bluuebunny/crossref_metadata_2025 huggingface dataset:
QT Interval Prolongation Is a Novel Predictor of 1-Year Mortality in Patients With COVID-19 Infection
Authors: Banai Ariel , Szekely Yishay , Lupu Lior , Borohovitz Ariel , Levi Erez , Ghantous Eihab , Taieb Philippe , Hochstadt Aviram , Banai Shmuel , Topilsky Yan , Chorin Ehud
Published: June 2022

Background

QT interval prolongation is common in critically ill patients and is associated with increased mortality. However, the predictive value of a prolonged corrected QT interval (QTc) for myocardial injury and long-term mortality among patients hospitalized with COVID-19 infection is not well known.

Purpose

To evaluate the association of prolonged QTc with myocardial injury and with 1-year mortality among patients hospitalized with COVID-19 infection.

Materials and Methods

A total of 335 consecutive patients hospitalized with COVID-19 infection were prospectively studied. All patients underwent a comprehensive echocardiographic evaluation within 48 h from admission. Using the Bazett formula, the QTc interval was calculated from the first ECG tracing recorded at the ER. QTc ≥ 440 ms in males and ≥450 ms in females was considered prolonged. Patients with elevated cardiac biomarkers and/or echocardiographic signs of myocardial dysfunction were considered to have myocardial injury. The predictive value of QTc prolongation for myocardial injury was calculated using a multivariate binary regression model. One-year mortality rate of patients with and without QTc prolongation was compared using the log-rank test, and a multivariate Cox regression model adjusting for multiple covariates was performed to evaluate the 1-year mortality risk.

Results

One-hundred and nine (32.5%) patients had a prolonged QTc. Compared to patients without QTc prolongation, patients with prolonged QTc were older (70 ± 14.4 vs. 62.7 ± 16.6, p < 0.001), had more comorbidities, and presented with a more severe disease. Prolonged QTc was an independent predictor for severe or critical disease (adjusted HR 2.14, 95% CI 1.3–3.5; p = 0.002) and myocardial injury (adjusted HR 2.07, 95% CI 1.22–3.5; p = 0.007). One-year mortality of patients with prolonged QTc was higher than those with no QTc prolongation (40.4% vs. 15.5; p < 0.001). Following adjustment to multiple covariates including myocardial injury and disease severity, QTc prolongation was found to be associated with increased 1-year mortality risk (HR 1.69, 95% CI 1.06–2.68, p = 0.027).

Conclusion

Prolonged QTc is associated with disease severity, myocardial injury and 1-year mortality among patients hospitalized with COVID-19 infection.
Modified Shock Index as Simple Clinical Independent Predictor of In-Hospital Mortality in Acute Coronary Syndrome Patients: A Retrospective Cohort Study
Authors: Pramudyo Miftah , Marindani Vani , Achmad Chaerul , Putra Iwan Cahyo Santosa
Published: June 2022

Introduction

Despite being the current most accurate risk scoring system for predicting in-hospital mortality for patients with acute coronary syndrome (ACS), the Global Registry of Acute Coronary Events (GRACE) risk score is time consuming due to the requirement for electrocardiography and laboratory examinations. This study is aimed to evaluate the association between modified shock index (MSI), as a simple and convenient index, with in-hospital mortality and revascularization in hospitalized patients with ACS.

Methods

A single-centered, retrospective cohort study, involving 1,393 patients with ACS aged ≥ 18 years old, was conducted between January 2018 and January 2022. Study subjects were allocated into two cohorts: high MSI ≥ 1 (n = 423) and low MSI < 1 group (n = 970). The outcome was in-hospital mortality and revascularization. The association between MSI score and interest outcomes was evaluated using binary logistic regression analysis. The area under the curve (AUC) between MSI and GRACE score was compared using De Long’s method.

Results

Modified shock index ≥ 1 had 61.1% sensitivity and 73.7% specificity. A high MSI score was significantly and independently associated with in-hospital mortality in patients with ACS [odds ratio (OR) = 2.72(1.6–4.58), p < 0.001]. However, ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) patients with high MSI did not significantly increase the probability of revascularization procedures. Receiver operating characteristic (ROC) analysis demonstrated that although MSI and GRACE scores were both good predictors of in-hospital mortality with the AUC values of 0.715 (0.666–0.764) and 0.815 (0.775–0.855), respectively, MSI was still inferior as compared to GRACE scores in predicting mortality risk in patients with ACS (p < 0.001).

Conclusion

Modified shock index, particularly with a score ≥ 1, was a useful and simple parameter for predicting in-hospital mortality in patients presenting with ACS.
Healthy Lifestyles of University Students, According to Demographics, Nationality, and Study Specialty With Special Reference to Sport Studies
Authors: Cicchella Antonio , Vecenane Helena , Usca Svetlana
Published: June 2022

This study compares lifestyles behavior in Italian and Latvian university students, with special reference to sport students, to assess if there are differences for sex, age, university, or studies specialties. An online questionnaire investigating healthy lifestyle habits and 8 wellness dimensions has been compiled by 156 students (43.6% females) from Italy and 105 from Latvia (82.9% females). Answers were collected between April and December 2020. Presence of smokers in our sample is negligible. The questionnaire showed a good internal consistency (Cronbach α = 0.929). On the total group, statistically significant differences were found in all the dimensions regarding age, sex, study specialty and university. Physical activity was associated with healthier lifestyles choices. Geographical differences were found (eating and sleep behaviors, alcohol awareness) as well as socio-economic differences. Female students shown to be more stressed than males. Occupational wellness increased by age. Sport students shown more health awareness. Many of the differences found between males and females in the total group disappeared when comparing only sport students of the two universities.
Understanding Identity Development as a Science Teacher Educator Through Shifts in Pedagogical Equilibrium
Authors: Mansfield Jennifer , Park Rogers Meredith , Berry Amanda
Published: June 2022

This article reports research investigating the identity development of a science teacher educator (STE) (Author 1) through the lens of pedagogical equilibrium. Despite previous experience as a secondary science teacher and STE, Jennifer found herself questioning her feelings of legitimacy and relevance when teaching pre-service primary science teachers. Identifying moments of disturbance in her pedagogical equilibrium, and working with a critical friend to analyze her ideas and experiences, she began to develop her professional self-understanding, contributing to improved feelings of credibility, and professional identity development. Emerging from this study, Jennifer experienced two important shifts in her perspective and understanding of her role. The first shift concerned recognizing the different sources that comprised her “authority of experience” as a STE, while the second shift involved learning to see pre-service teachers in her classes as future teachers, rather than students. These shifts in perspective were facilitated through applying self-study as the research methodology. The study provides insights into the identity formation processes of an early career teacher educator, as well as the value of pedagogical equilibrium and self-study for exploring teacher educator identity.
University Instructors’ Enactment of Professional Agency in Teaching Spoken English as a Foreign Language
Authors: Wang Lan , Lam Ricky
Published: June 2022

Although previous studies on teacher agency have examined its manifestations and significance from the socio-cultural perspective, university English as a foreign language (EFL)-speaking instructors’ professional agency has been underrepresented in the Chinese context. Based on a narrative inquiry approach and cross-case analysis, this qualitative multiple case study explores how four university EFL-speaking instructors exercise their professional agency and the key factors facilitating their agency enactment. The study finds that EFL-speaking instructors work as agentic practitioners to translate their career pursuits into concrete teaching duties, teacher learning, and researching. Their different professional agency enactment is closely related to their agency competence, agency disposition, and identity commitment as well as multifarious contextual factors. The findings imply that understanding the trajectories of teachers’ career development and fostering their teacher agency can assist more practitioners in getting ready for future challenges. It is suggested that frontline teachers hold onto the notion of life-long learning, build academic research profiles, and conduct active reflections to enhance their agency. University administrators should consider creating a more conducive environment to boost EFL-speaking instructors’ agency to facilitate their professional development.
Sex Differences in Hypercortisolism and Glucose-Metabolism Disturbances in Patients with Mild Autonomous Cortisol Secretion: Findings From a Single Center in China
Authors: Ouyang Ru , Yin Yaqi , Wang Jie , Su Wanlu , Zang Li , Chen Kang , Du Jin , Lyu Zhaohui , Dou Jingtao , Mu Yiming , Gu Weijun
Published: June 2022

Background and objective

Mild autonomous cortisol secretion (MACS) presents with a marked female preponderance, but whether the sex difference in its distribution has any relevance to the presentation and outcome of the disease is unknown. The aim of this study was therefore to compare biochemical indices of hypercortisolism and impaired glucose metabolism between male and female patients with MACS.

Method

We enrolled a total of 98 patients with autonomous/possible autonomous cortisol secretion in our study, and indices of hypercortisolism and glucose metabolism were collected and compared between the male and female patients. Logistic regression models were used to evaluate the association between sex and cortisol-secretory ability, as well as between the latter and glucose metabolism. In addition, we conducted further stratified analyses according to the degree of autonomous cortisol secretion and menopausal status.

Results

Cortisol levels at 00:00 and 08:00 h after a 1-mg dexamethasone suppression test (DST) and low-dose DST were significantly higher in female than in male MACS patients, and the inhibition rate of 1-mg DST was lower in the women than in the men. This significant difference still remained after adjusting for age, BMI, and the course of the disease. Logistic regression analysis revealed a significant association between autonomous cortisol secretion and fasting C-peptide, as well as with the C-peptide-to-glucose ratio in females relative to male patients. In addition, stratified analyses indicated that this association was observed only among women with autonomous cortisol secretion and who were premenopausal.

Conclusion

The level of autonomic cortisol secretion in female patients with MACS was higher than in male patients, and the association between autonomous cortisol secretory ability and glucose homeostasis was only noted in patients with autonomous cortisol secretion and in premenopausal women. This phenomenon will, however, require closer follow-up.
Current Perspectives on Kisspeptins Role in Behaviour
Authors: Mills Edouard G. , Yang Lisa , Abbara Ali , Dhillo Waljit S. , Comninos Alexander N.
Published: June 2022

The neuropeptide kisspeptin is now well-established as the master regulator of the mammalian reproductive axis. Beyond the hypothalamus, kisspeptin and its cognate receptor are also extensively distributed in extra-hypothalamic brain regions. An expanding pool of animal and human data demonstrates that kisspeptin sits within an extensive neuroanatomical and functional framework through which it can integrate a range of internal and external cues with appropriate neuroendocrine and behavioural responses. In keeping with this, recent studies reveal wide-reaching effects of kisspeptin on key behaviours such as olfactory-mediated partner preference, sexual motivation, copulatory behaviour, bonding, mood, and emotions. In this review, we provide a comprehensive update on the current animal and human literature highlighting the far-reaching behaviour and mood-altering roles of kisspeptin. A comprehensive understanding of this important area in kisspeptin biology is key to the escalating development of kisspeptin-based therapies for common reproductive and related psychological and psychosexual disorders.
Supply Chain Finance and the Sustainable Growth of Chinese Firms: The Moderating Effect of Digital Finance
Authors: Liu Tinghua , Liu Weiya , Elahi Ehsan , Liu Xiao
Published: June 2022

Sustainable development is crucial to the survival and healthy development of enterprises, which is closely related to their financing situation. Supply chain finance is an effective way to improve and enhance the financing situation by easing financing constraints and reducing financing costs. As an important source of supply chain short-term financing, trade credit plays an important role in enterprise production and circulation. Taking Chinese listed companies from 2011 to 2020 as samples, this paper studied the impact of trade credit on sustainable growth and its internal mechanism. Furthermore, we analyzed the moderating effect of digital finance development on the influence of trade credit on sustainable growth. It is found that receiving trade credit benefited firms’ sustainable growth. Furthermore, study found that receiving trade credit has a greater positive impact on the sustainable growth of enterprises in regions with higher levels of financial development, high-tech industries, state-owned enterprises and small enterprises. Whereas, the provision of trade credit had an obvious inhibiting effect on the sustainable growth of enterprises in the regions with low level of financial development, non-high-tech industries, private enterprises and small enterprises. The results of the influencing mechanism showed that receiving trade credit promoted firm’s sustainable growth by “agency cost reducing effect,” while providing trade credit inhibited firm’s sustainable growth by “forcing effect.” In addition, the development of digital finance weakens the positive impact of trade credit financing on enterprises’ sustainable growth but strengthens the negative impact of providing trade credit on sustainable growth. From the perspective of sustainable growth, this paper explained the role of trade credit financing in alleviating the financing dilemma of enterprises, which is urgently needed by most emerging economies pursuing high-quality development. Therefore, in order to give full play to the role of trade credit financing, the government should actively create a good credit environment. At the same time, the government should vigorously develop digital finance to enhance its ability to serve the real economy.
Agents on a Landscape: Simulating Spatial and Temporal Interactions in Economic and Ecological Systems
Authors: Johnson Justin Andrew , Salemi Colette
Published: June 2022

Modeling how communities benefit from common-property, depletable ecosystem services, such as non-timber forest product (NTFP) extraction, is challenging because it depends on agent proximity to resources and competition among agents. This challenge is greater when agents face complex economic decisions that depend on the state of the landscape and the actions of other agents. We address this complexity by developing an agent-based model, founded on standard economic theory, that defines household production and utility functions for millions of spatially-explicit economic agents. Inter-agent competition is directly modeled by defining how NTFP extraction of one agent changes the extraction efficiency and travel-time of nearby agents, thereby modifying agents’ profit functions and utility maximization. We demonstrate our simulation using Tanzania as a case study. Our application relies on estimates of NTFP stocks, local wages, and traversal times across a landscape network of grid-cells, which we derive using geospatial and household data. The results of our simulation provide spatially explicit and aggregate estimates of NTFP extraction and household profit. Our model provides a methodological advance for studies that require understanding the impacts of conservation policies on households that rely on natural capital from forests. More broadly, our model shows that agent-based approaches to spatial activity can incorporate valuable insights on decision-making from economics without simplifying the underlying theory, making strong assumptions on agent homogeneity, or ignoring spatial heterogeneity.
Ecological Factors Determining Barking Deer Distribution and Habitat Use in the Mid-Hills of Nepal
Authors: Neupane Bijaya , Dhami Bijaya , Bista Shreyashi , Sadadev Bipana Maiya , Regmi Siddhartha , Shrestha Sami , Shrestha Bikram , Traxmandlová Iva , Varachova Sona , Kindlmann Pavel
Published: June 2022

Barking deer is found in dense tropical and subtropical forests of Asia. It is listed as “least concerned” by the International Union of Conservation of Nature and as “vulnerable” in Nepal, where it is also protected. Due to the habitat loss and fragmentation by human activities, barking deer abundance is decreasing, which may even ultimately lead to its extinction. This in turn might negatively affect local ecosystem such as the abundance of the endangered common leopard, for which barking deer is the main prey species in the mid-hills of Nepal. We therefore need to know factors affecting barking deer abundance and its habitat preferences. To determine these factors, we recorded barking deer either by direct sighting or by any evidence of its indirect presence observed through transect surveys in January and February, 2019. To analyze habitat preference, the presence of barking deer was set to 1 if the barking deer or any sign of its presence were observed “used plots,” or to 0 if the barking deer or any sign of its presence were not observed (“habitat availability plot”). We measured main four ecological drivers such as forest management regime, microclimate, disturbance and food resources, which include 11 habitat characteristics in spots where barking deer was present, and in randomly selected spots. We found that elevation, slope, distance from settlement, presence of tree species, depth of leaf litter and percentage cover of leaf litter were most significantly affecting its presence. These results can serve as guidelines for local authorities to prevent decline in abundance of barking deer.
Semelparous Death as one Element of Iteroparous Aging Gone Large
Authors: Kern Carina C. , Gems David
Published: June 2022

The aging process in semelparous and iteroparous species is different, but how different? Death in semelparous organisms (e.g., Pacific salmon) results from suicidal reproductive effort (reproductive death). Aging (senescence) in iteroparous organisms such as humans is often viewed as a quite different process. Recent findings suggest that the nematode Caenorhabditis elegans, widely used to study aging, undergoes reproductive death. In post-reproductive C. elegans hermaphrodites, intestinal biomass is repurposed to produce yolk which when vented serves as a milk to support larval growth. This apparent benefit of lactation comes at the cost of intestinal atrophy in the mother. Germline removal and inhibition of insulin/IGF-1 signaling (IIS) suppress C. elegans reproductive pathology and greatly increase lifespan. Blocking sexual maturity, e.g., by gonadectomy, suppresses reproductive death thereby strongly increasing lifespan in semelparous organisms, but typically has little effect on lifespan in iteroparous ones. Similarly, reduced IIS causes relatively modest increases in lifespan in iteroparous organisms. We argue that the more regulated and plastic mechanisms of senescence in semelparous organisms, involving costly resource reallocation under endocrine control, exist as one extreme of an etiological continuum with mechanisms operative in iteroparous organisms. We suggest that reproductive death evolved by exaggeration of mechanisms operative in iteroparous species, where other mechanisms also promote senescence. Thus, knowledge of C. elegans senescence can guide understanding of mechanisms contributing to human aging.
The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy
Authors: Li Zhi-Fan , Wu Na-Qiong
Published: June 2022

Refractory hypercholesterolemia (RH), including homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia, is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) despite existing cholesterol-lowering methods at maximal tolerable doses. Patients with RH have early onset and higher risk of atherosclerotic cardiovascular disease (ASCVD) under insufficient treatment. Therefore, it is urgent to seek new therapies to maintain the blood lipids in refractory hyperlipidemia at normal levels. Currently, new cholesterol-lowering strategies are on the market, not only at the protein level [i.e., bempedoic acid (inhibiting ATP-citrate lyase), alirocumab and evolocumab (monoclonal antibodies against PCSK9), evinacumab (monoclonal antibody against ANGPTL3)] but also at the transcript level [i.e., mipomersen (antisense oligonucleotide inhibiting ApoB), inclisiran (siRNA targeting PCSK9)], providing more options for RH patients to achieve their lipid-lowering targets. More RNA-based therapies targeting RH-related genes have been designed for the treatment. However, for a proportion of patients, especially those with LDLR deficiency, the available treatments are still insufficient. More recently, emerging genome engineering based on CRISPR/Cas9 techniques, and advanced delivery technologies such as lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, lipid nanoparticles, and exosomes are being rapidly developed and implemented as novel therapies for RH. Gene therapy targeting RH-related genes has been successfully conducted in cells, mice, and non-human primates with high efficacy in lipid lowering and good tolerability. Especially the new generation of genome editing technique, base editing, performed in vivo with ideal lipid-lowering effect and limited occurrence of unwanted results. Excitingly, a phase I/II clinical study of LDLR gene replacement has been recently completed in RH patients, likely to be employed in clinical practice in the future. Furthermore, new targets for cholesterol reduction such as REV-ERB, G protein-coupled receptor, Ubiquitin specific peptidase 20 are continually being developed. This narrative review updates recent advances in treatment for RH, summarizes related clinical trials and preclinical studies, especially on the prospect of gene therapy.
Ena/VASP Protein-Mediated Actin Polymerization Contributes to Naïve CD8+ T Cell Activation and Expansion by Promoting T Cell–APC Interactions In Vivo
Authors: Waldman Monique M. , Rahkola Jeremy T. , Sigler Ashton L. , Chung Jeffrey W. , Willett Benjamin A. S. , Kedl Ross M. , Friedman Rachel S. , Jacobelli Jordan
Published: June 2022

Naïve T cell activation in secondary lymphoid organs such as lymph nodes (LNs) occurs upon recognition of cognate antigen presented by antigen presenting cells (APCs). T cell activation requires cytoskeleton rearrangement and sustained interactions with APCs. Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) proteins are a family of cytoskeletal effector proteins responsible for actin polymerization and are frequently found at the leading edge of motile cells. Ena/VASP proteins have been implicated in motility and adhesion in various cell types, but their role in primary T cell interstitial motility and activation has not been explored. Our goal was to determine the contribution of Ena/VASP proteins to T cell–APC interactions, T cell activation, and T cell expansion in vivo. Our results showed that naïve T cells from Ena/VASP-deficient mice have a significant reduction in antigen-specific T cell accumulation following Listeria monocytogenes infection. The kinetics of T cell expansion impairment were further confirmed in Ena/VASP-deficient T cells stimulated via dendritic cell immunization. To investigate the cause of this T cell expansion defect, we analyzed T cell–APC interactions in vivo by two-photon microscopy and observed fewer Ena/VASP-deficient naïve T cells interacting with APCs in LNs during priming. We also determined that Ena/VASP-deficient T cells formed conjugates with significantly less actin polymerization at the T cell–APC synapse, and that these conjugates were less stable than their WT counterparts. Finally, we found that Ena/VASP-deficient T cells have less LFA-1 polarized to the T cell–APC synapse. Thus, we conclude that Ena/VASP proteins contribute to T cell actin remodeling during T cell–APC interactions, which promotes the initiation of stable T cell conjugates during APC scanning. Therefore, Ena/VASP proteins are required for efficient activation and expansion of T cells in vivo.
Cardiovascular Disease in Primary Sjögren’s Syndrome: Raising Clinicians’ Awareness
Authors: Casian Mihnea , Jurcut Ciprian , Dima Alina , Mihai Ancuta , Stanciu Silviu , Jurcut Ruxandra
Published: June 2022

In the ever evolving landscape of systemic immune mediated diseases, an increased awareness regarding the associated cardiovascular system impairment has been noted in recent years. Even though primary Sjögren’s Syndrome (pSS) is one of the most frequent autoimmune diseases affecting middle-aged individuals, the cardiovascular profile of this specific population is far less studied, at least compared to other autoimmune diseases. Traditional cardiovascular risk factors and disease specific risk factors are inextricably intertwined in this particular case. Therefore, the cardiovascular risk profile in pSS is a multifaceted issue, sometimes difficult to assess. Furthermore, in the era of multimodality imaging, the diagnosis of subclinical myocardial and vascular damage is possible, with recent data pointing that the prevalence of such involvement is higher in pSS than in the general population. Nevertheless, when approaching patients with pSS in terms of cardiovascular diseases, clinicians are often faced with the difficult task of translating data from the literature into their everyday practice. The present review aims to synthesize the existing evidence on pSS associated cardiovascular changes in a clinically relevant manner.
Hepatic Tumor Stiffness Measured by Shear Wave Elastography Is Prognostic for HCC Progression Following Treatment With Anti-PD-1 Antibodies Plus Lenvatinib: A Retrospective Analysis of Two Independent Cohorts
Authors: Yuan Guosheng , Xie Fuli , Song Yangda , Li Qi , Li Rong , Hu Xiaoyun , Zang Mengya , Cheng Xiao , Lu Guanting , Huang Jing , Fan Wenzhe , Rong Xiaoxiang , Sun Jian , Chen Jinzhang
Published: June 2022

Background

The clinical significance of liver stiffness (LS) measured by shear wave elastography (SWE) in programmed cell death protein-1 (PD-1) inhibitors treated advanced hepatocellular carcinoma (HCC) patients remains unknown. This study aimed to explore the prognostic value of baseline LS by SWE prior to PD-1 inhibitor treatment in combination with lenvatinib.

Methods

We retrospectively evaluated patients (n=133) with HCC who received anti-PD-1 antibodies plus lenvatinib at two high-volume medical centres, between January 2020 and June 2021. Univariate and multivariate logistic regression analysis were used to develop a novel nomogram. RNA sequencing and immunohistochemical staining were used to assess the heterogeneity of biological and immune characteristics associated with tumor stiffness.

Results

The objective response rate (ORR) and disease control rate (DCR) of the whole population were 23.4% and 72.2%, respectively. A LS value of the baseline tumorous foci of 19.53 kPa had the maximum sum of sensitivity and specificity, making it the optimal cut-off value for predicting PD-1 inhibitor efficacy. The nomogram comprised baseline tumor LS and albumin-bilirubin grade (ALBI), which provided favorable calibration and discrimination in the training dataset with an AUC of 0.840 (95%CI: 0.750-0.931) and a C-index of 0.828. Further, it showed acceptable discrimination in the validation cohort, with an AUC of 0.827 (95%CI: 0.673-0.980) and C-index of 0.803. The differentially expressed genes enriched in high stiffness tumors were predominantly associated with metabolic pathways, while those enriched in low stiffness tumors were related to DNA damage repair. Furthermore, patients with high stiffness tumors had a relatively lower infiltration of immune cells and histone deacetylase pathway inhibitors were identified as candidate drugs to promote the efficacy of immunotherapy.

Conclusions

Baseline LS value of tumorous foci by SWE—that is, before administration of a PD-1 inhibitor in combination with lenvatinib—is a convenient predictor of PD-1 inhibitor efficacy in patients with advanced HCC, which has potential to be used for pretreatment stratification to optimize treatment of advanced HCC.
Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion
Authors: Teixeira Leandro D. , Harrison Natalie A. , da Silva Danilo R. , Mathews Clayton E. , Gonzalez Claudio F. , Lorca Graciela L.
Published: June 2022

L. johnsonii N6.2 releases nano-sized vesicles (NVs) with distinct protein and lipid contents. We hypothesized that these NVs play a central role in the delivery of bioactive molecules that may act as mechanistic effectors in immune modulation. In this report, we observed that addition of NVs to the human pancreatic cell line βlox5 reduced cytokine-induced apoptosis. Through RNAseq analyses, increased expression of CYP1A1, CYP1B1, AHRR, and TIPARP genes in the aryl hydrocarbon receptor (AHR) pathways were found to be significantly induced in presence of NVs. AHR nuclear translocation was confirmed by confocal microscopy. The role of NVs on beta cell function was further evaluated using primary human pancreatic islets. It was found that NVs significantly increased insulin secretion in presence of high glucose concentrations. These increases positively correlated with increased GLUT6 and SREBF1 mRNA and coincided with reduced oxidative stress markers. Furthermore, incubation of NVs with THP-1 macrophages promoted the M2 tolerogenic phenotype through STAT3 activation, expression of AHR-dependent genes and secretion of IL10. Altogether, our findings indicate that bacterial NVs have the potential to modulate glucose homeostasis in the host by directly affecting insulin secretion by islets and through the induction of a tolerogenic immune phenotype.
High Serum Vitamin D Concentrations, Induced via Diet, Trigger Immune and Intestinal Microbiota Alterations Leading to Type 1 Diabetes Protection in NOD Mice
Authors: Martens Pieter-Jan , Centelles-Lodeiro Javier , Ellis Darcy , Cook Dana Paulina , Sassi Gabriele , Verlinden Lieve , Verstuyf Annemieke , Raes Jeroen , Mathieu Chantal , Gysemans Conny
Published: June 2022

The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D3, can modulate both innate and adaptive immunity, through binding to the nuclear vitamin D receptor expressed in most immune cells. A high dose of regular vitamin D protected non-obese diabetic (NOD) mice against type 1 diabetes (T1D), when initiated at birth and given lifelong. However, considerable controversy exists on the level of circulating vitamin D (25-hydroxyvitamin D3, 25(OH)D3) needed to modulate the immune system in autoimmune-prone subjects and protect against T1D onset. Here, we evaluated the impact of two doses of dietary vitamin D supplementation (400 and 800 IU/day), given to female NOD mice from 3 until 25 weeks of age, on disease development, peripheral and gut immune system, gut epithelial barrier function, and gut bacterial taxonomy. Whereas serum 25(OH)D3 concentrations were 2.6- (400 IU/day) and 3.9-fold (800 IU/day) higher with dietary vitamin D supplementation compared to normal chow (NC), only the 800 IU/day vitamin D-supplemented diet delayed and reduced T1D incidence compared to NC. Flow cytometry analyses revealed an increased frequency of FoxP3+ Treg cells in the spleen of mice receiving the 800 IU/day vitamin D-supplemented diet. This vitamin D-induced increase in FoxP3+ Treg cells, also expressing the ecto-5’-nucleotidase CD73, only persisted in the spleen of mice at 25 weeks of age. At this time point, the frequency of IL-10-secreting CD4+ T cells was also increased in all studied immune organs. High-dose vitamin D supplementation was unable to correct gut leakiness nor did it significantly modify the increased gut microbial diversity and richness over time observed in NOD mice receiving NC. Intriguingly, the rise in alpha-diversity during maturation occurred especially in mice not progressing to hyperglycaemia. Principal coordinates analysis identified that both diet and disease status significantly influenced the inter-individual microbiota variation at the genus level. The abundance of the genera Ruminoclostridium_9 and Marvinbryantia gradually increased or decreased, respectively in faecal samples of mice on the 800 IU/day vitamin D-supplemented diet compared to mice on the 400 IU/day vitamin D-supplemented diet or NC, irrespective of disease outcome. In summary, dietary vitamin D reduced T1D incidence in female NOD mice at a dose of 800, but not of 400, IU/day, and was accompanied by an expansion of Treg cells in various lymphoid organs and an altered intestinal microbiota signature.
Fc-Mediated Functions of Porcine IgG Subclasses
Authors: Paudyal Basudev , Mwangi William , Rijal Pramila , Schwartz John C. , Noble Alistair , Shaw Andrew , Sealy Joshua E. , Bonnet-Di Placido Marie , Graham Simon P. , Townsend Alain , Hammond John A. , Tchilian Elma
Published: June 2022

The pig is an important agricultural species and powerful biomedical model. We have established the pig, a large natural host animal for influenza with many physiological similarities to humans, as a robust model for testing the therapeutic potential of monoclonal antibodies. Antibodies provide protection through neutralization and recruitment of innate effector functions through the Fc domain. However very little is known about the Fc-mediated functions of porcine IgG subclasses. We have generated 8 subclasses of two porcine monoclonal anti influenza hemagglutinin antibodies. We characterized their ability to activate complement, trigger cytotoxicity and phagocytosis by immune cells and assayed their binding to monocytes, macrophages, and natural killer cells. We show that IgG1, IgG2a, IgG2b, IgG2c and IgG4 bind well to targeted cell types and mediate complement mediated cellular cytotoxicity (CDCC), antibody dependent cellular cytotoxicity (ADCC) and antibody mediated cell phagocytosis (ADCP). IgG5b and IgG5c exhibited weak binding and variable and poor functional activity. Immune complexes of porcine IgG3 did not show any Fc-mediated functions except for binding to monocytes and macrophages and weak binding to NK cells. Interestingly, functionally similar porcine IgG subclasses clustered together in the genome. These novel findings will enhance the utility of the pig model for investigation of therapeutic antibodies.
Serpin–4 Facilitates Baculovirus Infection by Inhibiting Melanization in Asian Corn Borer, Ostrinia furnacalis (Guenée)
Authors: Ji Jiayue , Shen Dongxu , Zhang Shasha , Wang Lei , An Chunju
Published: June 2022

Phenoloxidase (PO)–catalyzed melanization is a vital immune response in insects for defense against pathogen infection. This process is mediated by clip domain serine proteases and regulated by members of the serpin superfamily. We here revealed that the infection of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) significantly inhibited the PO activity in Ostrinia furnacalis hemolymph and induced the expression of O. furnacalis serpin–4. Addition of recombinant serpin-4 protein to O. furnacalis hemolymph resulted in a great increase of AcMNPV copies. Serpin-4 significantly suppressed the PO activity and the amidase activity in cleaving colorimetric substrate IEARpNA (IEARase activity) of hemolymph. Further experiments indicated it formed covalent complexes with three serine proteases (SP1, SP13 and SP105) and prevented them from cleaving their cognate downstream proteases in vitro. Altogether, O. furnacalis melanization restricted AcMNPV replication and serpin-4 facilitated AcMNPV infection by inhibiting serine proteases, SP1, SP13, and SP105 which were all involved in the melanization response.
Identification of a Novel Densovirus in Aphid, and Uncovering the Possible Antiviral Process During Its Infection
Authors: Li Tong , Li Haichao , Wu Yuqing , Li Shaojian , Yuan Guohui , Xu Pengjun
Published: June 2022

Densoviruses (DVs) are single-stranded DNA viruses and exclusively happen in invertebrates. Most of DVs reported in insects are pathogenic to their native hosts, however, no pathogenic effect of them has been examined in vertebrates. Hence, DVs are the potential agents used in pest managements. Aphids are the primary vectors of plant viruses. In this study, we identified a novel DV in Chinese Sitobion miscanthi population, provisionally named “Sitobion miscanthi densovirus” (SmDV). Taxonomically, SmDV belongs to genus Hemiambidensovirus. In S. miscanthi, SmDV is hosted in diverse cells and can be horizontally transmitted via wheat feeding. Subject to SmDV, aphids activate their intrinsic antiviral autophagy pathway. Grouped with ascorbate and aldarate metabolism, chlorophyll metabolism, p450 related drug metabolism, and retinoid metabolism, aphids form a complex immune network response to the infection of SmDV. Obviously, it works as elder aphids still alive even they contain the highest examined concentration of SmDV. This study provides a foundation for the identifications of novel DVs, and further improves the understanding of the molecular interactions between insects and DVs.
The Roles of Adipose Tissue Macrophages in Human Disease
Authors: Liang Weizheng , Qi Yanxu , Yi Hongyang , Mao Chenyu , Meng Qingxue , Wang Hao , Zheng Chunfu
Published: June 2022

Macrophages are a population of immune cells functioning in antigen presentation and inflammatory response. Research has demonstrated that macrophages belong to a cell lineage with strong plasticity and heterogeneity and can be polarized into different phenotypes under different microenvironments or stimuli. Many macrophages can be recruited by various cytokines secreted by adipose tissue. The recruited macrophages further secrete various inflammatory factors to act on adipocytes, and the interaction between the two leads to chronic inflammation. Previous studies have indicated that adipose tissue macrophages (ATMs) are closely related to metabolic diseases like obesity and diabetes. Here, we will not only conclude the current progress of factors affecting the polarization of adipose tissue macrophages but also elucidate the relationship between ATMs and human diseases. Furthermore, we will highlight its potential in preventing and treating metabolic diseases as immunotherapy targets.
Maternal Lineage and Habitat Use Patterns Explain Variation in the Fecundity of a Critically Endangered Baleen Whale
Authors: Bishop Ana L. , Crowe Leah M. , Hamilton Philip K. , Meyer-Gutbrod Erin L.
Published: June 2022

The critically endangered North Atlantic right whale population (Eubalaena glacialis) has experienced multiple periods of decreased reproduction within its observable history, which have played a role in the overall decline of the species. In addition to this synchronized variation in reproduction across the population, there exists considerable individual variation in fecundity. To determine the impacts of family history and habitat use behavior on these individual variations in fecundity, photo identification data collected during four decades of visual monitoring were used to create a calving index for sexually mature females that could be used to evaluate matrilineal influence on fecundity. Reproductive life histories were analyzed to assess fecundity variation within matrilines over time. Individual variations in fecundity were also assessed with respect to a recent climate-driven habitat distribution shift by a loyal cohort of right whales that use the Gulf of St. Lawrence during the summer and autumn seasons. Lifetime fecundity in the oldest known living reproductive female, or matriarch, in a matriline was positively associated with the fecundity of her female progeny. Sexually mature females that have used the Gulf of St. Lawrence since 2015 were significantly more likely to give birth over this time period compared to individuals who did not use that habitat. Individuals of both sexes were significantly more likely to use the Gulf of St. Lawrence if their mothers did as well; however, this association declined as offspring aged. These results provide insight on the environmental, behavioral, and genetic factors that contribute to individual variation in fecundity. Low calving rates and increased dangers posed by habitat use shifts in the past decade have played a major role in the species’ decline, and these new insights into the mechanistic drivers of right whale reproduction and habitat use show that lineage guides progeny behavior and reproductive success. As anthropogenic climate change continues to disrupt right whale seasonal distributions through changing ocean circulation patterns, understanding the demographic consequences of novel habitat use patterns will be essential to updating protective policies.
CMOS-MEMS Vibro-Impact Devices and Applications
Authors: Tsai Chun-Pu , Li Wei-Chang
Published: June 2022

CMOS-MEMS-based vibro-impact devices that utilize impact-induced nonlinear dynamics have been shown to yield unique and unprecedented functionalities with on-chip integration capability. For example, a 0.35-µm CMOS-based capacitively transduced comb-driven folded-beam resonant switch has been integrated with backend circuits to demonstrate a zero-quiescent power wireless receiver operating at the low-frequency (LF) band. In addition, CMOS-MEMS vibro-impact resonators have been used as AFM-alike surface condition monitoring for detecting chemical coating on structural sidewalls and clock generators with controllable duty cycles by manipulating the actuation conditions. This article will review these achievements and discuss the limitations and challenges in developing the vibro-impact devices using the CMOS-MEMS technology.
Changes in HIV Testing Utilization Among Chinese Men Who Have Sex With Men During the COVID-19 Pandemic in Shenzhen, China: An Observational Prospective Cohort Study
Authors: Zhang Kechun , Chen Siyu , Chan Paul Shing-fong , Fang Yuan , Cao He , Chen Hongbiao , Hu Tian , Chen Yaqi , Zhou Xiaofeng , Wang Zixin
Published: June 2022

Background

The Coronavirus Diseases 2019 (COVID-19) directly affects HIV prevention and sexual health services utilization among men who have sex with men (MSM). This study investigated changes in human immunodeficiency virus (HIV) testing utilization among MSM before and after the COVID-19 pandemic received initial control in Shenzhen, China.

Methods

This study was a sub-analysis of a prospective observational cohort study conducted among MSM in Shenzhen, China between August 2020 and May 2021. Participants were recruited through outreaching in gay venues, online recruitment, and peer referral. Participants completed a baseline online survey between August and September 2020 and a follow-up online survey between April and May 2021. This study was based on 412 MSM who reported to be HIV-negative/unknown sero-status at baseline, 297 (72.1%) of them completed the follow-up online survey. Multilevel logistic regression models (level 1: sources of recruitment; level 2: individual participants) were fitted.

Results

When comparing follow-up data with baseline data, a significant increase was observed in the uptake of any type of HIV testing (77.9% at Month 6 vs. 59.2% at baseline, p < 0.001). After adjusting for age group, education level, current employment status and monthly personal income, two predisposing factors were associated with higher uptake of HIV testing during the follow-up period. They were: (1) condomless anal intercourse with male non-regular male sex partners at follow-up only (AOR: 5.29, 95%CI: 1.27, 22.01) and (2) sanitizing before and after sex at baseline (AOR: 1.26, 95%CI: 1.02, 1.47). Regarding enabling factors, utilization of HIV testing (AOR: 3.90, 95%CI: 2.27, 6.69) and STI testing (AOR: 2.43, 95%CI: 1.20, 4.93) 6 months prior to the baseline survey was associated with higher uptake of HIV testing during the follow-up period. Having the experience that HIV testing service providers reduced service hours during the follow-up period was also positively associated with the dependent variable (AOR: 3.45, 95%CI: 1.26, 9.41).

Conclusions

HIV testing utilization among MSM might rebound to the level before the COVID-19 outbreak after the pandemic received initial control in China. This study offered a comprehensive overview to identify potential reasons that can influence the uptake of HIV testing among Chinese MSM.
Expression and Clinical Significance of the m6A RNA-Binding Proteins YTHDF2 in Peripheral Blood Mononuclear Cells From New-Onset Ankylosing Spondylitis
Authors: Luo Qing , Guo Yongqin , Xiao Qiuyun , Fu Biqi , Zhang Lu , Guo Yang , Huang Zikun , Li Junming
Published: June 2022

This study has focused on determining the association of m6A methyltransferase [methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), and Wilms tumor 1-associating protein (WTAP)], demethylase [fat mass and obesity-associated protein (FTO) and alkylation repair homolog protein 5 (ALKBH5)], RNA-binding proteins [YT521-B homology domains 2 (YTHDF2)], and ankylosing spondylitis (AS). A total of 154 specimens, containing 79 patients with new-onset AS and 75 healthy controls (HCs), participated in the study. The mRNA expressions of these m6A methyltransferase, demethylase, and RNA-binding protein in peripheral blood mononuclear cells (PBMCs) were detected by quantitative real-time PCR (qRT-PCR). The data showed that the mRNA expressions of YTHDF2 and ALKBH5 in PBMC from patients with new-onset AS were significantly decreased, and there was a positive correlation between RNA-binding proteins (YTHDF2) and demethylase (ALKBH5) in patients with new-onset AS. Logistic regression analysis demonstrated that the expression of YTHDF2 mRNA in PBMC is a risk factor of AS. Receiver operating characteristic (ROC) analysis of the area under the curve (AUC) for mRNA YTHDF2 in new-onset AS and HC was 0.692, with a cutoff value of <0.8724, a sensitivity of 67%, and a specificity of 63%. Moreover, we constructed a novel predictive model based on a combination of mRNA YTHDF2 and systemic immune-inflammation index (SII) for AS diagnosis (AUC = 0.865, sensitivity = 79.45%, specificity = 84.00%), and the predictive model correlated with the activity and severity of AS. This study indicates that the mRNA expression of YTHDF2 in PBMC may be involved in AS pathogenesis and a predictive model based on a combination of mRNA YTHDF2 and SII acts as a marker for diagnosis and progression of diseases.