bluuebunny/crossref_metadata_2025 huggingface dataset:
Homocysteine Causes Endothelial Dysfunction via Inflammatory Factor-Mediated Activation of Epithelial Sodium Channel (ENaC)
Authors: Liang Chen , Wang Qiu-Shi , Yang Xu , Zhu Di , Sun Yu , Niu Na , Yao Jie , Dong Bi-Han , Jiang Shuai , Tang Liang-Liang , Lou Jie , Yu Chang-Jiang , Shao Qun , Wu Ming-Ming , Zhang Zhi-Ren
Published: June 2021

Background

Hyperhomocysteinemia (HHcy) causes cardiovascular diseases via regulating inflammatory responses. We investigated whether and how the epithelial sodium channel (ENaC), a recently identified ion channel in endothelial cells, plays a role in HHcy-induced endothelial dysfunction.

Methods

Cell-attached patch-clamp recording in acute split-open aortic endothelial cells, western blot, confocal imaging, and wire myograph combined with pharmacological approaches were used to determine whether HHcy-mediated inflammatory signaling leads to endothelial dysfunction via stimulating ENaC.

Results

The data showed that 4 weeks after L-methionine diet the levels of plasma Hcy were significantly increased and the ENaC was dramatically activated in mouse aortic endothelial cells. Administration of benzamil, a specific ENaC blocker, ameliorated L-methionine diet-induced impairment of endothelium-dependent relaxation (EDR) and reversed Hcy-induced increase in ENaC activity. Pharmacological inhibition of NADPH oxidase, reactive oxygen species (ROS), cyclooxygenase-2 (COX-2)/thromboxane B2 (TXB2), or serum/glucocorticoid regulated kinase 1 (SGK1) effectively attenuated both the Hcy-induced activation of endothelial ENaC and impairment of EDR. Our in vitro data showed that both NADPH oxidase inhibitor and an ROS scavenger reversed Hcy-induced increase in COX-2 expression in human umbilical vein endothelial cells (HUVECs). Moreover, Hcy-induced increase in expression levels of SGK-1, phosphorylated-SGK-1, and phosphorylated neural precursor cell-expressed developmentally downregulated protein 4-2 (p-Nedd4-2) in HUVECs were significantly blunted by a COX-2 inhibitor.

Conclusion

We show that Hcy activates endothelial ENaC and subsequently impairs EDR of mouse aorta, via ROS/COX-2-dependent activation of SGK-1/Nedd4-2 signaling. Our study provides a rational that blockade of the endothelial ENaC could be potential method to prevent and/or to treat Hcy-induced cardiovascular disease.
Disruption of the Interfacial Membrane Leads to Magnaporthe oryzae Effector Re-location and Lifestyle Switch During Rice Blast Disease
Authors: Jones Kiersun , Zhu Jie , Jenkinson Cory B. , Kim Dong Won , Pfeifer Mariel A. , Khang Chang Hyun
Published: June 2021

To cause the devastating rice blast disease, the hemibiotrophic fungus Magnaporthe oryzae produces invasive hyphae (IH) that are enclosed in a plant-derived interfacial membrane, known as the extra-invasive hyphal membrane (EIHM), in living rice cells. Little is known about when the EIHM is disrupted and how the disruption contributes to blast disease. Here we show that the disruption of the EIHM correlates with the hyphal growth stage in first-invaded susceptible rice cells. Our approach utilized GFP that was secreted from IH as an EIHM integrity reporter. Secreted GFP (sec-GFP) accumulated in the EIHM compartment but appeared in the host cytoplasm when the integrity of the EIHM was compromised. Live-cell imaging coupled with sec-GFP and various fluorescent reporters revealed that the loss of EIHM integrity preceded shrinkage and eventual rupture of the rice vacuole. The vacuole rupture coincided with host cell death, which was limited to the invaded cell with presumed closure of plasmodesmata. We report that EIHM disruption and host cell death are landmarks that delineate three distinct infection phases (early biotrophic, late biotrophic, and transient necrotrophic phases) within the first-invaded cell before reestablishment of biotrophy in second-invaded cells. M. oryzae effectors exhibited infection phase-specific localizations, including entry of the apoplastic effector Bas4 into the host cytoplasm through the disrupted EIHM during the late biotrophic phase. Understanding how infection phase-specific cellular dynamics are regulated and linked to host susceptibility will offer potential targets that can be exploited to control blast disease.
The Safety, Immunogenicity, and Immunopersistence of Hepatitis A Vaccine in HBs-Ag-Positive Participants: A Retrospective Study
Authors: Wang Xiaodan , Luo Jia , Ma Fubao , Kang Guodong , Ding Zhengrong , Pan Yue , Zhao Yujiao , Chen Junying , Feng Kai , Yan Lingmei , Zhang Juan , Li Linhao , Lan Qiangping , Li Daiying , Yang Xiaolei , Li Guoliang , Yang Jingsi , Sun Qiangming
Published: June 2021

Objectives

To compare the safety, immunogenicity, and immune persistence of hepatitis A (HA) vaccines between HBs-Ag-positive and -negative participants.

Method

9000 participants were enrolled in the phase IV study of live attenuated HA (HA-L) or inactivated HA (HA-I) vaccines. The HBs-Ag-positive subjects were detected and became an independent observation group. Adverse reactions (ARs), geometric mean concentrations (GMCs) and seroconversion rates (SRs) of the vaccines were analyzed at five time points until three years after vaccination. Results: 120 HBs-Ag-positive subjects were screened out, only 1 participant had grade 1 experienced ARs after HA-L injection. Except the time point of two years, the SRs of HBs-Ag-positive group were 100% for both vaccines. The GMCs were not statistically different between HBs-Ag-positive and -negative groups after the HA-L vaccination. The logarithmically transformed GMCs for HBs-Ag-positive and -negative groups were 3.21 mIU/mL (95% CI, 2.03-4.39 mIU/mL) and 2.95 mIU/mL (95% CI, 2.88-3.02 mIU/mL) 28 days after the HA-L vaccination, respectively.

Conclusions

Both HA-L and HA-I vaccines were safe for HBs-Ag-positive participants and may provide an excellent long-term protection against HAV in this study. The results indicated that people positive or negative for HBs-Ag can receive both HA-L and HA-I vaccines (ClinicalTrials.gov number, NCT02601040).
Ice Core Science Meets Computer Vision: Challenges and Perspectives
Authors: Bohleber Pascal , Roman Marco , Barbante Carlo , Vascon Sebastiano , Siddiqi Kaleem , Pelillo Marcello
Published: June 2021

Polar ice cores play a central role in studies of the earth’s climate system through natural archives. A pressing issue is the analysis of the oldest, highly thinned ice core sections, where the identification of paleoclimate signals is particularly challenging. For this, state-of-the-art imaging by laser-ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) has the potential to be revolutionary due to its combination of micron-scale 2D chemical information with visual features. However, the quantitative study of record preservation in chemical images raises new questions that call for the expertise of the computer vision community. To illustrate this new inter-disciplinary frontier, we describe a selected set of key questions. One critical task is to assess the paleoclimate significance of single line profiles along the main core axis, which we show is a scale-dependent problem for which advanced image analysis methods are critical. Another important issue is the evaluation of post-depositional layer changes, for which the chemical images provide rich information. Accordingly, the time is ripe to begin an intensified exchange between the two scientific communities of computer vision and ice core science. The collaborative building of a new framework for investigating high-resolution chemical images with automated image analysis techniques will also benefit the already wide-spread application of laser-ablation inductively-coupled plasma mass spectrometry chemical imaging in the geosciences.
Attenuating the Variability of Lipids Is Beneficial for the Hypertension Management to Reduce the Cardiovascular Morbidity and Mortality in Older Adults
Authors: Dong Yuanli , Liu Xukui , Zhao Yingxin , Chai Qiang , Zhang Hua , Gao Yumei , Liu Zhendong
Published: June 2021

Objective: To investigate the beneficial of attenuating the variability of lipids to the hypertension management in older adults.

Methods: Between April 2008 and November 2010, 1,244 hypertensive patients aged ≥60 years were recruited and randomized into placebo and rosuvastatin groups. Outcomes and inter-visit plasma lipids variability were assessed.

Results: Over an average follow-up of 83.5 months, the coefficients of variation (CVs) in total cholesterol (TCHO), triglycerides, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were significantly lower in the rosuvastatin group than the placebo group (p < 0.05). The risks of composite cardiovascular event, myocardial infarction, coronary revascularization, heart failure, total stroke, ischemic stroke, cardiovascular death, and all-cause death were significantly lower in the rosuvastatin group than the placebo group (all p < 0.05). The differences in the risks were significantly diminished after the CVs for TCHO, triglycerides, HDL-c, and LDL-c were separately included as confounders. One-SD of CVs for TCHO, triglycerides, HDL-c, and LDL-c increment were significantly associated with the risks of composite cardiovascular event, myocardial infarction, heart failure, total stroke, ischemic stroke, cardiovascular death, and all-cause death, respectively (all p < 0.05).

Conclusions: Rosuvastatin significantly attenuated the intra-visit variability in lipids and decreased the risk of cardiovascular mortality and morbidity. Controlling the variability of lipids is as important as antihypertensive treatment to reduce the cardiovascular morbidity and mortality in the management of older hypertensive patients.

Clinical Trial Registration:ChiCTR.org.cn, ChiCTR-IOR-17013557.
Sinking Diatom Assemblages as a Key Driver for Deep Carbon and Silicon Export in the Scotia Sea (Southern Ocean)
Authors: Zúñiga D. , Sanchez-Vidal A. , Flexas M. M. , Carroll D. , Rufino M. M. , Spreen G. , Calafat A. , Abrantes F.
Published: June 2021

Physical and biogeochemical processes in the Southern Ocean are fundamental for modulating global climate. In this context, a process-based understanding of how Antarctic diatoms control primary production and carbon export, and hence global-ocean carbon sequestration, has been identified as a scientific priority. Here we use novel sediment trap observations in combination with a data-assimilative ocean biogeochemistry model (ECCO-Darwin) to understand how environmental conditions trigger diatom ecology in the iron-fertilized southern Scotia Sea. We unravel the role of diatoms assemblage in controlling the biogeochemistry of sinking material escaping from the euphotic zone, and discuss the link between changes in upper-ocean environmental conditions and the composition of settling material exported from the surface to 1,000 m depth from March 2012 to January 2013. The combined analysis of in situ observations and model simulation suggests that an anomalous sea-ice episode in early summer 2012–2013 favored (via restratification due to sea-ice melt) an early massive bloom of Corethron pennatum that rapidly sank to depth. This event drove high biogenic silicon to organic carbon export ratios, while modulating the carbon and nitrogen isotopic signals of sinking organic matter reaching the deep ocean. Our findings highlight the role of diatom ecology in modulating silicon vs. carbon sequestration efficiency, a critical factor for determining the stoichiometric relationship of limiting nutrients in the Southern Ocean.
Effect of SGLT2 Inhibitors on Type 2 Diabetes Mellitus With Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials
Authors: Wei Qiong , Xu Xinyue , Guo Li , Li Jia , Li Ling
Published: June 2021

Objective

Clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors can improve non-alcoholic fatty liver disease (NAFLD). In this work, a meta-analysis of randomized controlled trials was conducted to evaluate the effect of SGLT2 inhibitors on type 2 diabetes mellitus (T2DM) with NAFLD.

Methods

PubMed, Embase, Web of Science, and Cochrane Libraries were used for the systematic literature review to determine eligible studies. A randomized effect model was adapted to perform a meta-analysis on these eligible studies to estimate the combined effect sizes. Differences were expressed as the weighted average difference (WMD) of the continuous results and the 95% confidence interval (CI).

Results

Ten randomized controlled trials with 573 participants were included. SGLT2 inhibitors significantly reduced the levels of alanine transaminase (WMD -5.36 [95% CI: -8.86, -1.85], p = 0.003) and Aspartate Transaminase (WMD -2.56 [95% CI: -3.83, -1.29], p <0.0001). In terms of body composition, liver proton density fat fraction (WMD -2.20 [95% CI: -3.67, -0.74], p = 0.003), visceral fat mass area (WMD -20.71 [95% CI: -28.19, -13.23], p <0.00001), subcutaneous fat areas (WMD -14.68 [95% CI: -26.96, -2.40], p = 0.02) were also significantly reduced.

Conclusion

SGLT2 inhibitors can remarkably reduce hepatic enzymes, hepatic fat and improve body composition. Thus, they may become a new treatment option for NAFLD.

Systematic Review Registration

PROSPERO, identifier CRD42020215570.
The Role of Traditional Chinese Formula Ding-Kun Pill (DKP) in Expected Poor Ovarian Response Women (POSEIDON Group 4) Undergoing In Vitro Fertilization-Embryo Transfer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Song Jing-Yan , Gao Dan-Dan , Cao Xian-Ling , Xiang Shan , Chen Yan-Hua , Teng Yi-Li , Li Xiu-Fang , Liu Hai-Ping , Wang Fu-Xin , Zhang Bin , Xu Li-Hua , Zhou Li , Huang Xiang-Hong , Sun Zhen-Gao
Published: June 2021

Objective

The primary objective of the study was to assess traditional Chinese formula DKP supplementation in terms of efficacy and safety on reproductive outcomes of expected poor ovarian responder (POR, POSEIDON Group 4) undergoing in vitro fertilization-embryo transfer (IVF-ET).

Design, Setting, and Participants

Women eligible for IVF-ET were invited to participate in this randomized, double-blind, placebo-controlled, superiority trial at academic fertility centers of ten public hospitals in Chinese Mainland. A total of 462 patients (35–44 years) equally divided between DKP and placebo groups with antral follicle count (AFC) <5 or anti-müllerian hormone (AMH) <1.2 ng/ml were randomized.

Interventions

All participants were given DKP or 7 g placebo twice daily on the previous menstrual cycle day 5 until oocyte retrieval, which took approximately 5 to 6 weeks.

Main Outcome Measure

The primary outcome was the ongoing pregnancy defined as more than 20 gestational weeks of an intrauterine living fetus confirmed by pelvic ultrasonography.

Results

Demographic characteristics were equally distributed between the study populations. Intention-to-treat (ITT) analysis revealed that ongoing pregnancy rate (OPR) was not significantly different between DKP and placebo groups [26.4% (61/231) versus 24.2% (56/231); relative risk (RR) 1.09, 95% confidence interval (CI) 0.80 to 1.49, P = 0.593]. No significant differences between groups were observed for the secondary outcomes. The additional per protocol (PP) analysis was in line with ITT results: OPR in DKP group was 27.2% (61/224) versus 24.1% (55/228) in placebo group [RR 1.13, 95%CI (0.82 to 1.55), P = 0.449]. After subgroup analysis the findings concluded that POR population of 35–37 years had a significantly higher OPR after 5–6 weeks of oral DKP (41.8%, 33/79) versus placebo (25.4%, 18/71) [RR 1.65, 95% CI (1.02 to 2.65), P = 0.034, P for interaction = 0.028].

Conclusion

This well-designed randomized controlled trial (RCT) offers new high-quality evidence to supplement existing retrospective literature concerning DKP performance in expected PORs. DKP could be recommended as a safe and natural remedy for expected PORs (aged 35–37 years) who fulfill the POSEIDON group 4 criteria. However, additional interventional clinical studies are undoubtedly required to be conducted in the future to validate this hypothesis.

Clinical Trial Registration

www.chictr.org.cn, identifier ChiCTR1900026614.
Diet Drives Differences in Reproductive Synchrony in Two Sympatric Mountain Ungulates in the Himalaya
Authors: Srivastava Tanushree , Kumar Ajith , Kumar Vinod , Umapathy Govindhaswamy
Published: June 2021

Ungulates in higher latitudes and altitudes experience sharp seasonal changes in forage abundance and quality. In response, ungulates show varying degrees of synchrony in reproduction. Diet type has been hypothesized to be a determinant of differences in reproductive synchrony. Analyses at global scales using proxies of plant phenology such as climate, latitude and Normalized Difference Vegetation Index (NDVI) have found no evidence in support because such proxies do not capture differences in phenology among plant taxa at local scales. We compared seasonal variations in diet quality with reproductive synchrony in the Himalayan musk deer (Moschus chrysogaster), a browser, and the Himalayan goral (Naemorhedus goral), a grazer, in mid-altitude Himalaya. We also compared seasonal variations in physiological stress using fecal glucocorticoid metabolite (FGM). We identified different stages of female reproductive cycle using fecal concentrations of metabolites of estradiol, pregnanediol-3-glucuronide (PdG) and testosterone and used fecal crude protein (CP) as an indicator of diet quality. In musk deer, fecal estradiol and PdG concentrations showed a dispersed estrous and parturition, respectively. Goral had a more synchronized estrous and parturition. Estrous cycles in both species occurred when diet quality was poor, but parturition occurred when diet quality was high. Greater seasonality in reproduction in goral is driven by sharp phenological changes in graminoids on which it feeds, compared to slow changes in browse on which musk deer feeds. Thus, we show that diet type drives the differences in reproductive synchrony in these two sympatric species. Spring and summer with highest diet quality were times of highest stress in both the ungulates. We hypothesize predation pressure from feral dogs and resource competition with livestock as plausible explanations for this, which need to be tested in future. Our findings also highlight the need for studying relationships among plant phenology, diet type and reproductive biology of ungulates at local scales if we are to understand species responses to global phenomena such as climate change.
Investigating Transcriptional Dynamics Changes and Time-Dependent Marker Gene Expression in the Early Period After Skeletal Muscle Injury in Rats
Authors: Ren Kang , Wang Liangliang , Wang Liang , Du Qiuxiang , Cao Jie , Jin Qianqian , An Guoshuai , Li Na , Dang Lihong , Tian Yingjie , Wang Yingyuan , Sun Junhong
Published: June 2021

Following skeletal muscle injury (SMI), from post-injury reaction to repair consists of a complex series of dynamic changes. However, there is a paucity of research on detailed transcriptional dynamics and time-dependent marker gene expression in the early stages after SMI. In this study, skeletal muscle tissue in rats was taken at 4 to 48 h after injury for next-generation sequencing. We examined the transcriptional kinetics characteristics during above time periods after injury. STEM and maSigPro were used to screen time-correlated genes. Integrating 188 time-correlated genes with 161 genes in each time-related gene module by WGCNA, we finally identified 18 network-node regulatory genes after SMI. Histological staining analyses confirmed the mechanisms underlying changes in the tissue damage to repair process. Our research linked a variety of dynamic biological processes with specific time periods and provided insight into the characteristics of transcriptional dynamics, as well as screened time-related biological indicators with biological significance in the early stages after SMI.
Novel Autophagy-Related Gene Signature Investigation for Patients With Oral Squamous Cell Carcinoma
Authors: Huang Lihong , Yu Xinghao , Jiang Zhou , Zeng Ping
Published: June 2021

The correlation between autophagy defects and oral squamous cell carcinoma (OSCC) has been previously studied, but only based on a limited number of autophagy-related genes in cell lines or animal models. The aim of the present study was to analyze differentially expressed autophagy-related genes through The Cancer Genome Atlas (TCGA) database to explore enriched pathways and potential biological function. Based on TCGA database, a signature composed of four autophagy-related genes (CDKN2A, NKX2-3, NRG3, andFADD) was established by using multivariate Cox regression models and two Gene Expression Omnibus datasets were applied for external validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to study the function of autophagy-related genes and their pathways. The most significant GO and KEGG pathways were enriched in several key pathways that were related to the progression of autophagy and OSCC. Furthermore, a prognostic risk score was constructed based on the four genes; patients were then divided into two groups (i.e., high risk and low risk) in terms of the median of risk score. Prognosis of the two groups and results showed that patients at the low-risk group had a much better prognosis than those at the high-risk group, regardless of whether they were in the training datasets or validation datasets. Multivariate Cox regression results indicated that the risk score of the autophagy-related gene signatures could greatly predict the prognosis of patients after controlling for several clinical covariates. The findings of the present study revealed that autophagy-related gene signatures play an important role in OSCC and are potential prognostic biomarkers and therapeutic targets.
Practices of Care in Times of COVID-19
Authors: Gómez Becerra Marlene , Muneri-Wangari Eunice
Published: June 2021

We argue that the COVID-19 virus has been a trigger for emerging practices of care by being an actor with agency that transforms the everyday life of subjects by placing them under uncertainty. Therefore, this paper aims to show how practices of care emerged or were maintained as vulnerable groups were confronted by restrictions to movement and uncertainties following the outbreak of COVID-19. We demonstrate this using two case studies of the Maasai pastoral community in Narok, Kenya and the community kitchens in the city of Berlin, Germany. Thus, we seek to show how practices of care for, care about, and care with are carried out by the members of these communities during pandemic times. Granted that care remains highly contentious in feminist literature, this paper contributes to a growing body of literature on care in Feminist Political Ecology by broadening the conceptualization of care. The research builds on a typology of care relations based on practices of distribution, exchange, and reciprocity. This allows us to show when care is exercised in a unidirectional and hierarchical way and when in a multidirectional way reinforcing social bonds of responsibility and collective care that transcends the socio-nature boundaries.
Japanese Encephalitis Virus Infected Human Monocyte-Derived Dendritic Cells Activate a Transcriptional Network Leading to an Antiviral Inflammatory Response
Authors: Chauhan Shailendra , Rathore Deepak Kumar , Sachan Shilpa , Lacroix-Desmazes Sebastien , Gupta Nimesh , Awasthi Amit , Vrati Sudhanshu , Kalia Manjula
Published: June 2021

A comprehensive understanding of the human immune response to virus infection is imperative for developing effective therapies, antivirals, and vaccines. Dendritic cells (DCs) are among the first cells to encounter the virus and are also key antigen-presenting cells that link the innate and adaptive immune system. In this study, we focus on the human immune response to the mosquito-borne Japanese encephalitis virus (JEV), which is the leading cause of virus-induced encephalitis in south-east Asia and has the potential to become a global pathogen. We describe the gene regulatory circuit of JEV infection in human monocyte-derived DCs (moDCs) along with its functional validation. We observe that JEV can productively infect human moDCs leading to robust transcriptional activation of the interferon and NF-κB-mediated antiviral and inflammatory pathways. This is accompanied with DC maturation and release of pro-inflammatory cytokines and chemokines TNFα, IL-6, IL-8, IL-12, MCP-1. and RANTES. JEV-infected moDCs activated T-regulatory cells (Tregs) in allogenic mixed lymphocyte reactions (MLR) as seen by upregulated FOXP3 mRNA expression, suggestive of a host response to reduce virus-induced immunopathology. The virus also downregulated transcripts involved in Peroxisome Proliferator Activated Receptor (PPAR) signalling and fatty acid metabolism pathways suggesting that changes in cellular metabolism play a crucial role in driving the DC maturation and antiviral responses. Collectively, our data describe and corroborate the human DC transcriptional network that is engaged upon JEV sensing.
A Tale of Two Immune Cells in Rheumatoid Arthritis: The Crosstalk Between Macrophages and T Cells in the Synovium
Authors: Tu Jiajie , Huang Wei , Zhang Weiwei , Mei Jiawei , Zhu Chen
Published: June 2021

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.
Children With Asthma Have Impaired Innate Immunity and Increased Numbers of Type 2 Innate Lymphoid Cells Compared With Healthy Controls
Authors: Hosseini Banafshe , Berthon Bronwyn S. , Starkey Malcolm R. , Collison Adam , McLoughlin Rebecca F. , Williams Evan J. , Nichol Kristy , Wark Peter AB. , Jensen Megan E. , Da Silva Sena Carla Rebeca , Baines Katherine J. , Mattes Joerg , Wood Lisa G.
Published: June 2021

Background

Asthma is the most frequent cause of hospitalisation among children; however, little is known regarding the effects of asthma on immune responses in children.

Objective

The present study aimed to evaluate cytokine responses of peripheral blood mononuclear cells (PBMCs), PBMC composition and lung function in children with and without asthma.

Methods

Using a case-control design, we compared 48 children with asthma aged 3-11 years with 14 age-matched healthy controls. PBMC composition and cytokine production including interferon (IFN)-γ, interleukin (IL)-1β, IL-5 and lL-6 following stimulation with rhinovirus-1B (RV1B), house dust mite (HDM) and lipopolysaccharide (LPS) were measured. Lung function was assessed using impulse oscillometry and nitrogen multiple breath washout.

Results

The frequency of group 2 innate lymphoid cells were significantly higher in asthmatics and PBMCs from asthmatics had deficient IFN-γ production in response to both RV1B and LPS compared with controls (P<0.01). RV1B-induced IL-1β response and HDM-stimulated IL-5 production was higher in asthmatics than controls (P<0.05). In contrast, IL-1β and IL-6 were significantly reduced in response to HDM and LPS in asthmatics compared to controls (P<0.05). Children with asthma also had reduced pulmonary function, indicated by lower respiratory reactance as well as higher area of-reactance and lung clearance index values compared with controls (P<0.05).

Conclusion

Our study indicates that children with asthma have a reduced lung function in concert with impaired immune responses and altered immune cell subsets. Improving our understanding of immune responses to viral and bacterial infection in childhood asthma can help to tailor management of the disease.
A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair
Authors: Strubbe Steven , De Bruyne Marieke , Pannicke Ulrich , Beyls Elien , Vandekerckhove Bart , Leclercq Georges , De Baere Elfride , Bordon Victoria , Vral Anne , Schwarz Klaus , Haerynck Filomeen , Taghon Tom
Published: June 2021

Severe Combined Immune Deficiency (SCID) is a primary deficiency of the immune system in which opportunistic and recurring infections are often fatal during neonatal or infant life. SCID is caused by an increasing number of genetic defects that induce an abrogation of T lymphocyte development or function in which B and NK cells might be affected as well. Because of the increased availability and usage of next-generation sequencing (NGS), many novel variants in SCID genes are being identified and cause a heterogeneous disease spectrum. However, the molecular and functional implications of these new variants, of which some are non-coding, are often not characterized in detail. Using targeted NGS, we identified a novel homozygous c.465-1G>C splice acceptor site variant in the DCLRE1C gene in a T-B-NK+ SCID patient and fully characterized the molecular and functional impact. By performing a minigene splicing reporter assay, we revealed deregulated splicing of the DCLRE1C transcript since a cryptic splice acceptor in exon 7 was employed. This induced a frameshift and the generation of a p.Arg155Serfs*15 premature termination codon (PTC) within all DCLRE1C splice variants, resulting in the absence of full-length ARTEMIS protein. Consistently, a V(D)J recombination assay and a G0 micronucleus assay demonstrated the inability of the predicted mutant ARTEMIS protein to perform V(D)J recombination and DNA damage repair, respectively. Together, these experiments molecularly and functionally clarify how a newly identified c.465-1G>C variant in the DCLRE1C gene is responsible for inducing SCID. In a clinical context, this demonstrates how the experimental validation of new gene variants, that are identified by NGS, can facilitate the diagnosis of SCID which can be vital for implementing appropriate therapies.
Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis
Authors: Tang Li , Tang Bo , Lei Yuanyuan , Yang Min , Wang Sumin , Hu Shiping , Xie Zhuo , Liu Yaojiang , Vlodavsky Israel , Yang Shiming
Published: June 2021

Chronic gastritis caused by Helicobacter pylori (H. pylori) infection has been widely recognized as the most important risk factor for gastric cancer. Analysis of the interaction between the key participants in gastric mucosal immunity and H. pylori infection is expected to provide important insights for the treatment of chronic gastritis and the prevention of gastric cancer. Heparanase is an endoglycosidase that degrades heparan sulfate, resulting in remodeling of the extracellular matrix thereby facilitating the extravasation and migration of immune cells towards sites of inflammation. Heparanase also releases heparan sulfate-bound cytokines and chemokines that further promote directed motility and recruitment of immune cells. Heparanase is highly expressed in a variety of inflammatory conditions and diseases, but its role in chronic gastritis has not been sufficiently explored. In this study, we report that H. pylori infection promotes up-regulation of heparanase in gastritis, which in turn facilitates the colonization of H. pylori in the gastric mucosa, thereby aggravating gastritis. By sustaining continuous activation, polarization and recruitment of macrophages that supply pro-inflammatory and pro-tumorigenic cytokines (i.e., IL-1, IL-6, IL-1β, TNF-α, MIP-2, iNOS), heparanase participates in the generation of a vicious circle, driven by enhanced NFκB and p38-MAPK signaling, that supports the development and progression of gastric cancer. These results suggest that inhibition of heparanase may block this self-sustaining cycle, and thereby reduce the risk of gastritis and gastric cancer.
S100a9 Protects Male Lupus-Prone NZBWF1 Mice From Disease Development
Authors: Davison Laura M. , Alberto Andres A. , Dand Hardik A. , Keller Emma J. , Patt Madeline , Khan Ayesha , Dvorina Nina , White Alexandra , Sakurai Nodoka , Liegl Lauren N. , Vogl Thomas , Jorgensen Trine N.
Published: June 2021

Systemic lupus erythematosus (SLE) is an autoimmune disorder disproportionally affecting women. A similar sex difference exists in the murine New Zealand Black/White hybrid model (NZBWF1) of SLE with all females, but only 30-40% of males, developing disease within the first year of life. Myeloid-derived suppressor cells (MDSCs) are prominent in NZBWF1 males and while depletion of these cells in males, but not females, promotes disease development, the mechanism of suppression remains unknown. S100a9, expressed by neutrophils and MDSCs, has previously been shown to exert immunosuppressive functions in cancer and inflammation. Here we investigated if S100a9 exerts immunosuppressive functions in NZBWF1 male and female mice.S100a9+/+,S100a9+/-andS100a9-/-NZBWF1 mice were followed for disease development for up to 8 months of age. Serum autoantibody levels, splenomegaly, lymphocyte activation, glomerulonephritis and proteinuria were measured longitudinally or at the time of harvest. In accordance with an immunosuppressive function of MDSCs in male mice,S100a9-deficient male NZBWF1 mice developed accelerated autoimmunity as indicated by increased numbers of differentiated effector B and T cells, elevated serum autoantibody levels, increased immune-complex deposition and renal inflammation, and accelerated development of proteinuria. In contrast, female mice showed either no response to S100a9-deficiency or even a slight reduction in disease symptoms. Furthermore, male, but not female,S100a9-/-NZBWF1 mice displayed an elevated type I interferon-induced gene signature, suggesting that S100a9 may dampen a pathogenic type I interferon signal in male mice. Taken together, S100a9 exerts an immunosuppressive function in male NZBWF1 mice effectively moderating lupus-like disease developmentviainhibition of type I interferon production, lymphocyte activation, autoantibody production and the development of renal disease.
Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment
Authors: Kaweme Natasha Mupeta , Zhou Fuling
Published: June 2021

Natural killer (NK) cells are prominent cytotoxic and cytokine-producing components of the innate immune system representing crucial effector cells in cancer immunotherapy. Presently, various NK cell-based immunotherapies have contributed to the substantial improvement in the reconstitution of NK cells against advanced-staged and high-risk AML. Various NK cell sources, including haploidentical NK cells, adaptive NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, chimeric antigen receptor NK cells, cytokine-induced memory-like NK cells, and NK cell lines have been identified. Devising innovative approaches to improve the generation of therapeutic NK cells from the aforementioned sources is likely to enhance NK cell expansion and activation, stimulateex vivoandin vivopersistence of NK cells and improve conventional treatment response of myeloid leukemia. The tumor-promoting properties of the tumor microenvironment and downmodulation of NK cellular metabolic activity in solid tumors and hematological malignancies constitute a significant impediment in enhancing the anti-tumor effects of NK cells. In this review, we discuss the current NK cell sources, highlight ongoing interventions in enhancing NK cell function, and outline novel strategies to circumvent immunosuppressive factors in the tumor microenvironment to improve the efficacy of NK cell-based immunotherapy and expand their future success in treating myeloid leukemia.
Mapping Salivary Proteases in Sjögren’s Syndrome Patients Reveals Overexpression of Dipeptidyl Peptidase-4/CD26
Authors: Garreto Laís , Charneau Sébastien , Mandacaru Samuel Coelho , Nóbrega Otávio T. , Motta Flávia N. , de Araújo Carla N. , Tonet Audrey C. , Modesto Flávia M. B. , Paula Lilian M. , de Sousa Marcelo Valle , Santana Jaime M. , Acevedo Ana Carolina , Bastos Izabela M. D.
Published: June 2021

Sjögren’s Syndrome (SS) is an autoimmune exocrinopathy characterized by the progressive damage of salivary and lacrimal glands associated with lymphocytic infiltration. Identifying new non-invasive biomarkers for SS diagnosis remains a challenge, and alterations in saliva composition reported in patients turn this fluid into a source of potential biomarkers. Among these, proteases are promising candidates since they are involved in several key physio-pathological processes. This study evaluated differentially expressed proteases in SS individuals’ saliva using synthetic fluorogenic substrates, zymography, ELISA, and proteomic approaches. Here we reported, for the first time, increased activity of the serine protease dipeptidyl peptidase-4/CD26 (DPP4/CD26) in pSS saliva, the expression level of which was corroborated by ELISA assay. Gelatin zymograms showed that metalloproteinase proteolytic band profiles differed significantly in intensity between control and SS groups. Focusing on matrix metalloproteinase-9 (MMP9) expression, an increased tendency in pSS saliva (p = 0.0527) was observed compared to the control group. Samples of control, pSS, and sSS were analyzed by mass spectrometry to reveal a general panorama of proteases in saliva. Forty-eight protein groups of proteases were identified, among which were the serine proteases cathepsin G (CTSG), neutrophil elastase (ELANE), myeloblastin (PRTN3), MMP9 and several protease inhibitors. This work paves the way for proteases to be explored in the future as biomarkers, emphasizing DPP4 by its association in several autoimmune and inflammatory diseases. Besides its proteolytic role, DPP4/CD26 acts as a cell surface receptor, signal transduction mediator, adhesion and costimulatory protein involved in T lymphocytes activation.
Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling
Authors: Saul-McBeth Jessica , Dillon John , Lee Aaron , Launder Dylan , Kratch Jacqueline M. , Abutaha Eanas , Williamson Alexandria A. , Schroering Allen G. , Michalski Grace , Biswas Priosmita , Conti Samuel R. , Shetty Amol C. , McCracken Carrie , Bruno Vincent M. , Parsai E. Ishmael , Conti Heather R.
Published: June 2021

Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra−/− mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra−/− mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.
Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2
Authors: Fernández-Lázaro Diego , Fernandez-Lazaro Cesar I. , Mielgo-Ayuso Juan , Adams David P. , García Hernández Juan Luis , González-Bernal Jerónimo , González-Gross Marcela
Published: June 2021

The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.
Demo-Genetic Approach for the Conservation and Restoration of a Habitat-Forming Octocoral: The Case of Red Coral, Corallium rubrum, in the Réserve Naturelle de Scandola
Authors: Gazulla Carlota R. , López-Sendino Paula , Antunes Agostinho , Aurelle Didier , Montero-Serra Ignasi , Dominici Jean-Marie , Linares Cristina , Garrabou Joaquim , Ledoux Jean-Baptiste
Published: June 2021

Marine protected areas (MPAs) are one of the most efficient conservation tools to buffer marine biodiversity loss induced by human activities. Beside effective enforcement, an accurate understanding of the eco-evolutionary processes underlying the patterns of biodiversity is needed to reap the benefits of management policies. In this context, integrating population genetics with demographic data, the demo-genetic approach, is particularly relevant to shift from a “species-based pattern” toward an “eco-evolutionary-based processes” conservation. Here, targeting a key species in the Mediterranean coralligenous, the red coral, Corallium rubrum, in an emblematic Mediterranean MPA, the “Réserve Naturelle de Scandola” (France), we applied demo-genetic approaches at two contrasted spatial scales, among populations and within one population, to (i) infer the demographic connectivity among populations in the metapopulation network and (ii) shed new light on the genetic connectivity and on the demographic transitions underlying the dynamics of a near-pristine population. Integrating different spatial and temporal scales, we demonstrated (i) an apparent temporal stability in the pattern of genetic diversity and structure in the MPA in spite of a dramatic demographic decline and (ii) contrasted levels of genetic isolation but substantial demographic connectivity among populations. Focusing on the near-pristine population, we complemented the characterization of red coral demographic connectivity suggesting (iii) temporal variability and (iv) the occurrence of collective dispersal. In addition, we demonstrated (v) contrasted patterns of spatial genetic structure (SGS), depending on the considered stage-class (adults vs. juveniles), in the near-pristine population. This last result points out that the overall SGS resulted from a restricted dispersal of locally produced juveniles (SGS among adults and juveniles) combined to mortality during early life stages (decrease of SGS from juveniles to adults). Demonstrating the occurrence of two management units and the importance of two populations (CAVB and ALE) for the network of connectivity, we made recommendations for the management of the Réserve Naturelle de Scandola. Besides, we contributed to the implementation of scientifically driven restoration protocols in red coral by providing estimates for the size, density, and distances among patches of transplanted colonies.
Do Primary Care Physicians Contribute to the Immunization Status of Their Adult Patients? A Story of Patients' Overconfidence Coupled With Physicians' Passivity
Authors: Papis Thibaut , Clavien Christine
Published: June 2021

Context:Immunization coverage counts among the priorities of public health services. To identify factors that motivate or fail to motivate patients to update their vaccination status would help to design future strategies and awareness campaigns.

Objective:Our aim was to assess the impact of primary care physicians on the immunization status of their adult patients, and to explore possible explanations.

Methods:We invited students and collaborators of Geneva University to bring their paper vaccination records to receive an assessment of their immunization status and personalized vaccination recommendations. Participants completed a first questionnaire at the recruitment phase, and a second 2–3 months later. We assessed their immunization status with the viavac algorithms based on the Swiss national immunization plan.

Results:Having a primary care physician did not correlate with better immunization status: only 22.5% patients who reported having a physician and 20% who reported having no physician were up-to-date (n= 432;p> 0.5). A linear regression indicates that the frequency of medical consultations did not affect patients' immunization status either. Even the participants who recently showed their vaccination record to their primary care physician did not have a better vaccination status. We explored possible explanatory factors and found evidence for the patients' overconfidence about their own immunization status: 71.2% of the participants who predicted that they were up-to-date were wrong about their actual status, and 2–3 months after having received their immunization assessment, 52.8% of the participants who “remembered” having received the assessment that they were up-to-date were wrong: they had in fact received the opposite information that they were not up-to-date. This substantial proportion of wrong beliefs suggests that adult patients are unworried and overconfident about their own immunization status, which is likely to induce a passive resistance toward vaccination updating.

Conclusions:This study indicates that the vaccination coverage and beliefs of adults about their immunization status is suboptimal, and that primary care physicians need further support to improve their health-protection mandate through routine immunization check-ups. We highlight that the current covid vaccination campaigns offer a rare opportunity to update patients' immunization status and urge physicians to do so.