bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring Autophagy at Cellular and Molecular Level in Crassostrea gigas During an Experimental Ostreid Herpesvirus 1 (OsHV-1) Infection
Authors: Picot Sandy , Faury Nicole , Pelletier Camille , Arzul Isabelle , Chollet Bruno , Dégremont Lionel , Renault Tristan , Morga Benjamin
Published: April 2022

Mortality outbreaks of young Pacific oysters, Crassostrea gigas, have seriously affected the oyster-farming economy in several countries around the world. Although the causes of these mortality outbreaks appear complex, a viral agent has been identified as the main factor: a herpesvirus called ostreid herpesvirus 1 (OsHV-1). Autophagy is an important degradation pathway involved in the response to several pathologies including viral diseases. In C. gigas, recent studies indicate that this pathway is conserved and functional in at least haemocytes and the mantle. Furthermore, an experimental infection in combination with compounds known to inhibit or induce autophagy in mammals revealed that autophagy is involved in the response to OsHV-1 infection. In light of these results, the aim of this study was to determine the role of autophagy in the response of the Pacific oyster to infection by virus OsHV-1. For this purpose, an experimental infection in combination with a modulator of autophagy was performed on Pacific oysters known to have intermediate susceptibility to OsHV-1 infection. In haemolymph and the mantle, the autophagy response was monitored by flow cytometry, western blotting, and real-time PCR. At the same time, viral infection was evaluated by quantifying viral DNA and RNA amounts by real-time PCR. Although the results showed activation of autophagy in haemolymph and the mantle 14 hours post infection (after viral replication was initiated), they were also indicative of different regulatory mechanisms of autophagy in the two tissues, thus supporting an important function of autophagy in the response to virus OsHV-1.
Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease
Authors: Peng Rui , Li Binbin , Chen Shuxia , Shi Zhiwen , Yu Liwei , Gao Yunqian , Yang Xueyan , Lu Lei , Wang Hongyan
Published: April 2022

The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc. Deleterious mutations in GLI genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in GLI1-3 genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human GLI1-3 genes were identified. Functional analyses showed that GLI1 c.820G> T (p.G274C) is a gain-of-function mutation, while GLI1 c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in GLI1 gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.
Epidemiology of Atrial Fibrillation and Related Myocardial Ischemia or Arrhythmia Events in Chinese Community Population in 2019
Authors: Li Cheng , Wang Haicheng , Li Mohan , Qiu Xiangjun , Wang Qunshan , Sun Jian , Yang Mei , Feng Xiangfei , Meng Shu , Zhang Pengpai , Liu Bo , Li Wei , Chen Mu , Zhao Yan , Zhang Rui , Mo Binfeng , Zhu Yuling , Zhou Baohong , Chen Min , Liu Xia , Zhao Yuelin , Shen Mingzhen , Huang Jinkang , Luo Li , Wu Hong , Li Yi-Gang
Published: April 2022

Background

Atrial fibrillation (AF) is the most common arrhythmia, and the incidence increases rapidly all over the world. The global prevalence of AF (age-adjusted) is 0.60% for men and 0.37% for women and the prevalence of AF in China is 0.65%. It is expected that the number of patients with AF will continue to rise in the future worldwide due to population aging.

Objective

To explore the prevalence of AF in Chinese community population in 2019 and clarify the prevalence of AF complicated with other arrhythmias and myocardial ischemia (MI) events.

Methods

The remote electrocardiogram (ECG) diagnosis system of Xinhua Hospital was assessed to the screen participants with ECG evidence of AF between January 1 and December 31, 2019. The prevalence rates of AF and its association with other arrhythmias and MI events were analyzed and subgroup analysis was performed between different sexes and age groups.

Results

A total of 22,016 AF cases were identified out of all ECGs derived from the remote ECG diagnosis system in 2019. It is estimated that AF was presented in nearly 10.15 million people in China (age-adjusted standardized rate 0.72%, 95% CI 0.20–1.25%) in 2019 and 62% of the AF cases (6.27 million) affected people aged 65 years and above (age-adjusted standardized rate 3.56%, 95% CI 3.28–3.85%). The prevalence rate of AF in males was higher than that in females (p < 0.001), and the ventricular rate of AF patients was faster in females (p < 0.001) and younger patients (p < 0.001). AF patients with lower ventricular rate (under 60 beats per min) were associated with increased prevalence of ventricular escape/escape rhythm [p < 0.001, odds ratio (OR) 5.14] and third-degree atrioventricular block (p < 0.001, OR 32.05).

Conclusion

The prevalence of AF is higher in the Chinese community population than that was previously reported. AF patients complicated with ECG patterns suggesting myocardial infarction is common in men, and stricter measures should be taken to control the common risk factors of AF and coronary heart disease. It is also important that more attention should be paid to recognize fatal arrhythmias, especially in elderly male patients with AF.
Clinical Implications of Atrial Fibrillation Detection Using Wearable Devices in Patients With Cryptogenic Stroke (CANDLE-AF) Trial: Design and Rationale
Authors: Jung Sodam , Lee Hye Ah , Kang In Sook , Shin Sang Hoon , Chang Yoonkyung , Woo Shin Dong , Park Moo-Seok , Kim Young Dae , Nam Hyo Suk , Heo Ji Hoe , Kim Tae-Hoon , Yu Hee Tae , Lee Jung Myung , Heo Sung Hyuk , Woo Ho Geol , Park Jin-Kyu , Roh Seung-Young , Kim Chi Kyung , Lee Young-Soo , Do Jin Kuk , Kim Dong-Hyeok , Song Tae-Jin , Park Junbeom ,   CANDLE-AF Trial Investigators
Published: April 2022

Background

Although many electrocardiography wearable devices have been released recently for the detection of atrial fibrillation (AF), there are few studies reporting prospective data for wearable devices compared to the strategy of the existing guidelines in the detection of atrial fibrillation (AF) after cryptogenic stroke. A tiny single-patch monitor is more convenient than a conventional Holter monitor recording device and, therefore, longer duration of monitoring may be acceptable.

Methods and Design

The CANDLE-AF study is a multicenter, prospective, randomized controlled trial. Patients with transient ischemic attack or ischemic stroke without any history of AF will be enrolled. The superiority of the 72-h single-patch monitor to standard strategy and non-inferiority of the 72-h single-patch monitor to an event-recorder-type device will be investigated. Single-patch monitor arm will repeat monitoring at 1, 3, 6, and 12 months, event-recorder-type arm will repeat monitoring twice daily for 12 months. The enrollment goal is a total of 600 patients, and the primary outcome is the detection of AF which continues at least 30 s during study period. The secondary outcome is the rate of changes from antiplatelet to anticoagulant and major adverse cardiac and cerebrovascular events within 1 year.

Conclusions

The results of CANDLE-AF will clarify the role of a single-lead patch ECG for the early detection of AF in patients with acute ischemic stroke. In addition, the secondary outcome will be analyzed to determine whether more sensitive AF detection can affect the prognosis and if further device development is meaningful. (cris.nih.go.kr KCT0005592).
A Multistep Approach to Deal With Advanced Heart Failure: A Case Report on the Positive Effect of Cardiac Contractility Modulation Therapy on Pulmonary Pressure Measured by CardioMEMS
Authors: Visco Valeria , Esposito Cristina , Manzo Michele , Fiorentino Antonio , Galasso Gennaro , Vecchione Carmine , Ciccarelli Michele
Published: April 2022

During the last years, the management of heart failure (HF) made substantial progress, focusing on device-based therapies to meet the demands of this complex syndrome. In this case report, we present a multistep approach to deal with HF. Specifically, we report the first patient subjected to the implantation of both Optimizer Smart® (Impulse Dynamics Inc., Marlton, NJ, USA) and CardioMEMS devices. A 72-year-old male patient with HF and reduced ejection fraction (HFrEF) was admitted to our cardiology department in January 2021, following a progressive shortening of the time between hospitalizations for levosimendan infusions. Specifically, the patient was monitored daily by CardioMEMS, and a strategy of levosimendan infusions guided by the device had been adopted. He was also a carrier of MitraClips and cardiac resynchronization therapy defibrillator (CRT-D) and had optimized HF medical therapy. In January 2021, the patient implanted Optimizer Smart® device for cardiac contractility modulation (CCM) therapy because of poor response to therapy and elevated pulmonary artery pressure (PAP). CCM significantly reduced PAP values following discharge (systolic PAP 33.67 ± 2.92 vs. 40.6 ± 3.37 mmHg, diastolic PAP 14.5 ± 2.01 vs. 22.5 ± 2.53 mmHg, mean PAP 22.87 ± 2.20 vs. 30.9 ± 2.99 mmHg, HR 60.93 ± 1.53 vs. 80.83 ± 3.66 bpm; p < 0.0001), with persisting effect at 9 months. The usefulness of CCM is objectively demonstrated for the first time by continuous invasive monitoring of PAP by CardioMEMS, which can suggest the correct timing for CCM implantation.
The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism
Authors: Kong Linghui , Tang Xiaofeng , Kang Yuanyuan , Dong Lei , Tong Jianhua , Xu Jianzhong , Gao Ping-jin , Wang Ji-guang , Shen Weili , Zhu Limin
Published: April 2022

Background

Adrenal venous sampling (AVS) is recognized as the gold standard for subtyping primary aldosteronism (PA), but its invasive nature and technical challenges limit its availability. A recent study reported that sodium chloride cotransporter (NCC) in urinary extracellular vesicles (uEVs) is a promising marker for assessing the biological activity of aldosterone and can be treated as a potential biomarker of PA. The current study was conducted to verify the hypothesis that the expression of NCC and its phosphorylated form (pNCC) in uEVs are different in various subtypes and genotypes of PA and can be used to select AVS candidates.

Methods

A total of 50 patients with PA were enrolled in the study. Urinary extracellular vesicles (uEVs) were isolated from spot urine samples using ultracentrifugation. NCC and pNCC expressions were tested in patients diagnosed with PA who underwent AVS. Sanger sequencing of KCNJ5 was performed on DNA extracted from adrenal adenoma.

Results

pNCC (1.89 folds, P<.0001) and NCC (1.82 folds, P=0.0002) was more abundant in the uEVs in the high lateralization index (h-LI, ≥ 4) group than in the low LI (l-LI, < 4) group. Carriers of the somatic KCNJ5 mutations, compared with non-carriers, had more abundant pNCC expression (2.16 folds, P=0.0039). Positive correlation between pNCC abundance and plasma aldosterone level was found in this study (R = 0.1220, P = 0.0129).

Conclusions

The expression of pNCC in uEVs in patients with PA with various subtypes and genotypes was different. It can be used as biomarker of AVS for PA subtyping.
Feasibility of Random Forest and Multivariate Adaptive Regression Splines for Predicting Long-Term Mean Monthly Dew Point Temperature
Authors: Zhang Guodao , Bateni Sayed M. , Jun Changhyun , Khoshkam Helaleh , Band Shahab S. , Mosavi Amir
Published: April 2022

The accurate estimation of dew point temperature (Tdew) is important in climatological, agricultural, and agronomical studies. In this study, the feasibility of two soft computing methods, random forest (RF) and multivariate adaptive regression splines (MARS), is evaluated for predicting the long-term mean monthly Tdew. Various weather variables including air temperature, sunshine duration, relative humidity, and incoming solar radiation from 50 weather stations in Iran as well as their geographical information (or a subset of them) are used in RF and MARS as inputs. Three statistical indicators namely, root mean square error (RMSE), mean absolute error (MAE), and correlation coefficient (R) are used to assess the accuracy of Tdew estimates from both models for different input configurations. The results demonstrate the capability of the RF and MARS methods for predicting the long-term mean monthly Tdew. The combined scenarios in both the RF and MARS methods are found to produce the best Tdew estimates. The best Tdew estimates were obtained by the MARS model with the RMSE, MAE, and R of respectively 0.17°C, 0.14°C, and 1.000 in the training phase; 0.15°C, 0.12°C, and 1.000 in the validation phase; and 0.18°C, 0.14°C, and 0.999 in the testing phase.
Nexuses Between Energy Efficiency, Renewable Energy Consumption, Foreign Direct Investment, Energy Consumption, Global Trade, Logistics and Manufacturing Industries of Emerging Economies: In the Era of COVID-19 Pandemic
Authors: Rehman Khan Syed Abdul , Hassan Shafiqul , Khan Mubashir Ali , Khan M. R. , Godil Danish Iqbal , Tanveer Muhammad
Published: April 2022

This study aims to find the nexuses among energy efficiency, renewable energy consumption, foreign direct investment, logistics industry, manufacturing industry and global trade during the COVID-19 pandemic and their impact on global supply chains in exporting nations of the world. The data for this study has been extracted from the World Development Indicators and Statista 2021 for 13 years ranging from 2007-to 2020 for nine top exporting countries. The fixed effect panel estimation technique was implied to examine and analyze the data. The results of our study revealed that highly risky diseases significantly impact supply chain operations globally. Global supply chains, logistics and manufacturing industries significantly influence global trade operations. Our results implicate that the overall international trade and logistics can be enhanced by improving the manufacturing and logistics industries by coping with the risk of pandemic diseases. Moreover, by utilizing cost-effective, renewable and efficient energy resources companies address sustainability issues of global trade and operations. By exerting further attention to the proficiency of the levies approval process, competence and quality of logistics services, and ease of assembling competitively priced shipments, the governments can significantly enhance the export from the logistics industry. Also, increasing manufacturing and agricultural value-added healthier consequences might be acquired in global supply chain operations from the manufacturing industry.
Physiological Acclimation Extrapolates the Kinetics and Thermodynamics of Methanogenesis From Laboratory Experiments to Natural Environments
Authors: Wu Qiong , Guthrie Megan J. , Jin Qusheng
Published: April 2022

Chemotrophic microorganisms face the steep challenge of limited energy resources in natural environments. This observation has important implications for interpreting and modeling the kinetics and thermodynamics of microbial reactions. Current modeling frameworks treat microbes as autocatalysts, and simulate microbial energy conservation and growth with fixed kinetic and thermodynamic parameters. However, microbes are capable of acclimating to the environment and modulating their parameters in order to gain competitive fitness. Here we constructed an optimization model and described microbes as self-adapting catalysts by linking microbial parameters to intracellular metabolic resources. From the optimization results, we related microbial parameters to the substrate concentration and the energy available in the environment, and simplified the relationship between the kinetics and the thermodynamics of microbial reactions. We took as examplesMethanosarcinaandMethanosaeta– the methanogens that produce methane from acetate – and showed how the acclimation model extrapolated laboratory observations to natural environments and improved the simulation of methanogenesis and the dominance ofMethanosaetaoverMethanosarcinain lake sediments. These results highlight the importance of physiological acclimation in shaping the kinetics and thermodynamics of microbial reactions and in determining the outcome of microbial interactions.
In-Silico Functional Annotation of Plasmodium falciparum Hypothetical Proteins to Identify Novel Drug Targets
Authors: Singh Gagandeep , Gupta Dinesh
Published: April 2022

Plasmodium falciparum is one of the plasmodium species responsible for the majority of life-threatening malaria cases. The current antimalarial therapies are becoming less effective due to growing drug resistance, leading to the urgent requirement for alternative and more effective antimalarial drugs or vaccines. To facilitate the novel drug discovery or vaccine development efforts, recent advances in sequencing technologies provide valuable information about the whole genome of the parasite, yet a lot more needs to be deciphered due to its incomplete proteome annotation. Surprisingly, out of the 5,389 proteins currently annotated in the Plasmodium falciparum 3D7 strain, 1,626 proteins (∼30% data) are annotated as hypothetical proteins. In parasite genomic studies, the challenge to annotate hypothetical proteins is often ignored, which may obscure the crucial information related to the pathogenicity of the parasite. In this study, we attempt to characterize hypothetical proteins of the parasite to identify novel drug targets using a computational pipeline. The study reveals that out of the overall pool of the hypothetical proteins, 266 proteins have conserved functional signatures. Furthermore, the pathway analysis of these proteins revealed that 23 proteins have an essential role in various biochemical, signalling and metabolic pathways. Additionally, all the proteins (266) were subjected to computational structure analysis. We could successfully model 11 proteins. We validated and checked the structural stability of the models by performing molecular dynamics simulation. Interestingly, eight proteins show stable conformations, and seven proteins are specific for Plasmodium falciparum, based on homology analysis. Lastly, mapping the seven shortlisted hypothetical proteins on the Plasmodium falciparum protein-protein interaction network revealed 3,299 nodes and 2,750,692 edges. Our study revealed interesting functional details of seven hypothetical proteins of the parasite, which help learn more about the less-studied molecules and their interactions, providing valuable clues to unravel the role of these proteins via future experimental validation.
Clinical and Genetic Analysis in Neurological Wilson’s Disease Patients With Neurological Worsening Following Chelator Therapy
Authors: Hou Haiman , Chen Dingbang , Liu Junxiu , Feng Li , Zhang Jiwei , Liang Xiuling , Xu Yuming , Li Xunhua
Published: April 2022

Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening.

Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated.

Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening.

Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.
Conceptualizing “Vulnerability” in the European Legal Space: Mixed Migration Flows and Human Trafficking as a Test
Authors: De Stefani Paolo
Published: April 2022

The article discusses the role of “vulnerability” in the legal and political discourse of today's Europe as a dual-mode dispositive. On the one hand, “vulnerability” allows the legal formalism to incorporate the precarious subjects that the traditional language of “rights” risks to exclude. Compared with the human rights language, “vulnerability” better articulates the relationship between legal categories and rapidly changing social and ecological landscapes. The “vulnerability language” captures intersectionality. On the other hand, however, through examples taken from the EU normative production on irregular and mixed migrations, with a focus on refugee “screening” and reception and on managing identification and referral procedures of persons victims of human trafficking, this article shows that the assignment of an individual to a “vulnerable group” has the effect not only of expanding and intensifying their protection under normative human rights regimes, but also of accentuating some risks already inherent in human rights discourse, namely paternalism and essentialism. Paradoxically, a possible outcome can be fragmentation of rights protection frameworks, and exclusion. Vulnerable migrants may have to face additional challenges stemming from their inability (coupled with objective difficulty) to decodify communications and instructions concerning their status. Divergent ways of conceiving vulnerability, depending on subjective assessments, public policy standards, the legal framework, and the political agenda on welfare, contribute to neutralizing the potentially emancipatory impact of the vulnerability language.
The Women of FOCIS: Promoting Equality and Inclusiveness in a Professional Federation of Clinical Immunology Societies
Authors: Reed Elaine F. , Chong Anita S. , Levings Megan K. , Mutrie Caley , Laufer Terri M. , Roncarolo Maria Grazia , Sykes Megan
Published: April 2022

The authors of this article, all women who have been deeply committed to the Federation of Clinical Immunology Societies (FOCIS), performed a retrospective analysis of gender equality practices of FOCIS to identify areas for improvement and make recommendations accordingly. Gender data were obtained and analyzed for the period from January 2010 to July 2021. Outcome measures included numbers of men and women across the following categories: membership enrollment, meeting and course faculty and attendees, committee and leadership composition. FOCIS’ past and present leaders, steering committee members, FCE directors, individual members, as well as education, annual meeting scientific program and FCE committee members and management staff of FOCIS were surveyed by email questionnaire for feedback on FOCIS policies and practice with respect to gender equality and inclusion. Although women represent 50% of the membership, they have been underrepresented in all leadership, educational, and committee roles within the FOCIS organization. Surveying FOCIS leadership and membership revealed a growing recognition of disparities in female leadership across all FOCIS missions, leading to significant improvement in multiple areas since 2016. We highlight these changes and propose a number of recommendations that can be used by FOCIS to improve gender equality.
Inflammation in Cerebral Venous Thrombosis
Authors: Ding Jiayue , Song Baoying , Xie Xiran , Li Xaingyu , Chen Zhiying , Wang Zhongao , Pan Liqun , Lan Duo , Meng Ran
Published: April 2022

Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that impairs people’s wellbeing and quality of life. Inflammation is considered to play an important role in CVT initiation and progression. Several studies have reported the important role of leukocytes, proinflammatory cytokines, and adherence molecules in the CVT-related inflammatory process. Moreover, inflammatory factors exacerbate CVT-induced brain tissue injury leading to poor prognosis. Based on clinical observations, emerging evidence shows that peripheral blood inflammatory biomarkers—especially neutrophil-to-lymphocyte ratio (NLR) and lymphocyte count—are correlated with CVT [mean difference (MD) (95%CI), 0.74 (0.11, 1.38), p = 0.02 and −0.29 (−0.51, −0.06), p = 0.01, respectively]. Moreover, increased NLR and systemic immune-inflammation index (SII) portend poor patient outcomes. Evidence accumulated since the outbreak of coronavirus disease-19 (COVID-19) indicates that COVID-19 infection and COVID-19 vaccine can induce CVT through inflammatory reactions. Given the poor understanding of the association between inflammation and CVT, many conundrums remain unsolved. Further investigations are needed to elucidate the exact relationship between inflammation and CVT in the future.
Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas
Authors: Wei Cheng , Wang Bo , Peng Dazhao , Zhang Xiaoyang , Li Zesheng , Luo Lin , He Yingjie , Liang Hao , Du Xuezhi , Li Shenghui , Zhang Shu , Zhang Zhenyu , Han Lei , Zhang Jianning
Published: April 2022

Background

AlkB homolog 5 (ALKBH5) is a N6-methyladenosine (m6A) demethylase associated with the development, growth, and progression of multiple cancer types. However, the biological role of ALKBH5 has not been investigated in pan-cancer datasets. Therefore, in this study, comprehensive bioinformatics analysis of pan-cancer datasets was performed to determine the mechanisms through which ALKBH5 regulates tumorigenesis.

Methods

Online websites and databases such as NCBI, UCSC, CCLE, HPA, TIMER2, GEPIA2, cBioPortal, UALCAN, STRING, SangerBox, ImmuCellAl, xCell, and GenePattern were used to extract data of ALKBH5 in multiple cancers. The pan-cancer patient datasets were analyzed to determine the relationship between ALKBH5 expression, genetic alterations, methylation status, and tumor immunity. Targetscan, miRWalk, miRDB, miRabel, LncBase databases and Cytoscape tool were used to identify microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) that regulate expression of ALKBH5 and construct the lncRNA-miRNA-ALKBH5 network. In vitro CCK-8, wound healing, Transwell and M2 macrophage infiltration assays as well as in vivo xenograft animal experiments were performed to determine the biological functions of ALKBH5 in glioma cells.

Results

The pan-cancer analysis showed that ALKBH5 was upregulated in several solid tumors. ALKBH5 expression significantly correlated with the prognosis of cancer patients. Genetic alterations including duplications and deep mutations of the ALKBH5 gene were identified in several cancer types. Alterations in the ALKBH5 gene correlated with tumor prognosis. GO and KEGG enrichment analyses showed that ALKBH5-related genes were enriched in the inflammatory, metabolic, and immune signaling pathways in glioma. ALKBH5 expression correlated with the expression of immune checkpoint (ICP) genes, and influenced sensitivity to immunotherapy. We constructed a lncRNA-miRNA network that regulates ALKBH5 expression in tumor development and progression. In vitro and in vivo experiments showed that ALKBH5 promoted proliferation, migration, and invasion of glioma cells and recruited the M2 macrophage to glioma cells.

Conclusions

ALKBH5 was overexpressed in multiple cancer types and promoted the development and progression of cancers through several mechanisms including regulation of the tumor-infiltration of immune cells. Our study shows that ALKBH5 is a promising prognostic and immunotherapeutic biomarker in some malignant tumors.
YTHDF1 Negatively Regulates Treponema pallidum-Induced Inflammation in THP-1 Macrophages by Promoting SOCS3 Translation in an m6A-Dependent Manner
Authors: Li Zhijia , Teng Muzhou , Jiang Yinbo , Zhang Litian , Luo Xi , Liao Yuhui , Yang Bin
Published: April 2022

Background

Previous studies have confirmed that the bacterium Treponema pallidum (TP) or its proteins provide signals to macrophages that induce an inflammatory response; however, little is known about the negative regulation of this macrophage-mediated inflammatory response during syphilis infection or the underlying mechanism. Recent evidence suggests the role of the RNA modification, N6-adenosine methylation (m6A), in regulating the inflammatory response and pathogen-host cell interactions. Therefore, we hypothesized that m6A plays a role in the regulation of the inflammatory response in macrophages exposed to TP.

Methods

We first assessed m6A levels in TP-infected macrophages differentiated from the human monocyte cell line THP-1. The binding and interaction between the m6A “writer” methyltransferase-like 3 (METTL3) or the m6A “reader” YT521-B homology (YTH) domain-containing protein YTHDF1 and the suppressor of cytokine signaling 3 (SOCS3), as a major regulator of the inflammatory response, were explored in differentiated TP-infected THP-1 cells as well as in secondary syphilitic lesions from patients. The mechanisms by which YTHDF1 and SOCS3 regulate the inflammatory response in macrophages were assessed.

Results and Conclusion

After macrophages were stimulated by TP, YTHDF1 was upregulated in the cells. YTHDF1 was also upregulated in the syphilitic lesions compared to adjacent tissue in patients. YTHDF1 recognizes and binds to the m6A methylation site of SOCS3 mRNA, consequently promoting its translation, thereby inhibiting the JAK2/STAT3 pathway, and reducing the secretion of inflammatory factors, which results in anti-inflammatory regulation. This study provides the first demonstration of the role of m6A methylation in the pathological process of syphilis and further offers new insight into the pathogenesis of TP infection.
Comparative Effectiveness of Rituximab and Common Induction Therapies for Lupus Nephritis: A Systematic Review and Network Meta-Analysis
Authors: Li Kang , Yu Yanqiu , Gao Yuan , Zhao Fei , Liang Zheng , Gao Junjie
Published: April 2022

Objective

This study aimed to compare the efficacy and safety (infection events) between rituximab (RTX), tacrolimus (TAC), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) as induction therapies in lupus nephritis (LN).

Methods

Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched from inception up to December 9, 2021. Bayesian network meta-analysis was used to combine the direct and indirect evidence of different drugs for LN patients. The pooled relative effects were shown using odds ratios (ORs) and 95% credible intervals (CrIs).

Results

Nineteen studies (1,566 patients) met the inclusion criteria and were selected in the present study. The network meta-analysis reported that no statistically significant differences were found in partial remission (PR) and infection among the four drugs. RTX showed a significantly higher complete remission (CR) than MMF (OR = 2.60, 95% CrI = 1.00–7.10) and seemed to be more effective than CYC (OR = 4.20, 95% CrI = 1.70–14.00). MMF had a better CR than CYC (OR = 1.60, 95% CrI = 1.00–3.20). TAC presented a better overall response than CYC (OR = 3.70, 95% CrI = 1.20–12.00). Regarding CR and overall response, the maximum surface under the cumulative ranking curve (SUCRA) values were 96.94% for RTX and 80.15% for TAC. The maximum SUCRA value of infection reaction was 74.98% for RTX and the minimum value was 30.17% for TAC, respectively.

Conclusions

RTX and TAC were the most effective drugs for induction remission in LN. Among the four drugs, TAC had the lowest probability of infection, and RTX showed the highest probability of experiencing an infection. This meta-analysis could not conclude about other adverse events.
Structural Models for Roseolovirus U20 And U21: Non-Classical MHC-I Like Proteins From HHV-6A, HHV-6B, and HHV-7
Authors: Weaver Grant C. , Arya Richa , Schneider Christine L. , Hudson Amy W. , Stern Lawrence J.
Published: April 2022

Human roseolovirus U20 and U21 are type I membrane glycoproteins that have been implicated in immune evasion by interfering with recognition of classical and non-classical MHC proteins. U20 and U21 are predicted to be type I glycoproteins with extracytosolic immunoglobulin-like domains, but detailed structural information is lacking. AlphaFold and RoseTTAfold are next generation machine-learning-based prediction engines that recently have revolutionized the field of computational three-dimensional protein structure prediction. Here, we review the structural biology of viral immunoevasins and the current status of computational structure prediction algorithms. We use these computational tools to generate structural models for U20 and U21 proteins, which are predicted to adopt MHC-Ia-like folds with closed MHC platforms and immunoglobulin-like domains. We evaluate these structural models and place them within current understanding of the structural basis for viral immune evasion of T cell and natural killer cell recognition.
Decreased CD73+ Double-Negative T Cells and Elevated Level of Soluble CD73 Correlated With and Predicted Poor Immune Reconstitution in HIV-Infected Patients After Antiretroviral Therapy
Authors: Wang Xinyue , Zhang Leidan , Du Juan , Wei Yuqing , Wang Di , Song Chuan , Chen Danying , Li Bei , Jiang Meiqing , Zhang Mengyuan , Zhao Hongxin , Kong Yaxian
Published: April 2022

Although extensive use of antiretroviral therapy (ART) has made great progress in controlling HIV replication and improving CD4+ T cell recovery, the immune reconstitution remained insufficient in some patients, who were defined as poor immunological responders (PIRs). These PIRs were at a high risk of AIDS-related and non-AIDS complications, resulting in higher morbidity and mortality rate. Thus, it is a major challenge and urgently needed to distinguish PIRs early and improve their immune function in time. Immune activation is a key factor that leads to impaired immune reconstitution in people living with HIV (PLWH) who are receiving effective ART. Double negative T cells (DNT) were reported to associate with the control of immune activation during HIV infection. However, the precise mechanisms by which DNT cells exerted their suppressive capacity during HIV infection remained puzzled. CD73, both a soluble and a membrane-bound form, display immunosuppressive effects through producing adenosine (ADO). Thus, whether DNT cells expressed CD73 and mediated immune suppression through CD73-ADO pathway needs to be investigated. Here, we found a significant downregulation of CD73 expression on DNT cells in treatment-naïve PLWH (TNs) compared to healthy controls, accompanied with increased concentration of sCD73 in plasma. Both the frequency of CD73+ DNT cells and the level of plasma sCD73 recovered after ART treatment. However, PIRs showed decreased percentage of CD73+ DNT cells compared to immunological responders (IRs). The frequency of CD73+ DNT cells was positively correlated with CD4+ T cell count and CD4/CD8 ratio, and negatively correlated with immune activation in PLWH. The level of sCD73 also showed a negative correlation to CD4+ T cell count and CD4/CD8 ratio. More importantly, in the present cohort, a higher level of sCD73 at the time of initiating ART could predict poor immune reconstitution in PLWH after long-term ART. Our findings highlighted the importance of CD73+ DNT cells and sCD73 in the disease progression and immune reconstitution of PLWH, and provided evidences for sCD73 as a potential biomarker of predicting immune recovery.
The Response of North Sea Ecosystem Functional Groups to Warming and Changes in Fishing
Authors: Thorpe Robert B. , Arroyo Nina L. , Safi Georges , Niquil Nathalie , Preciado Izaskun , Heath Michael , Pace Matthew C. , Lynam Christopher P.
Published: April 2022

Achieving Good Environmental Status (GES) requires managing ecosystems subject to a variety of pressures such as climate change, eutrophication, and fishing. However, ecosystem models are generally much better at representing top-down impacts from fishing than bottom-up impacts due to warming or changes in nutrient loading. Bottom-up processes often have to be parameterised with little data or worse still taken as a system input rather than being represented explicitly. In this study we use an end-to-end ecosystem model (StrathE2E2) for the North Sea with 18 broad functional groups, five resource pools, and representations of feeding, metabolism, reproduction, active migrations, advection, and mixing. Environmental driving data include temperature, irradiance, hydrodynamics, and nutrient inputs from rivers, atmosphere, and ocean boundaries, so the model is designed to evaluate rigorously top-down and bottom-up impacts and is ideal for looking at possible changes in energy flows and “big picture” ecosystem function. In this study we considered the impacts of warming (2 and 4°C) and various levels of fishing, by demersal and pelagic fleets, on the structure and function of the foodweb. A key aim is to demonstrate whether monitoring of broad ecosystem groups could assist in deciding whether GES was being achieved. We found that warming raised primary productivity and increased the size (total biomass) of the ecosystem. Warming raised metabolic demands on omnivorous zooplankton and reduced their abundance, thus favouring benthivorous and piscivorous demersal fish at the expense of planktivorous pelagic fish but otherwise had modest effects on energy pathways and top predators, whereas changes in fishing patterns could materially alter foodweb function and the relative outcomes for top predators. We suggest that GES should be defined in terms of an unfished state and that abundances of broad groupings and the balance between them can help to assess whether indicator outcomes were consistent with GES. Our findings underwrite the need for an ecosystem approach for the management of human activities supported by relevant monitoring. We also highlight the need to improve our basic understanding of bottom-up processes, improve their representation within models, and ensure that our ecosystem models can capture growth limitation by nitrogen and other elements, and not just food/energy uptake.
Case Report: Oncocytic Schneiderian Papilloma Originating From the Sphenoid Sinus
Authors: Karpischenko Sergey A. , Vereschagina Olga E. , Stancheva Olga A. , Bibik Pavel R. , Kaplun Dmitry I. , Bogachev Mikhail I. , Kayumov Airat R.
Published: April 2022

A rare case of oncocytic Schneiderian papilloma originating from the sphenoid sinus characterised, for 3 years, by non-specific symptoms of severe headache, a block of nasal breathing, and deprecating sense of smell was presented by an elderly female patient. Sphenoid sinus functional endoscopic sinus surgery (FESS), with a one-block tumour excision, through an endonasal approach, with a histological study of removed tumour masses, were performed on the patient. Long observation in the post-operative period was necessary, considering the risk of recurrence and malignancy of oncocytic Schneiderian papilloma (OSP). Although the oncocytic papilloma of the sphenoid sinus is rare, non-specific symptoms make this pathology easily misdiagnosed. Thus, any isolated unilateral process in the paranasal sinuses with long-existing symptoms must be given careful attention due to the chance of this process being an inverted papilloma with malignization. CT scan indicating a unilateral opacification of paranasal sinuses with local calcifications is a typical manifestation, and endoscopic sphenoidotomy can be recommended as a treatment of choice.
Cardiovascular Protective Effects of Oral Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat in the Treatment of Type 4 Cardiorenal-Anemia Syndrome: Protocol of a Randomized Controlled Trial
Authors: Wen Yumin , Xu Yang , Tian Hui , Jiang Sizhu , Jiang Guofang , Li Puqing
Published: April 2022

Background

Patients with chronic kidney disease (CKD) are at high risk of developing heart failure and anemia, which is defined as type 4 cardiorenal-anemia syndrome (CRAS). CRAS aggravates the deterioration of both kidney and heart function, ultimately resulting in a high mortality. This study aims to examine the efficacy and safety of roxadustat in the treatment of type 4 CRAS.

Methods and Design

This study is designed as a randomized, open-label, controlled trial. A total of 68 patients diagnosed with type 4 CRAS will be randomly divided into roxadustat group and erythropoietin with a 1:1 ratio. Participants in the roxadustat group will receive roxadustat with an initial dose of 70 or 100 mg three times a week, and participants in the erythropoietin group will receive subcutaneous injection of erythropoietin for 24 weeks, to maintain a hemoglobin ranging from 100 to 120 g per liter. The primary outcome is the change in heart function, including brain natriuretic peptide (BNP), 6-min walk test (6-WT), and left ventricular ejection fraction (LVEF). Secondary outcomes to be assessed include death, cardiovascular events, hospitalization regarding heart failure, Minnesota Heart Failure Quality of life scale (MLHFQ) score, New York Heart Association (NYHA) cardiac function grade, echocardiographic parameters including left ventricular diastolic diameter and volume (LVDD and LVDV) and ventricular mass (LVM), anemia related parameters, inflammatory parameters, and safety assessments.

Conclusion

The findings of this study will provide potential evidence for roxadustat in CRAS management.

Trial Registration

Chinese Clinical Trial Registry, ID: ChiCTR2100050031. Registered on 16 August 2021.
Embedding the Community and Individuals in Disease Prevention
Authors: Bellanger Martine M. , Zhou Ke , Lelièvre Sophie A.
Published: April 2022

The primary prevention of non-communicable diseases is one of the most challenging and exciting aspects of medicine and primary care this century. For cancer, it is an urgent matter in light of the increasing burden of the disease among younger people and the higher frequency of more aggressive forms of the disease for all ages. Most chronic disorders result from the influence of the environment on the expression of genes within an individual. The environment at-large encompasses lifestyle (including nutrition), and chemical/physical and social exposures. In cancer, the interaction between the (epi)genetic makeup of an individual and a multiplicity of environmental risk and protecting factors is considered key to disease onset. Thus, like for precision therapy developed for patients, personalized or precision prevention is envisioned for individuals at risk. Prevention means identifying people at higher risk and intervening to reduce the risk. It requires biological markers of risk and non-aggressive preventive actions for the individual, but it also involves acting on the environment and the community. Social scientists are considering micro (individual/family), meso (community), and macro (country population) levels of care to illustrate that problems and solutions exist on different scales. Ideally, the design of interventions in prevention should integrate all these levels. In this perspective article, using the example of breast cancer, we are discussing challenges and possible solutions for a multidisciplinary community of scientists, primary health care practitioners and citizens to develop a holistic approach of primary prevention, keeping in mind equitable access to care.
Virtual OSCE Delivery and Quality Assurance During a Pandemic: Implications for the Future
Authors: Saad Shannon L. , Richmond Cassandra , Jones Karina , Schlipalius Michelle , Rienits Helen , Malau-Aduli Bunmi S.
Published: April 2022

Background

During 2020, the COVID-19 pandemic caused worldwide disruption to the delivery of clinical assessments, requiring medicals schools to rapidly adjust their design of established tools. Derived from the traditional face-to-face Objective Structured Clinical Examination (OSCE), the virtual OSCE (vOSCE) was delivered online, using a range of school-dependent designs. The quality of these new formats was evaluated remotely through virtual quality assurance (vQA). This study synthesizes the vOSCE and vQA experiences of stakeholders from participating Australian medical schools based on a Quality framework.

Methods

This study utilized a descriptive phenomenological qualitative design. Focus group discussions (FGD) were held with 23 stakeholders, including examiners, academics, simulated patients, professional staff, students and quality assurance examiners. The data was analyzed using a theory-driven conceptual Quality framework.

Results

The vOSCE was perceived as a relatively fit-for purpose assessment during pandemic physical distancing mandates. Additionally, the vOSCE was identified as being value-for-money and was noted to provide procedural benefits which lead to an enhanced experience for those involved. However, despite being largely delivered fault-free, the current designs are considered limited in the scope of skills they can assess, and thus do not meet the established quality of the traditional OSCE.

Conclusions

Whilst virtual clinical assessments are limited in their scope of assessing clinical competency when compared with the traditional OSCE, their integration into programs of assessment does, in fact, have significant potential. Scholarly review of stakeholder experiences has elucidated quality aspects that can inform iterative improvements to the design and implementation of future vOSCEs.