Publications by authors named "A J Cheng"

4,519 Publications

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Association between risk factors, molecular features and CpG island methylator phenotype colorectal cancer among different age groups in a Taiwanese cohort.

Br J Cancer 2021 Apr 12. Epub 2021 Apr 12.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background: CpG island methylator phenotype (CIMP) represents a carcinogenesis pathway of colorectal cancer (CRC) and the association between CIMP CRC, molecular features and risk factors in East Asian population is less studied.

Methods: We prospectively enrolled newly diagnosed CRC patients at the National Taiwan University Hospital. Clinicopathological data and risk factors for CRC were collected during interview. The tumour samples were subjected to CIMP, RAS/BRAF mutation and microsatellite instability tests. CIMP-high was determined when ≧3 methylated loci of p16, MINT1, MINT2, MINT31 and MLH1 were identified. Multivariate logistic regression was used to evaluate the association between risk factors and CIMP-high CRC.

Results: Compared with CIMP-low/negative CRC, CIMP-high CRC was associated with more stage IV disease, BRAF V600E mutation and high body mass index (BMI ≧ 27.5 kg/m) in younger patients (age < 50 y), and more right-sided tumour, BRAF V600E mutation, MSI-high and colorectal polyp in elder patients (age ≧ 50 y). Multivariate analyses showed that BMI ≧27.5 kg/m was significantly associated with CIMP-high CRC in younger patients.

Conclusions: We identified distinct clinicopathological features for CIMP-high CRC among different age groups in Taiwan. Our data suggest the association between BMI ≧27.5 kg/m and CIMP-high CRC in patients younger than 50 years.
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http://dx.doi.org/10.1038/s41416-021-01300-5DOI Listing
April 2021

Clinical characteristics and outcome of influenza virus infection among adults hospitalized with severe COVID-19: a retrospective cohort study from Wuhan, China.

BMC Infect Dis 2021 Apr 12;21(1):341. Epub 2021 Apr 12.

Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, the Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Background: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that rapidly spreads worldwide and co-infection of COVID-19 and influenza may occur in some cases. We aimed to describe clinical features and outcomes of severe COVID-19 patients with co-infection of influenza virus.

Methods: Retrospective cohort study was performed and a total of 140 patients with severe COVID-19 were enrolled in designated wards of Sino-French New City Branch of Tongji Hospital between Feb 8th and March 15th in Wuhan city, Hubei province, China. The demographic, clinical features, laboratory indices, treatment and outcomes of these patients were collected.

Results: Of 140 severe COVID-19 hospitalized patients, including 73 patients (52.14%) with median age 62 years were influenza virus IgM-positive and 67 patients (47.86%) with median age 66 years were influenza virus IgM-negative. 76 (54.4%) of severe COVID-19 patients were males. Chronic comorbidities consisting mainly of hypertension (45.3%), diabetes (15.8%), chronic respiratory disease (7.2%), cardiovascular disease (5.8%), malignancy (4.3%) and chronic kidney disease (2.2%). Clinical features, including fever (≥38 °C), chill, cough, chest pain, dyspnea, diarrhea and fatigue or myalgia were collected. Fatigue or myalgia was less found in COVID-19 patients with IgM-positive (33.3% vs 50/7%, P = 0.0375). Higher proportion of prolonged activated partial thromboplastin time (APTT) > 42 s was observed in COVID-19 patients with influenza virus IgM-negative (43.8% vs 23.6%, P = 0.0127). Severe COVID-19 Patients with influenza virus IgM positive have a higher cumulative survivor rate than that of patients with influenza virus IgM negative (Log-rank P = 0.0308). Considering age is a potential confounding variable, difference in age was adjusted between different influenza virus IgM status groups, the HR was 0.29 (95% CI, 0.081-1.100). Similarly, difference in gender was adjusted as above, the HR was 0.262 (95% CI, 0.072-0.952) in the COX regression model.

Conclusions: Influenza virus IgM positive may be associated with decreasing in-hospital death.
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http://dx.doi.org/10.1186/s12879-021-05975-2DOI Listing
April 2021

Barriers and Challenges to Making Referrals for Treatment and Services for Opioid Misuse in Family Planning Settings.

J Womens Health (Larchmt) 2021 Apr 12. Epub 2021 Apr 12.

School of Nursing and Health Studies, University of Missouri Kansas City, Kansas City, Missouri, USA.

In this opioid overdose epidemic, women are an overlooked group seeing increasing rates of overdose death. Implementation challenges have prevented evidence-based interventions from effectively reaching women who misuse opioids, with gaps in access to effective treatment and services. Family planning clinics could serve as important points of contact for referral to needed treatments and services. The study explores how family planning staff knowledge and attitudes related to opioid misuse serve as potential barriers and challenges in making referrals for evidence-based services and treatments. In 2018, we conducted a national online survey of family planning staff, assessing knowledge and attitudes of treatments and services for opioid misuse. A total of 691 family planning staff completed the survey. Most respondents agreed that opioid misuse was a major problem in their community (86.0%) and identified challenges in responding to it, including a lack of treatment access (70.3%), the absence of in-house behavioral health staff (67.2%), and unfamiliarity with local treatment providers (54.1%). Respondents reported low levels of acceptability for syringe services programs (46.0%), medications such as methadone and buprenorphine (55.4%), and naloxone to reverse opioid overdose (60.1%). Controlling for other factors, race/ethnicity, urbanicity, workplace role, and substance use training were associated with differences in acceptability. Family planning settings could play a critical role in connecting women who misuse opioids to treatment and services. Strategies are needed to increase the acceptability of evidence-based interventions and the feasibility of having family planning staff play a linkage role.
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http://dx.doi.org/10.1089/jwh.2020.8761DOI Listing
April 2021

The Dual Regulation of Apoptosis by Flavivirus.

Front Microbiol 2021 24;12:654494. Epub 2021 Mar 24.

Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.

Apoptosis is a form of programmed cell death, which maintains cellular homeostasis by eliminating pathogen-infected cells. It contains three signaling pathways: death receptor pathway, mitochondria-mediated pathway, and endoplasmic reticulum pathway. Its importance in host defenses is highlighted by the observation that many viruses evade, hinder or destroy apoptosis, thereby weakening the host's immune response. Flaviviruses such as Dengue virus, Japanese encephalitis virus, and West Nile virus utilize various strategies to activate or inhibit cell apoptosis. This article reviews the research progress of apoptosis mechanism during flaviviruses infection, including flaviviruses proteins and subgenomic flaviviral RNA to regulate apoptosis by interacting with host proteins, as well as various signaling pathways involved in flaviviruses-induced apoptosis, which provides a scientific basis for understanding the pathogenesis of flaviviruses and helps in developing an effective antiviral therapy.
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http://dx.doi.org/10.3389/fmicb.2021.654494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024479PMC
March 2021

Glycemic Control and Cardiovascular Risk Factor Management in Adults With Type 2 Diabetes With and Without Chronic Kidney Disease Before Sodium-Glucose Cotransporter Protein 2 Inhibitors: Insights From the Diabetes Mellitus Status in Canada Survey.

Can J Diabetes 2021 Feb 24. Epub 2021 Feb 24.

Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: Optimal control of cardiovascular risk factors in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) is challenging. Limited data are available from the primary care setting on achievement of guideline-recommended targets in this population before the use of sodium-glucose cotransporter protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

Methods: The Diabetes Mellitus Status in Canada survey included 5,172 patients with T2D seen by primary care physicians (PCPs) in November 2012. We compared treatment targets and therapeutic interventions in patients with and without CKD.

Results: Compared with those without CKD (n=3,804), patients with CKD (n=1,368) were older, more likely to be female, had a longer duration of diabetes and had more vascular complications. CKD patients more frequently had a less stringent glycated hemoglobin (A1C) target of ≤8.0% set by PCPs (10.3% vs 20%, p<0.001), and fewer CKD patients met the A1C target of ≤7.0% (50.9% vs 47.1%, p=0.016) than those without CKD. Both groups had a similar likelihood of achieving the blood pressure (BP) target of ≤130/80 mmHg (36.8% vs 34.8%, p=0.20), whereas CKD patients more frequently achieved a low-density lipoprotein cholesterol target of ≤2.0 mmol/L (54.8% vs 61.3%, p<0.001). Overall, only 12.5% in both groups achieved all 3 targets (12.3% vs 13.3%, p=0.33).

Conclusions: Only 1 of 8 T2D patients achieved optimal glycemic, BP and cholesterol targets, regardless of the presence or absence of CKD. Although more medical interventions were used in CKD patients, a lower proportion achieved guideline-recommended targets for A1C. These findings provide a benchmark for future comparison.
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http://dx.doi.org/10.1016/j.jcjd.2021.02.003DOI Listing
February 2021

Upregulation of ZHX2 predicts poor prognosis and is correlated with immune infiltration in gastric cancer.

FEBS Open Bio 2021 Apr 10. Epub 2021 Apr 10.

Department of Gastrointestinal Surgery, Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.

The transcriptional repressor Zinc-finger and homeoboxes 2 (ZHX2) is reported to regulate tumor progression in several human cancers, but little is known about its role in gastric cancer (GC). In this study, we examined the expression of ZHX2 and its relationship with clinicopathological characteristics and prognosis of GC patients, and examined the effect of ZHX2 overexpression in GC cell lines. We used UALCAN and Tumor Immune Estimation Resource (TIMER) to examine ZHX2 mRNA expression, and used Kaplan-Meier plotter to determine whether ZHX2 expression was related to GC prognosis. Expression of ZHX2 protein was detected using immunohistochemical (IHC) staining assays. Cell proliferation was evaluated using CCK-8 assay and colony formation assay while apoptosis was examined by flow cytometry. Wound healing assay and transwell assay were used to detect cell migration and invasion. We also performed gene set enrichment analysis (GSEA) and used The Cancer Genome Atlas (TCGA) database to examine correlation of ZHX2 with immune infiltration. We report that ZHX2 is highly expressed in GC tissues and significantly associated with clinical characteristics. Upregulation of ZHX2 predicted poor prognosis in GC. Furthermore, ZHX2 overexpression can promote proliferation, invasion, and migration, but inhibit apoptosis of GC cells. High expression of ZHX2 in GC is correlated with the presence of infiltrating immune cells, including B cells, CD4 T cells, macrophages and dendritic cells. Our data suggest that high expression of ZHX2 in GC predicts poor prognosis. In addition, ZHX2 may promotes malignant behaviors of GC cells, and immune infiltration might be related to the oncogenic role of ZHX2 in GC.
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http://dx.doi.org/10.1002/2211-5463.13160DOI Listing
April 2021

Genesis of the Master Circadian Pacemaker in Mice.

Front Neurosci 2021 23;15:659974. Epub 2021 Mar 23.

Department of Biology, University of Toronto Mississauga, Mississauga, ON, Canada.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the central circadian clock of mammals. It is responsible for communicating temporal information to peripheral oscillators via humoral and endocrine signaling, ultimately controlling overt rhythms such as sleep-wake cycles, body temperature, and locomotor activity. Given the heterogeneity and complexity of the SCN, its genesis is tightly regulated by countless intrinsic and extrinsic factors. Here, we provide a brief overview of the development of the SCN, with special emphasis on the murine system.
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http://dx.doi.org/10.3389/fnins.2021.659974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021851PMC
March 2021

Global Genome Mining Reveals a Cytochrome P450-Catalyzed Cyclization of Crownlike Cyclodipeptides with Neuroprotective Activity.

Org Lett 2021 Apr 8. Epub 2021 Apr 8.

Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory, The Hong Kong University of Science and Technology, Hong Kong, China.

We conducted global genome mining of 162,672 bacterial genomes and identified 829 cyclodipeptide (CDP) biosynthesis gene clusters (BGC) containing a cytochrome P450 gene. Heterologous expression of BGC from DSM 44795 led to the identification of two novel crownlike CDPs, cyctetryptomycin A () and B (), which possess unprecedented complex macrocycle and show neuroprotective activity. The two cytochrome P450s found in the BGC catalyze sequential reactions leading to the cyclization of diketopiperazine dimers.
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http://dx.doi.org/10.1021/acs.orglett.1c01022DOI Listing
April 2021

A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma.

Sci Transl Med 2021 Apr;13(588)

School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.

Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8 T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8 T cells and potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.
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http://dx.doi.org/10.1126/scitranslmed.aaz6804DOI Listing
April 2021

The Role of CaMKII and ERK Signaling in Addiction.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.

Nicotine is the predominant addictive compound of tobacco and causes the acquisition of dependence through its interactions with nicotinic acetylcholine receptors and various neurotransmitter releases in the central nervous system. The Ca/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) play a pivotal role in synaptic plasticity in the hippocampus. CaMKII is involved in long-term potentiation induction, which underlies the consolidation of learning and memory; however, the roles of CaMKII in nicotine and other psychostimulant-induced addiction still require further investigation. This article reviews the molecular mechanisms and crucial roles of CaMKII and ERK in nicotine and other stimulant drug-induced addiction. We also discuss dopamine (DA) receptor signaling involved in nicotine-induced addiction in the brain reward circuitry. In the last section, we introduce the association of polyunsaturated fatty acids and cellular chaperones of fatty acid-binding protein 3 in the context of nicotine-induced addiction in the mouse nucleus accumbens and provide a novel target for the treatment of drug abuse affecting dopaminergic systems.
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http://dx.doi.org/10.3390/ijms22063189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004038PMC
March 2021

SC75741 antagonizes vesicular stomatitis virus, duck Tembusu virus, and duck plague virus infection in duck cells through promoting innate immune responses.

Poult Sci 2021 Mar 2;100(5):101085. Epub 2021 Mar 2.

Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China. Electronic address:

Duck Tembusu virus (DTMUV) and duck plague virus (DPV) are typical DNA and RNA viruses of waterfowl, causing drastic economic losses to the duck farm industry in terms of high mortality and decreased egg production. These 2 viruses reappear from time to time because the available vaccines fail to provide complete immunity and no clinical antiviral drugs are available for them. In the present study, we evaluated the antiviral activity of SC75741 for DTMUV, DPV, and the model virus, vesicular stomatitis virus infection in duck cells. SC75741, a nuclear factor-kappa B (NF-κB)-specific inhibitor in mammal cells, revealed the highest antiviral activity among the inhibitors specific to c-Jun NH-terminal kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (p38), and NF-κB signaling. The antiviral activity of SC75741 was dose-dependent and showed effects in different duck cell types. Time-addition and duration assay demonstrated that SC75741 inhibited virus infection in the middle of and after virus infection at least for 72 h in duck embro fibroblast cells. The DPV viral adsorption and genomic copy number were reduced, indicating that SC75741 blocks the phase of the virus life cycle at viral entry and genomic replication. In addition, SC75741 enhanced the expression of interferon only when stimulator of interferon genes (STING) was overexpressed or pre-activated by the virus infection, suggesting that SC75741 acts as a STING agonist. In conclusion, SC75741 is a candidate antiviral agent for DTMUV and DPV.
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http://dx.doi.org/10.1016/j.psj.2021.101085DOI Listing
March 2021

Systems serology detects functionally distinct coronavirus antibody features in children and elderly.

Nat Commun 2021 04 1;12(1):2037. Epub 2021 Apr 1.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
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http://dx.doi.org/10.1038/s41467-021-22236-7DOI Listing
April 2021

A Mixed-Methods Assessment of Health Care Providers' Knowledge, Attitudes, and Practices Around Fertility Awareness-Based Methods in Title X Clinics in the United States.

Womens Health Rep (New Rochelle) 2020 15;1(1):354-365. Epub 2020 Sep 15.

School of Nursing and Health Studies, University of Missouri-Kansas City, Kansas City, Missouri, USA.

To understand how Title X providers currently engage with fertility awareness-based methods (FABMs) for pregnancy prevention in Title X clinics across the United States. We developed a survey to assess knowledge of fertility for purposes of pregnancy prevention, attitudes toward FABMs use for pregnancy prevention, and practices when patients request FABMs for pregnancy prevention. In total, 329 participants who met all inclusion criteria completed the survey. Respondents were generally highly knowledgeable on fertility, felt neutrally toward FABMs or thought they were a nonviable option for most women, and were likely to respond to patient requests for FABMs for pregnancy prevention by providing information. Qualitative responses included several barriers to provision of FABMs for pregnancy prevention and few successes to provision. Fertility knowledge and discussion of specific methods increased with the number of methods included in the clinic's written materials or with the number of different FABMs someone at that clinic had been trained on. Significant clinician or administrative barriers may exist to offering FABMs to patients. Incorporating up-to-date information on a range of FABMs-rather than treating them as one method-into contraceptive counseling represents an opportunity to increase the contraceptive offering for clients who want them, leading to increased patient satisfaction and successful family planning outcomes.
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http://dx.doi.org/10.1089/whr.2020.0065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784735PMC
September 2020

Infection management processes in intensive care and their association with mortality.

J Antimicrob Chemother 2021 Mar 30. Epub 2021 Mar 30.

Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.

Background: ICU-specific tables of antimicrobial susceptibility for key microbial species ('antibiograms'), antimicrobial stewardship (AMS) programmes and routine rounds by infectious diseases (ID) physicians are processes aimed at improving patient care. Their impact on patient-centred outcomes in Australian and New Zealand ICUs is uncertain.

Objectives: To measure the association of these processes in ICU with in-hospital mortality.

Methods: The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database and Critical Care Resources registry were used to extract patient-level factors, ICU-level factors and the year in which each process took place. Descriptive statistics and hierarchical logistic regression were used to determine the relationship between each process and in-hospital mortality.

Results: The study included 799 901 adults admitted to 173 ICUs from July 2009 to June 2016. The proportion of patients exposed to each process of care was 38.7% (antibiograms), 77.5% (AMS programmes) and 74.0% (ID rounds). After adjusting for confounders, patients admitted to ICUs that used ICU-specific antibiograms had a lower risk of in-hospital mortality [OR 0.95 (99% CI 0.92-0.99), P = 0.001]. There was no association between the use of AMS programmes [OR 0.98 (99% CI 0.94-1.02), P = 0.16] or routine rounds with ID physicians [OR 0.96 (99% CI 0.09-1.02), P = 0.09] and in-hospital mortality.

Conclusions: Use of ICU-specific antibiograms was associated with lower in-hospital mortality for patients admitted to ICU. For hospitals that do not perform ICU-specific antibiograms, their implementation presents a low-risk infection management process that might improve patient outcomes.
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http://dx.doi.org/10.1093/jac/dkab103DOI Listing
March 2021

Multi-omic analysis suggests tumor suppressor genes evolved specific promoter features to optimize cancer resistance.

Brief Bioinform 2021 Mar 30. Epub 2021 Mar 30.

Chinese University of Hong Kong and a researcher at the CUHK-Shenzhen Research Institute, China.

Tumor suppressor genes (TSGs) exhibit distinct evolutionary features. We speculated that TSG promoters could have evolved specific features that facilitate their tumor-suppressing functions. We found that the promoter CpG dinucleotide frequencies of TSGs are significantly higher than that of non-cancer genes across vertebrate genomes, and positively correlated with gene expression across tissue types. The promoter CpG dinucleotide frequencies of all genes gradually increase with gene age, for which young TSGs have been subject to a stronger evolutionary pressure. Transcription-related features, namely chromatin accessibility, methylation and ZNF263-, SP1-, E2F4- and SP2-binding elements, are associated with gene expression. Moreover, higher promoter CpG dinucleotide frequencies and chromatin accessibility are positively associated with the ability of TSGs to resist downregulation during tumorigenesis. These results were successfully validated with independent datasets. In conclusion, TSGs evolved specific promoter features that optimized cancer resistance through achieving high expression in normal tissues and resistance to downregulation during tumorigenesis.
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http://dx.doi.org/10.1093/bib/bbab040DOI Listing
March 2021

Cerebral Ischemia-Reperfusion Is Associated With Upregulation of Cofilin-1 in the Motor Cortex.

Front Cell Dev Biol 2021 11;9:634347. Epub 2021 Mar 11.

Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Cerebral ischemia is one of the leading causes of death. Reperfusion is a critical stage after thrombolysis or thrombectomy, accompanied by oxidative stress, excitotoxicity, neuroinflammation, and defects in synapse structure. The process is closely related to the dephosphorylation of actin-binding proteins (e.g., cofilin-1) by specific phosphatases. Although studies of the molecular mechanisms of the actin cytoskeleton have been ongoing for decades, limited studies have directly investigated reperfusion-induced reorganization of actin-binding protein, and little is known about the gene expression of actin-binding proteins. The exact mechanism is still uncertain. The motor cortex is very important to save nerve function; therefore, we chose the penumbra to study the relationship between cerebral ischemia-reperfusion and actin-binding protein. After transient middle cerebral artery occlusion (MCAO) and reperfusion, we confirmed reperfusion and motor function deficit by cerebral blood flow and gait analysis. PCR was used to screen the high expression mRNAs in penumbra of the motor cortex. The high expression of cofilin in this region was confirmed by immunohistochemistry (IHC) and Western blot (WB). The change in cofilin-1 expression appears at the same time as gait imbalance, especially maximum variation and left front swing. It is suggested that cofilin-1 may partially affect motor cortex function. This result provides a potential mechanism for understanding cerebral ischemia-reperfusion.
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http://dx.doi.org/10.3389/fcell.2021.634347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991082PMC
March 2021

Coleus forskohlii and Garcinia indica extracts attenuated lipid accumulation by regulating energy metabolism and modulating gut microbiota in obese mice.

Food Res Int 2021 Apr 20;142:110143. Epub 2021 Jan 20.

Institute of Food Science and Technology, National Taiwan University, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan. Electronic address:

Obesity is related to energy imbalance and energy metabolism. In this study, we investigated the anti-obesity effects of Garcinia indica extract (GIE), Coleus forskohlii extract (CFE), and the combinations of these two extracts in a 3T3-L1 cells and high-fat diet (HFD)-induced obese mice. In vitro, GIE showed better effect on TG content than CFE, CFE showed better effect on glycerol released than GIE, and the combinations of GIE and CFE showed both effects compared with GIE and CFE alone. In vivo, GIE, LMIX (0.005% GIE + 0.025% CFE), and HMIX (0.01% GIE + 0.025% CFE) down-regulated adipogenesis-related transcription factors PPARγ and C/EBPα protein expression, CFE promoted lipolysis by up-regulated p-HSL and p-PKA protein expression, and four supplementations promoted fatty acid β-oxidation by up-regulating CPT-1A and PPARα protein expression to decrease lipid accumulation in adipose tissue. Moreover, we found that CFE, LMIX and HMIX, except GIE exert increasing the abundance of Bacteroides caccae compared with HFD group. Overall, GIE, CFE, and the combinations of GIE and CFE were able to decrease body weight and adipocyte size by promoting fatty acid β-oxidation and modulating gut microbiota in HFD-induced obese mice.
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http://dx.doi.org/10.1016/j.foodres.2021.110143DOI Listing
April 2021

Opioid use and social disadvantage in patients with chronic musculoskeletal pain.

PM R 2021 Mar 26. Epub 2021 Mar 26.

Department of Orthopaedic Surgery, Division of Physical Medicine and Rehabilitation, Washington University in St. Louis School of Medicine, St. Louis, Missouri.

Background: Historically, marginalized patients were prescribed less opioid medication than affluent, white patients. However, because of persistent differential access to non-opioid pain treatments, this direction of disparity in opioid prescribing may have reversed.

Objective: To compare social disadvantage and health in patients with chronic pain who were managed with vs without chronic opioid therapy. We hypothesized that patients routinely prescribed opioids would be more likely to live in socially disadvantaged communities and report worse health.

Design: Cross-sectional analysis of a retrospective cohort defined from medical records from 2000-2019.

Setting: Single tertiary safety net medical center.

Patients: Adult patients with chronic musculoskeletal pain who were managed longitudinally by a physiatric group practice from at least 2011 to 2015 (n = 1173), sub-grouped by chronic (≥4 years) adherent opioid usage (n = 356) vs no chronic opioid usage (n = 817).

Intervention: Not applicable.

Main Outcome Measures: The primary outcome was the unadjusted between-group difference in social disadvantage, defined by living in the worst national quartile of the Area Deprivation Index (ADI). An adjusted effect size was also calculated using logistic regression, with age, sex, race, and Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Physical Function scores as covariates. Secondary outcomes included adjusted differences in health by chronic opioid use (measured by PROMIS).

Results: Patients managed with chronic opioid therapy were more likely to live in a zip code within the most socially disadvantaged national quartile (34.9% [95%CI 29.9%-39.9%] vs 24.9% [21.9%-28.0%], P < .001), and social disadvantage was independently associated with chronic opioid use (OR 1.01 per ADI percentile [1.01-1.02]). Opioid use was also associated with meaningfully worse PROMIS Depression (3.8 points [2.4-5.1]), Anxiety (3.0 [1.4-4.5]), and Pain Interference (2.6 [1.7-3.5]) scores.

Conclusions: Patients prescribed chronic opioid treatment were more likely to live in socially disadvantaged neighborhoods, and chronic opioid use was independently associated with worse behavioral health. Improving access to multidisciplinary, non-opioid treatments for chronic pain may be key to successfully overcoming the opioid crisis. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/pmrj.12596DOI Listing
March 2021

A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma.

Sci Rep 2021 Mar 26;11(1):7009. Epub 2021 Mar 26.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.

Enhancer DNA methylation and expression of MYBPHL was studied in multiple myeloma (MM). By bisulfite genomic sequencing, among the three CpGs inside the MYBPHL enhancer, CpG1 was significantly hypomethylated in MM cell lines (6.7-50.0%) than normal plasma cells (37.5-75.0%) (P = 0.007), which was negatively correlated with qPCR-measured MYBPHL expression. In RPMI-8226 and WL-2 cells, bearing the highest CpG1 methylation, 5-azadC caused enhancer demethylation and expression of MYBPHL. In primary samples, higher CpG1 methylation was associated with lower MYBPHL expression. By luciferase assay, luciferase activity was enhanced by MYBPHL enhancer compared with empty vector control, but reduced by site-directed mutagenesis of each CpG. RNA-seq data of newly diagnosed MM patients showed that MYBPHL expression was associated with t(11;14). MOLP-8 cells carrying t(11;14) express the highest levels of MYBPHL, and its knockdown reduced cellular proliferation and increased cell death. Herein, as a proof-of-concept, our data demonstrated that the MYBPHL enhancer, particularly CpG1, was hypomethylated and associated with increased MYBPHL expression in MM, which was implicated in myelomagenesis.
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http://dx.doi.org/10.1038/s41598-021-86473-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997988PMC
March 2021

Pre-diagnosis and early post-diagnosis dietary soy isoflavone intake and survival outcomes: A prospective cohort study of early stage breast cancer survivors.

Cancer Treat Res Commun 2021 Mar 12;27:100350. Epub 2021 Mar 12.

Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong, New Territories, Hong Kong SAR, China.

Background: There is concern that the estrogen-like effects of soy isoflavones may stimulate mammary tumor growth and interfere with the efficacy of breast cancer treatment. This study aimed to examine prospectively the associations of dietary soy isoflavone intake with all-cause mortality and breast cancer (BC) specific mortality and recurrence among BC survivors.

Design: The study included 1460 Chinese women with early-stage incident BC. Pre-diagnosis and early post-diagnosis soy food intakes were assessed at study entry, and at 18-month follow-up using validated soy food frequency questionnaire. Associations of soy isoflavone intake with prognostic outcomes within 48 months were examined using multivariable adjusted Cox proportional hazards models.

Results: We observed increasing pre-diagnosis and early post-diagnosis soy isoflavone intakes up to the third quartile (Q3) were associated with reductions for adverse prognostic outcomes. Relative to the lowest quartile (Q1), the hazard ratios (HRs) for all-cause mortality for pre-diagnosis and post-diagnosis Q3 intake were respectively 0.34 (95% CI, 0.16-0.74), and 0.44 (95% CI, 0.22-0.89). A similar risk reduction was observed for pre- and post-diagnosis intakes and BC-specific mortality when comparing Q3 versus Q1 with the respective HRs 0.36 (95% CI, 0.16-0.82), and 0.49 (95% CI, 0.23-1.01). Subgroup analyses showed more favourable prognostic outcomes in association with moderate soy intake among premenopausal women, those with triple negative cancer and recipients of tamoxifen treatment.

Conclusion: Moderate soy isoflavone intake was associated with favourable prognostic outcomes in Chinese early stage BC survivors.
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http://dx.doi.org/10.1016/j.ctarc.2021.100350DOI Listing
March 2021

Nasopharyngeal carriage of otitis media pathogens in infants receiving 10-valent non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10), 13-valent pneumococcal conjugate vaccine (PCV13) or a mixed primary schedule of both vaccines: A randomised controlled trial.

Vaccine 2021 Apr 23;39(16):2264-2273. Epub 2021 Mar 23.

Child Health Division, Menzies School of Heath Research, Charles Darwin University, PO Box 41096, Casuarina, Northern Territory, Australia. Electronic address:

Background: Aboriginal children in Northern Australia have a high burden of otitis media, driven by early and persistent nasopharyngeal carriage of otopathogens, including non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). In this context, does a combined mixed primary series of Synflorix and Prevenar13 provide better protection against nasopharyngeal carriage of NTHi and Spn serotypes 3, 6A and 19A than either vaccine alone?

Methods: Aboriginal infants (n = 425) were randomised to receive Synflorix™ (S, PHiD-CV10) or Prevenar13™ (P, PCV13) at 2, 4 and 6 months (_SSS or _PPP, respectively), or a 4-dose early mixed primary series of PHiD-CV10 at 1, 2 and 4 months and PCV13 at 6 months of age (SSSP). Nasopharyngeal swabs were collected at 1, 2, 4, 6 and 7 months of age. Swabs of ear discharge were collected from tympanic membrane perforations.

Findings: At the primary endpoint at 7 months of age, the proportion of nasopharyngeal (Np) swabs positive for PCV13-only serotypes 3, 6A, or 19A was 0%, 0.8%, and 1.5% in the _PPP, _SSS, and SSSP groups respectively, and NTHi 55%, 52%, and 52% respectively, and no statistically significant vaccine group differences in other otopathogens at any age. The most common serotypes (in order) were 16F, 11A, 10A, 7B, 15A, 6C, 35B, 23B, 13, and 15B, accounting for 65% of carriage. Ear discharge swabs (n = 108) were culture positive for NTHi (52%), S. aureus (32%), and pneumococcus (20%).

Conclusions: Aboriginal infants experience nasopharyngeal colonisation and tympanic membrane perforations associated with NTHi, non-PCV13 pneumococcal serotypes and S. aureus in the first months of life. Nasopharyngeal carriage of pneumococcus or NTHi was not significantly reduced in the early 4-dose combined SSSP group compared to standard _PPP or _SSS schedules at any time point. Current pneumococcal conjugate vaccine formulations do not offer protection from early onset NTHi and pneumococcal colonisation in this high-risk population.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.032DOI Listing
April 2021

Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages.

J Immunother Cancer 2021 Mar;9(3)

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan

Background: Regorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined.

Methods: In vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow-derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation.

Results: Regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.

Conclusion: Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.
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http://dx.doi.org/10.1136/jitc-2020-001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986673PMC
March 2021

Natural Transformation of and Its Determinants.

Front Microbiol 2021 3;12:634895. Epub 2021 Mar 3.

Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.

In a previous study, it was shown that , a member of , is naturally competent. However, whether natural competence is universal in remains unknown. In this study, it was shown for the first time that was naturally competent in the laboratory condition; however, was not naturally competent under the same conditions. The competence of was maintained throughout the growth phases, and the transformation frequency was highest during the logarithmic phase. A competition assay revealed that preferentially took up its own genomic DNA over heterologous DNA. The natural transformation frequency of was significantly increased in GCB medium without peptone or phosphate. Furthermore, natural transformation of was inhibited by 0.5 mM EDTA, but could be restored by the addition of CaCl, MgCl, ZnCl, and MnCl, suggesting that these divalent cations promote the natural transformation of . Overall, this study revealed that natural competence is not universal in members and triggering of competence differs from species to species.
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http://dx.doi.org/10.3389/fmicb.2021.634895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965970PMC
March 2021

Key steps in our journey to a COVID-19 vaccine program.

Med J Aust 2021 04 21;214(6):249-251.e1. Epub 2021 Mar 21.

Monash University, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.50978DOI Listing
April 2021

Functional characterization of Fur in iron metabolism, oxidative stress resistance and virulence of Riemerella anatipestifer.

Vet Res 2021 Mar 19;52(1):48. Epub 2021 Mar 19.

Institute of Preventive Veterinary Medicine, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, 611130, Sichuan, China.

Iron is essential for most bacteria to survive, but excessive iron leads to damage by the Fenton reaction. Therefore, the concentration of intracellular free iron must be strictly controlled in bacteria. Riemerella anatipestifer (R. anatipestifer), a Gram-negative bacterium, encodes the iron uptake system. However, the iron homeostasis mechanism remains largely unknown. In this study, it was shown that compared with the wild type R. anatipestifer CH-1, R. anatipestifer CH-1Δfur was more sensitive to streptonigrin, and this effect was alleviated when the bacteria were cultured in iron-depleted medium, suggesting that the fur mutant led to excess iron accumulation inside cells. Similarly, compared with R. anatipestifer CH-1∆recA, R. anatipestifer CH-1∆recAΔfur was more sensitive to HO-induced oxidative stress when the bacteria were grown in iron-rich medium rather than iron-depleted medium. Accordingly, it was shown that R. anatipestifer CH-1∆recAΔfur produced more intracellular ROS than R. anatipestifer CH-1∆recA in iron-rich medium. Electrophoretic mobility shift assays showed that R. anatipestifer CH-1 Fur suppressed the transcription of putative iron uptake genes through binding to their promoter regions. Finally, it was shown that compared with the wild type, R. anatipestifer CH-1Δfur was significantly attenuated in ducklings and that the colonization ability of R. anatipestifer CH-1Δfur in various tissues or organs was decreased. All these results suggested that Fur is important for iron homeostasis in R. anatipestifer and its pathogenic mechanism.
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http://dx.doi.org/10.1186/s13567-021-00919-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976709PMC
March 2021

Real-World Experience with Coformulated Ledipasvir and Sofosbuvir for HIV-Positive Patients with HCV Genotype 2 Infection: A Multicenter, Retrospective Study.

Infect Dis Ther 2021 Mar 18. Epub 2021 Mar 18.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Introduction: While coformulated ledipasvir (90 mg)/sofosbuvir (400 mg) (LDV/SOF) is approved for the treatment of hepatitis C virus (HCV) genotype 2 (GT2) infection in Taiwan, Japan, and New Zealand, data regarding its use for HIV (Human Immunodeficiency Virus)-positive patients infected with HCV GT2 are sparse. We aimed to assess the effectiveness and tolerability of LDV/SOF for HIV-positive patients with HCV GT2 coinfection.

Methods: From January 2019 to July 2020, consecutive HIV-positive Taiwanese patients infected with HCV GT2 who received LDV/SOF were retrospectively included for analysis. The effectiveness was determined by sustained virologic response 12 weeks off-therapy (SVR12).

Results: Of the 114 patients (mean age, 38.6 years) initiating LDV/SOF during the study period, 0.9% had liver cirrhosis and 4.4% were HCV treatment-experienced. All patients had estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m and were receiving antiretroviral therapy with 98.2% having CD4 counts ≥ 200 cells/mm and 93.9% plasma HIV RNA load < 50 copies/ml. Antiretrovirals prescribed included tenofovir alafenamide/emtricitabine in 42.1%, tenofovir disoproxil fumarate (TDF)/emtricitabine 18.4%, other nucleoside reverse transcriptase inhibitors (NRTIs) 39.5%, non-NRTIs 12.3%, protease inhibitors 13.2%, and integrase inhibitors 74.6%. All patients had undetectable plasma HCV RNA load at the end of treatment, and 96.5% achieved SVR12 in intention-to-treat analysis. The on-treatment eGFR decline was more pronounced in those receiving TDF-containing antiretroviral therapy (mean change, - 8.33 ml/min/1.73 m), which was reversible after discontinuation of LDV/SOF. None of the patients interrupted LDV/SOF during the 12-week treatment course.

Conclusion: Similar to the response observed among HIV-negative patients, LDV/SOF is effective for HIV-positive patients coinfected with HCV GT2.
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http://dx.doi.org/10.1007/s40121-021-00424-8DOI Listing
March 2021

Risk Factors and Prognosis in Patients with COVID-19 and Liver Injury: A Retrospective Analysis.

J Multidiscip Healthc 2021 10;14:629-637. Epub 2021 Mar 10.

Department of Critical Care, Third People's Hospital of Yichang, Yichang, People's Republic of China.

Purpose: COVID-19 is a new infectious disease with global spread. The aim of the present study was to explore possible risk factors and evaluate prognosis in COVID-19 with liver injury.

Methods: A retrospective study was conducted on 356 COVID-19 patients in the Third People's Hospital of Yichang, Hubei, China. Clinical characteristics and laboratory tests between patients with and without liver injury were compared, while risk factors of COVID-19-related liver injury were analyzed. Univariate and multivariate Cox regression analyses were conducted to identify risk factors of in-hospital death.

Results: Of the patients with liver injury, severe and critical types of COVID-19 comprised 12.43% and 14.69%, respectively, higher than in patients without liver injury (both <0.05). CRP and male sex were independent risk factors for for patients with liver injury, while decreased lymphocyte count (HR 0.024, 95% CI 0.001-0.821) and elevated monocytes (HR 1.951, 95% CI 1.040-3.662) and CRP (HR 1.028, 95% CI 1.010-1.045) were independent risk factors of prognosis of death in COVID-19 patients with liver injury.

Conclusion: Liver injury is a common complication in severe COVID-19 patients. Male sex and elevated CRP were independent risk factors in COVID-19 complicated by liver damage. Liver damage with increased CRP and monocyte count and decreased lymphocyte count may imply a poor prognosis.
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http://dx.doi.org/10.2147/JMDH.S293378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956859PMC
March 2021

DPV UL41 gene encoding protein induces host shutoff activity and affects viral replication.

Vet Microbiol 2021 Apr 27;255:108979. Epub 2021 Feb 27.

Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, PR China; Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, PR China.

The virion host shutoff (VHS) protein, encoded by the UL41 gene of herpes simplex virus (HSV), specifically degrades mRNA and induces host shutoff. VHS and its homologs are highly conserved in the Alphaherpesvirinae subfamily. However, the role of the duck plague virus (DPV) UL41 gene is unclear. In this study, we found that the DPV UL41 gene-encoded protein (pUL41) degrades RNA polymerase (pol) II-transcribed translatable RNA and induces protein synthesis shutoff. DPV pUL41 was dispensable for viral replication, but the UL41-deleted mutant virus exhibited a significant viral growth defect and plaque size reduction in Duck embryo fibroblast (DEF) cells. Furthermore, DPV pUL41 regulated viral mRNA accumulation to affect viral DNA replication, release and cell-to-cell spread.
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http://dx.doi.org/10.1016/j.vetmic.2021.108979DOI Listing
April 2021