan , Zeng Hui , Dong Chen
Published: February 2021

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive immune responses in severe patients during acute phase have not been thoroughly studied. Here, we found that in a group of COVID-19 patients with acute respiratory distress syndrome (ARDS) during hospitalization, most of them mounted SARS-CoV-2-specific antibody responses, including neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, with decreased IFNγ expression in CD4+ T cells in peripheral blood from severe patients. Most notably, their peripheral blood lymphocytes failed in producing IFNγ against viral proteins. Thus, severe COVID-19 patients at acute infection stage developed SARS-CoV-2-specific antibody responses but were impaired in cellular immunity, which emphasizes on the role of cellular immunity in COVID-19.
15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis
Authors: Kim Wonki , Jang Jeong-Hoon , Zhong Xiancai , Seo Hyungseok , Surh Young-Joon
Published: February 2021

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ2 on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ2 on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ2 hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ2 accelerated the resolution of experimentally induced colitis. 15d-PGJ2 treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ2 treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ2, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.
Epidemiological Variations in the Global Burden of Psoriasis, an Analysis With Trends From 1990 to 2017
Authors: Peng Chen , Xu Xin , Chen Wenjuan , Li Xingzi , Yi Xuemei , Ding Yangfeng , Yu Ning , Lu Jiajing
Published: February 2021

Background: Although there have been many epidemiological studies, research focusing on psoriasis' health burden on a global scale is still lacking. Trends and variations in the global health burden of psoriasis are evaluated by time, age, gender, geographical location, and socioeconomic status, using disability-adjusted life years (DALYs) from the Global Burden of Disease Study.

Methods: The health burden of psoriasis was evaluated by DALYs, which combined years lost to disability (a morbidity component) with years of life lost (a mortality component). The global and national DALYs number, crude DALYs rate, and age-standardized DALYs rate were obtained from the GBD 2017 study database. The corresponding human development index (HDI) was collected from the United Nations Development Programme.

Results: From 1990 to 2017, the DALYs number and crude DALYs rate due to psoriasis increased by 73 and 22%, respectively. In comparison, the age-standardized DALYs rate showed a slight increase. Patients in the age range of 65–69 years bear a more significant psoriasis burden. Both males and females showed an increasing trend in burden caused by psoriasis over the past 27 years, with females bearing a more significant psoriasis burden than males. The health burden of psoriasis was substantially unequal in geography with a Gini coefficient of 0.27. The concentration indexes indicated a socioeconomic associated inequality in psoriasis burden with values of 0.22, accounting for 48.64% variance across countries (R2 = 0.4864, p < 0.001). Between-nation inequality in the distribution of psoriasis burden continued to decline throughout the past 27 years. Gini coefficients of psoriasis burden decreased from 0.280 in 1990 to 0.265 in 2017. The concentration indexes indicated the same trend with 0.236 in the 1990s and 0.223 in 2017.

Conclusions: Global health progress in psoriasis together with inequality in the past few decades. Although the inequality of psoriasis burden has shown some improvement during the past 27 years, disparities still exist in age, gender, geographical location, as well as socioeconomic status. The findings of this study highlight the global importance of psoriasis and is important in policy planning for psoriasis services on a global scale.
Akkermansia muciniphila Improves Host Defense Against Influenza Virus Infection
Authors: Hu Xiaotong , Zhao Ya , Yang Yong , Gong Wenxiao , Sun Xiaomei , Yang Li , Zhang Qiang , Jin Meilin
Published: February 2021

Influenza virus infection can alter the composition of the gut microbiota, while its pathogenicity can, in turn, be highly influenced by the gut microbiota. However, the details underlying these associations remain to be determined. The H7N9 influenza virus is an emerging zoonotic pathogen which has caused the death of 616 humans and has incurred huge losses in the poultry industry. Here, we investigated the effects of infection with highly pathogenic H7N9 on gut microbiota and determined potential anti-influenza microbes. 16S rRNA sequencing results show that H7N9 infection alters the mouse gut microbiota by promoting the growth of Akkermansia, Ruminococcus 1, and Ruminococcaceae UCG-010, and reducing the abundance of Rikenellaceae RC9 gut group and Lachnoclostridium. Although the abundance of Akkermansia muciniphila is positively related to H7N9 infection, the oral administration of cultures, especially of pasteurized A. muciniphila, can significantly reduce weight loss and mortality caused by H7N9 infection in mice. Furthermore, oral administration of live or pasteurized A. muciniphila significantly reduces pulmonary viral titers and the levels IL-1β and IL-6 but enhances the levels of IFN-β, IFN-γ, and IL-10 in H7N9-infected mice, suggesting that the anti-influenza role of A. muciniphila is due to its anti-inflammatory and immunoregulatory properties. Taken together, we showed that the changes in the gut microbiota are associated with H7N9 infection and demonstrated the anti-influenza role of A. muciniphila, which enriches current knowledge about how specific gut bacterial strains protect against influenza infection and suggests a potential anti-influenza probiotic.
Antimicrobial Synergy of Silver-Platinum Nanohybrids With Antibiotics
Authors: Ranpariya Bansi , Salunke Gayatri , Karmakar Srikanta , Babiya Kaushik , Sutar Santosh , Kadoo Narendra , Kumbhakar Pathik , Ghosh Sougata
Published: February 2021

Various bacterial pathogens are responsible for nosocomial infections resulting in critical pathophysiological conditions, mortality, and morbidity. Most of the bacterial infections are associated with biofilm formation, which is resistant to the available antimicrobial drugs. As a result, novel bactericidal agents need to be fabricated, which can effectively combat the biofilm-associated bacterial infections. Herein, for the first time we report the antimicrobial and antibiofilm properties of silver-platinum nanohybrids (AgPtNHs), silver nanoparticles (AgNPs), and platinum nanoparticles (PtNPs) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The AgPtNHs were synthesized by a green route using Dioscorea bulbifera tuber extract at 100°C for 5 h. The AgPtNHs ranged in size from 20 to 80 nm, with an average of ∼59 nm. AgNPs, PtNPs, and AgPtNHs showed a zeta potential of −14.46, −1.09, and −11.39 mV, respectively. High antimicrobial activity was observed against P. aeruginosa and S. aureus and AgPtNHs exhibited potent antimicrobial synergy in combination with antibiotics such as streptomycin, rifampicin, chloramphenicol, novobiocin, and ampicillin up to variable degrees. Interestingly, AgPtNHs could inhibit bacterial biofilm formation significantly. Hence, co-administration of AgPtNHs and antibiotics may serve as a powerful strategy to treat bacterial infections.
Copper Ions Facilitate the Conjugative Transfer of SXT/R391 Integrative and Conjugative Element Across Bacterial Genera
Authors: Song Zhou , Zuo Lei , Li Cui , Tian Yiming , Wang Hongning
Published: February 2021

Copper can persist stably in the environment for prolonged periods. Except for inducing antibiotic resistance in bacteria, copper ions (Cu2+) can facilitate the horizontal transfer of plasmid DNA. However, whether and how Cu2+ can accelerate the conjugative transfer of SXT/R391 integrative and conjugative element (ICE) is still largely unknown. In this study, Proteus mirabilis ChSC1905, harboring an SXT/R391 ICE that carried 21 antibiotic resistance genes (ARGs), was used as a donor, and Escherichia coli EC600 was used as a recipient. Cu2+, at subinhibitory and environmentally relevant concentrations (1–10 μmol/L), significantly accelerated the conjugative transfer of SXT/R391 ICE across bacterial genera (from P. mirabilis to E. coli) (p < 0.05). The combined analyses of phenotypic tests and genome-wide sequencing indicated that reactive oxygen species (ROS) production and cell membrane permeability were critical in the enhanced conjugative transfer of SXT/R391 ICE. Furthermore, the expression of genes related to cell adhesion and ATP synthesis was also significantly upregulated on exposure to Cu2+ at a concentration of 5 μmol/L. This study clarified the potential mechanisms of Cu2+ to promote the conjugative transfer of SXT/R391 ICE, revealing the potential risk imposed by Cu2+ on the horizontal transfer of SXT/R391 ICE-mediated ARGs.
RegX3-Mediated Regulation of Methylcitrate Cycle in Mycobacterium smegmatis
Authors: Pei Jin-Feng , Qi Nan , Li Yu-Xin , Wo Jing , Ye Bang-Ce
Published: February 2021

Mycobacterium tuberculosis is a global human pathogen that infects macrophages and can establish a latent infection. Emerging evidence has established the nutrients metabolism as a key point to study the pathogenesis of M. tuberculosis and host immunity. It was reported that fatty acids and cholesterol are the major nutrient sources of M. tuberculosis in the period of infection. However, the mechanism by which M. tuberculosis utilizes lipids for maintaining life activities in nutrient-deficiency macrophages is poorly understood. Mycobacterium smegmatis is fast-growing and generally used to study its pathogenic counterpart, M. tuberculosis. In this work, we found that the phosphate sensing regulator RegX3 of M. smegmatis is required for its growing on propionate and surviving in macrophages. We further demonstrated that the expression of prpR and related genes (prpDBC) in methylcitrate cycle could be enhanced by RegX3 in response to the phosphate-starvation condition. The binding sites of the promoter region of prpR for RegX3 and PrpR were investigated. In addition, cell morphology assay showed that RegX3 is responsible for cell morphological elongation, thus promoting the proliferation and survival of M. smegmatis in macrophages. Taken together, our findings revealed a novel transcriptional regulation mechanism of RegX3 on propionate metabolism, and uncovered that the nutrients-sensing regulatory system puts bacteria at metabolic steady state by altering cell morphology. More importantly, since we observed that M. tuberculosis RegX3 also binds to the prpR operon in vitro, the RegX3-mediated regulation might be general in M. tuberculosis and other mycobacteria for nutrient sensing and environmental adaptation.
Expression of NanoLuc Luciferase in Listeria innocua for Development of Biofilm Assay
Authors: Berlec Aleš , Janež Nika , Sterniša Meta , Klančnik Anja , Sabotič Jerica
Published: February 2021

Studies of biofilm formation by bacteria are crucial for understanding bacterial resistance and for development of novel antibacterial strategies. We have developed a new bioluminescence biofilm assay for Listeria innocua, which is considered a non-pathogenic surrogate for Listeria monocytogenes. L. innocua was transformed with a plasmid for inducible expression of NanoLuc luciferase (Nluc). Concentration-dependent bioluminescence signals were obtained over a concentration range of more than three log units. This biofilm assay enables absolute quantification of bacterial cells, with the necessary validation. For biofilm detection and quantification, this “Nluc bioluminescence” method has sensitivity of 1.0 × 104 and 3.0 × 104 colony forming units (CFU)/mL, respectively, with a dynamic range of 1.0 × 104 to 5.0 × 107 CFU/mL. These are accompanied by good precision (coefficient of variation, <8%) and acceptable accuracy (relative error for most samples, <15%). This novel method was applied to assess temporal biofilm formation of L. innocua as a function of concentration of inoculant, in comparison with conventional plating and CFU counting, the crystal violet assay, and the resazurin fluorescence assay. Good correlation (r = 0.9684) of this Nluc bioluminescence assay was obtained with CFU counting. The limitations of this Nluc bioluminescence assay include genetic engineering of bacteria and relatively high cost, while the advantages include direct detection, absolute cell quantification, broad dynamic range, low time requirement, and high sensitivity. Nluc-based detection of L. innocua should therefore be considered as a viable alternative or a complement to existing methods.
ELAC2, an Enzyme for tRNA Maturation, Plays a Role in the Cleavage of a Mature tRNA to Produce a tRNA-Derived RNA Fragment During Respiratory Syncytial Virus Infection
Authors: Choi Eun-Jin , Wu Wenzhe , Zhang Ke , Lee Inhan , Kim In-Hoo , Lee Yong Sun , Bao Xiaoyong
Published: February 2021

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children. However, effective treatment against RSV is unavailable. tRNA-derived RNA fragments (tRFs) are a recently discovered family of non-coding RNAs. We made an early observation that RSV infection causes significant induction of tRFs, which are mainly derived from the 5’-end of mature tRNAs (tRF5). However, their functions and biogenesis mechanism are not fully understood. Herein, we identified an enzyme responsible for the induction of a functional tRF5 derived from tRNA-Gln-CTG (tRF5-GlnCTG). We found that tRF5-GlnCTG promotes RSV replication and its induction, assessed by Northern blot and a new qRT-PCR-based method, is regulated by ribonuclease ELAC2. ELAC2-mediated tRF5 induction has never been reported. We also found that ELAC2 is associated with RSV N and NS1 proteins. Given the fact that tRF5-GlnCTG plays a role in RSV replication, the identification of ELAC2 being responsible for tRF5-GlnCTG induction could provide new insights into therapeutic strategy development against RSV infection.
The Therapeutic Targets of Fingolimod (FTY720) Are Involved in Pathological Processes in the Frontal Cortex of Alzheimer's Disease Patients: A Network Pharmacology Study
Authors: Yin Pengqi , Xue Yang , Wang Tingting , Zhong Di , Li Guozhong
Published: February 2021

Background: The sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, has recently been found to reduce pathological changes in the brain tissue of Alzheimer's disease (AD) animal models, but this has yet to be verified in human brain tissue. In this study, network pharmacology methods were applied to determine the potential pharmacological mechanisms of fingolimod in the frontal cortex of AD patients.

Methods: The pharmacological macromolecular targets of fingolimod and fingolimod phosphate were downloaded from SwissTarget and DrugBank. Systematic intersection analysis of the expression profiles of brain frontal cortex tissues (423 AD tissues and 266 control tissues) was performed to obtain AD-associated fingolimod targets (F-ADGs). Immune cell infiltration analysis and a primary mouse cortical culture RNA-seq drug screen database were used to identify immune-related F-ADGs and cortex-related F-ADGs. Then, the expression values of F-ADGs were correlated with the disease severity score (MMSE score) of AD patients to identify severity-related F-ADGs. We also analyzed miRNA expression microarray data in the frontal cortex of AD patients associated with disease severity to obtain severity-related F-ADG-miRNAs.

Results: A total of 188 F-ADGs were detected in the frontal cortices of AD patients and were enriched in biological processes such as synaptic signaling, inflammatory response, and response to oxygen-containing compounds. Eleven immune-related F-ADGs (like FPR1, BLNK.) and 17 cortex-related F-ADGs (like ALDH1L1, DUSP1.) were detected. Other F-ADGs, such as S1PR1 and GABBR2, although not classified into the above two categories, were still predicted by bioinformatics methods to play an important role in the development of AD. Two F-ADGs (GNAQ and MMP14) and 28 miRNAs (like miR- 323a-3p, miR-181a-5p.) were found to be associated with AD severity (MMSE 0-27 group). Fifteen F-ADGs (like ALDH1L1, FPR1, and IL6.) and 46 miRNAs (like miR-212-5p, miR-93-5p.) were found to be associated with mild or moderate dementia AD patients' severity (MMSE11-22 subgroup).

Conclusions: Fingolimod may affect the brain frontal cortex function of AD patients in many different ways, such as affecting immune cell infiltration, nerve cell, or glial cell function, and synaptic function. miRNAs may also be involved. ALDH1L1, FPR1, S1PR1, and GABBR2 may be core drug targets.
Cerebrotypes in Cephalopods: Brain Diversity and Its Correlation With Species Habits, Life History, and Physiological Adaptations
Authors: Ponte Giovanna , Taite Morag , Borrelli Luciana , Tarallo Andrea , Allcock A. Louise , Fiorito Graziano
Published: February 2021

Here we analyze existing quantitative data available for cephalopod brains based on classical contributions by J.Z. Young and colleagues, to cite some. We relate the relative brain size of selected regions (area and/or lobe), with behavior, life history, ecology and distribution of several cephalopod species here considered. After hierarchical clustering we identify and describe ten clusters grouping 52 cephalopod species. This allows us to describe cerebrotypes, i.e., differences of brain composition in different species, as a sign of their adaptation to specific niches and/or clades in cephalopod molluscs for the first time. Similarity reflecting niche type has been found in vertebrates, and it is reasonable to assume that it could also occur in Cephalopoda. We also attempted a phylogenetic PCA using data by Lindgren et al. (2012) as input tree. However, due to the limited overlap in species considered, the final analysis was carried out on <30 species, thus reducing the impact of this approach. Nevertheless, our analysis suggests that the phylogenetic signal alone cannot be a justification for the grouping of species, although biased by the limited set of data available to us. Based on these preliminary findings, we can only hypothesize that brains evolved in cephalopods on the basis of different factors including phylogeny, possible development, and the third factor, i.e., life-style adaptations. Our results support the working hypothesis that the taxon evolved different sensorial and computational strategies to cope with the various environments (niches) occupied in the oceans. This study is novel for invertebrates, to the best of our knowledge.