bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolactin Is Associated With Insulin Resistance and Beta-Cell Dysfunction in Infertile Women With Polycystic Ovary Syndrome
Authors: Yang Haiyan , Lin Jie , Li He , Liu Zhangwei , Chen Xia , Chen Qianqian
Published: February 2021

Background

Our study aimed to investigate if serum prolactin (PRL) levels associated with insulin resistance and beta-cell dysfunction in infertile patients with polycystic ovary syndrome (PCOS).

Methods

This was a retrospective cross-sectional study performed in the reproductive medicine center of the first affiliated hospital of Wenzhou Medical University. From January 2007 to August 2018, a total of 792 PCOS and 700 non-PCOS infertile women were included. All patients’ prolactin levels were in the normal range. PCOS was diagnosed according to the Rotterdam Criteria. Anthropometric parameters, blood pressure, serum prolactin levels, sex hormones, fasting lipids, fasting plasma glucose (FPG), fasting insulin (FINS) and hepatic biological parameters were measured in all subjects.

Results

Serum prolactin levels in PCOS women were significantly decreased compared with levels in non-PCOS women after adjusting for age and BMI (P < 0.05). Moreover, we found that prolactin levels were positively associated with high-density lipoprotein cholesterol (HDL-C) and negatively associated with age, BMI, waist circumference (WC), hip circumference (HC), luteinizing hormone/follicle stimulating hormone (LH/FSH), estradiol (E2), FINS, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β (HOMA-β), triglyceride (TG) and alanine aminotransferase (ALT) (P < 0.05). After adjusting for age and BMI, multiple linear regression analysis revealed that LH, LH/FSH, E2, FINS, HOMA-IR, and HOMA-β were negatively associated with serum PRL (P < 0.05).

Conclusions

Low serum PRL levels within the normal range associates with a higher incidence of insulin resistance and beta-cell dysfunction in infertile women with PCOS.
Prevalence of Obesity and Its Impact on Outcome in Patients With COVID-19: A Systematic Review and Meta-Analysis
Authors: Helvaci Nafiye , Eyupoglu Nesrin Damla , Karabulut Erdem , Yildiz Bulent Okan
Published: February 2021

Background and Objective

Obesity has been reported as a risk factor for adverse outcomes in COVID-19. However, available studies presenting data on obesity prevalence in patients with COVID-19 have conflicting results. The objective of this systematic review and meta-analysis is to evaluate the prevalence of obesity in these patients and to stratify the estimates by illness severity.

Methods

We performed a literature search with the use of Medline/PubMed and Google Scholar database from December 1, 2019 to June 27, 2020 and systematically reviewed studies reporting the number of obese patients with real-time reverse transcriptase polymerase chain reaction (rRT-PCR)-confirmed SARS-CoV-2 infection.

Results

Nineteen studies were identified. The pooled obesity prevalence rates were 0.32 (95% CI: 0.24–0.41) in hospitalized patients, 0.41 (95% CI: 0.36–0.45) in patients admitted to intensive care unit, 0.43 (95% CI: 0.36–0.51) in patients needing invasive mechanic ventilation (IMV), and 0.33 (95% CI: 0.26–0.41) in those who died. Obesity was associated with a higher risk for hospitalization [Odds ratio (OR): 1.3, 95% CI: 1.00–1.69; I2 52%, p = 0.05], ICU admission (OR: 1.51, 95% CI: 1.16–1.97; I2 72%, p = 0.002), and IMV requirement (OR: 1.77, 95% CI: 1.34–2.35; I2 0%, p < 0.001). The increase in risk of death did not reach statistical significance (OR: 1.28, 95% CI: 0.76–2.16, p = 0.35) which might be due to obesity survival paradox and/or unidentified factors.

Conclusions

Our data indicate that obese subjects may be at higher risk for serious illness if infected and obesity may play a role in the progression of COVID-19.
The Association of Myo-Inositol and Selenium Contrasts Cadmium-Induced Thyroid C Cell Hyperplasia and Hypertrophy in Mice
Authors: Benvenga Salvatore , Micali Antonio , Ieni Antonio , Antonelli Alessandro , Fallahi Poupak , Pallio Giovanni , Irrera Natasha , Squadrito Francesco , Picciolo Giacomo , Puzzolo Domenico , Minutoli Letteria
Published: February 2021

Previous studies have demonstrated that, in addition to inducing structural changes in thyroid follicles, cadmium (Cd) increased the number of C cells. We examined the effects of myo-inositol (MI), seleno-L-methionine (Se), MI + Se, and resveratrol on C cells of mice exposed to cadmium chloride (Cd Cl2), as no data are currently available on the possible protective effects of these molecules. In contrast, we have previously shown this protective effect against CdCl2 on the thyroid follicles of mice. Ninety-eight C57 BL/6J adult male mice were divided into 14 groups of seven mice each: (i) 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); (ii) Se (0.2 mg/kg/day per os); (iii) Se (0.4 mg/kg/day per os); (iv) MI (360 mg/kg/day per os); (v) Se (0.2 mg/kg/day) + MI; (vi) Se (0.4 mg/kg/day) + MI; (vii) resveratrol (20 mg/kg); (viii) CdCl2 (2 mg/kg/day i.p.) + vehicle; (ix) CdCl2 + Se (0.2 mg/kg/day); (x) CdCl2 + Se (0.4 mg/kg/day); (xi) CdCl2 + MI; (xii) CdCl2 + Se (0.2 mg/kg/day) + MI; (xiii) CdCl2 + Se (0.4 mg/kg/day) + MI; (xiv) CdCl2 + resveratrol (20 mg/kg). After 14 days, thyroids were processed for histological, immunohistochemical, and morphometric evaluation. Compared to vehicle, Cd significantly decreased follicle mean diameter, increased CT-positive cells number, area and cytoplasmic density, and caused the disappearance of TUNEL-positive C cells, namely, the disappearance of C cells undergoing apoptosis. Se at either 0.2 or 0.4 mg/kg/day failed to significantly increase follicular mean diameter, mildly decreased CT-positive cells number, area and cytoplasmic density, and was ineffective on TUNEL-positive C cells. Instead, MI alone increased significantly follicular mean diameter and TUNEL-positive cells number, and decreased significantly CT-positive cells number, area and cytoplasmic density. MI + Se 0.2 mg/kg/day or MI + Se 0.4 mg/kg/day administration improved all five indices more markedly. Indeed, follicular mean diameter and TUNEL-positive cells number increased significantly, while CT-positive cells number, area and cytoplasmic density decreased significantly. Thus, all five indices overlapped those observed in vehicle-treated mice. Resveratrol improved significantly all the considered parameters, with a magnitude comparable to that of MI alone. In conclusion, the association Myo + Se is effective in protecting the mouse thyroid from the Cd-induced hyperplasia and hypertrophy of C cells. This benefit adds to that exerted by Myo + Se on thyrocytes and testis.
Footprints of Immune Cells in the Pancreas in Type 1 Diabetes; to “B” or Not to “B”: Is That Still the Question?
Authors: Leete Pia , Morgan Noel G.
Published: February 2021

Significant progress has been made in understanding the phenotypes of circulating immune cell sub-populations in human type 1 diabetes but much less is known about the equivalent populations that infiltrate the islets to cause beta-cell loss. In particular, considerable uncertainties remain about the phenotype and role of B-lymphocytes in the pancreas. This gap in understanding reflects both the difficulty in accessing the gland to study islet inflammation during disease progression and the fact that the number and proportion of islet-associated B-lymphocytes varies significantly according to the disease endotype. In very young children (especially those <7 years at onset) pancreatic islets are infiltrated by both CD8+ T- and CD20+ B-lymphocytes in roughly equal proportions but it is widely held that the CD8+ T-lymphocytes are responsible for driving beta-cell toxicity. By contrast, the role played by B-lymphocytes remains enigmatic. This is compounded by the fact that, in older children and teenagers (those ≥13 years at diagnosis) the proportion of B-lymphocytes found in association with inflamed islets is much reduced by comparison with those who are younger at diagnosis (reflecting two endotypes of disease) whereas CD8+ T-lymphocytes form the predominant population in both groups. In the present paper, we review the current state of understanding and develop a proposal to stimulate further discussion of the roles played by islet-associated B-lymphocytes in human type 1 diabetes. We cite evidence indicating that sites of direct contact can be found between CD8+ and CD20+-lymphocytes in and around inflamed islets and propose that such interactions may be important in determining the efficiency of beta cell killing.
Impact of Long-Term Growth Hormone Replacement Therapy on Metabolic and Cardiovascular Parameters in Adult Growth Hormone Deficiency: Comparison Between Adult and Elderly Patients
Authors: Scarano Elisabetta , Riccio Enrico , Somma Teresa , Arianna Rossana , Romano Fiammetta , Di Benedetto Elea , de Alteriis Giulia , Colao Annamaria , Di Somma Carolina
Published: February 2021

Growth hormone deficiency (GHD) in adults is due to a reduced growth hormone (GH) secretion by the anterior pituitary gland which leads to a well-known syndrome characterized by decreased cognitive function and quality of life (QoL), decreased bone mineral density (BMD), increased central adiposity with a reduction in lean body mass, decreased exercise tolerance, hyperlipidemia and increased predisposition to atherogenesis. Considering some similar features between aging and GHD, it was thought that the relative GH insufficiency of the elderly person could make an important contribution to the fragility of elderly. GH stimulation tests are able to differentiate GHD in elderly patients (EGHD) from the physiological reduction of GH secretion that occurs with aging. Although there is no evidence that rhGH replacement therapy increases the risk of developing Diabetes Mellitus (DM), reducing insulin sensitivity and inducing cardiac hypertrophy, long-term monitoring is, however, also mandatory in terms of glucose metabolism and cardiovascular measurements. In our experience comparing the impact of seven years of rhGH treatment on metabolic and cardiovascular parameters in GHD patients divided in two groups [adult (AGHD) and elderly (EGHD) GHD patients], effects on body composition are evident especially in AGHD, but not in EGHD patients. The improvements in lipid profile were sustained in all groups of patients, and they had a lower prevalence of dyslipidemia than the general population. The effects on glucose metabolism were conflicting, but approximately unchanged. The risk of DM type 2 is, however, probably increased in obese GHD adults with impaired glucose homeostasis at baseline, but the prevalence of DM in GHD is like that of the general population. The increases in glucose levels, BMI, and SBP in GHD negatively affected the prevalence of Metabolic Syndrome (MS) in the long term, especially in AGHD patients. Our results are in accordance to other long-term studies in which the effects on body composition and lipid profile are prominent.
A Duty Cycle Controlled ZVS Buck Converter With Voltage Doubler Type Auxiliary Circuit
Authors: Basharat Sana , Awan Saeed Ehsan , Akhtar Rizwan , Hussain Alamdar , Iqbal Shahid , Shah Sayyar Ali , Yuan Aihua
Published: February 2021

DC–DC converters have wide applications in industries, motor drive circuits, electric vehicles, and power supplies. In traditional converters hard switching occurs due to switching losses. This imposes constraints on the converter’s efficiency which results in heat dissipation and reduction in the converter’s life. The proposed converter aims to encounter the hard switching problem with the provision of soft switching features. The presented topology is efficient with respect to the features of cost, compact size and durable lifetime of converter topology with the provision of low switching stresses. This research work proposes a novel stepdown converter with zero voltage switching characteristics. With the use of half bridge inverter switches and series resonant components in the auxiliary circuit, the target of zero voltage switching and reduction in switching stresses has been achieved. The proposed 500 W converter is designed to operate at frequency of 100 KHz with 300 V source input voltage. Output voltage of the converter is 150 V.
RETRACTED: Prospects of Bioenergy Production From Organic Waste Using Anaerobic Digestion Technology: A Mini Review
Authors: Uddin M. N. , Siddiki Sk. Yasir Arafat , Mofijur M. , Djavanroodi F. , Hazrat M. A. , Show Pau Loke , Ahmed S. F. , Chu Yu-Ming
Published: February 2021

Anaerobic digestion (AD) from organic waste has gained worldwide attention because it offers significant environmental and economic benefits. It can reduce the local waste through recycling which will conserve resources, reduce greenhouse gas emissions, and build economic resilience in the face of an uncertain future for energy production and waste disposal. The productive use of local waste through recycling conserves resources by reducing landfill space, the whole of life impacts of landfilling, and post-closure maintenance of landfills. Turning waste into a renewable energy source will assist the decarbonisation of the economy by reducing harmful emissions and pollutants. Therefore, this mini-review aims to summarise key factors and present valuable evidence for an efficient AD process. It also presents the pros and cons of different AD process to convert organic waste along with the reactor technologies. Besides, this paper highlights the challenges and the future perspective of the AD process. However, it is highlighted that for an effective and efficient AD process, appropriate temperature, pH, a strong inoculum to substrate ratio, good mixing and small particle sizes are important factors. The selection of suitable AD process and reactor is important because not all types of processes and reactors are not effective for processing organic waste. This study is of great importance for ongoing work on renewable energy generation from waste and provides important knowledge of innovative waste processing. Finally, it is recommended that the government should increase their support towards the AD technology and consider the unutilized significant potential of gaseous biofuel production.
Impacts of Global Change on the Spatial Dynamics of Treeline in Venezuelan Andes
Authors: Chacón-Moreno Eulogio , Rodríguez-Morales Mayanín , Paredes Daniela , Suárez del Moral Patricia , Albarrán Anderson
Published: February 2021

The treeline in the Andes is considered an essential ecotone between the Montane forest and Páramo. This treeline in the Venezuelan Andes corresponds with a transitional ecosystem defined as the Páramo forest. In this work, we identify and analyze the impact of climate warming and land transformation as agents altering the Páramo forest ecosystem’s spatial dynamics along the Venezuelan Andes’ altitudinal gradient. We carry out multitemporal studies of 57 years of the land transformation at different landscapes of the Cordillera de Mérida and made a detailed analysis to understand the replacement of the ecosystems potential distribution. We found that the main ecosystem transition is from Páramo to the Páramo forest and from Páramo to the Montane forest. Based on the difference between the current lower Páramo limit and the Forest upper limit for 1952, the treeline border’s displacement is 72.7 m in the 57 years of study, representing ∼12.8 m per decade. These changes are mainly driven by climate warming and are carried out through an ecological process of densification of the woody composition instead of the shrubland structure. We found that Páramo forest ecosystems practically have been replaced by the Pastures and fallow vegetation, and the Crops. We present a synthesis of the transition and displacement of the different ecosystems and vegetation types in the treeline zone. The impact of climate warming and deforestation on the Páramo forest as a representative ecosystem of the treeline shows us that this study is necessary for an integrated global change adaptation plan.
Visual Depictions of Our Evolutionary Past: A Broad Case Study Concerning the Need for Quantitative Methods of Soft Tissue Reconstruction and Art-Science Collaborations
Authors: Campbell Ryan M. , Vinas Gabriel , Henneberg Maciej , Diogo Rui
Published: February 2021

Flip through scientific textbooks illustrating ideas about human evolution or visit any number of museums of natural history and you will notice an abundance of reconstructions attempting to depict the appearance of ancient hominins. Spend some time comparing reconstructions of the same specimen and notice an obvious fact: hominin reconstructions vary in appearance considerably. In this review, we summarize existing methods of reconstruction to analyze this variability. It is argued that variability between hominin reconstructions is likely the result of unreliable reconstruction methods and misinterpretation of available evidence. We also discuss the risk of disseminating erroneous ideas about human evolution through the use of unscientific reconstructions in museums and publications. The role an artist plays is also analyzed and criticized given how the aforementioned reconstructions have become readily accepted to line the halls of even the most trusted institutions. In conclusion, improved reconstruction methods hold promise for the prediction of hominin soft tissues, as well as for disseminating current scientific understandings of human evolution in the future.
Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder
Authors: Krämer Johannes , Beer Meinrad , Bode Harald , Winter Benedikt
Published: February 2021

Introduction

Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in development. Among 43 reported cases with mutations in TRAPPC9, all (100%) showed ID and developmental delay. Among the cases including information about ASD, 26% were affected (19 cases with information, among them 5 with ASD). Nevertheless, in some cases not classified as ASD, descriptions of autistic features like hand-flapping movements were present.

Clinical Findings

The affected individual presented with delay of speech development. Physical development was normal. Besides lateral slope of the eye-lid axis no facial abnormalities were evident. The individual was diagnosed with ID and ASD by structured testing. Cerebral MRI revealed associated abnormalities.

Genetical Findings

The chromosome set was 46,XY without structural changes. Array-CGH showed a normal molecular karyotype (arr(1-22)x2,(X,Y)x1). PCR for the FMR1 gene showed 41 ± 1 CGG repeats, and therefore no evidence of fragile X syndrome. A panel diagnostic for syndromal ID (CASK, EP300, HIVEP2, KIF1A, TRAPPC9) revealed two structural changes in TRAPPC9 in the compound heterozygosity. The mutations c.1678C > T (p.Arg560Cys) and c.3370C > T (p.Pro1124Ser) are classified as missense mutations and are both not described in the literature.

Conclusion

We report two new missense mutations in the TRAPPC9 gene in one individual with ID and ASD. The TRAPPC9 gene should be part of the diagnostic assessment in ID. ASD must be considered as a feature of TRAPPC9-associated ID. It might have been neglected in the literature and should result in specific testing for ASD in affected individuals.
Identification of High-Confidence Structural Variants in Domesticated Rainbow Trout Using Whole-Genome Sequencing
Authors: Liu Sixin , Gao Guangtu , Layer Ryan M. , Thorgaard Gary H. , Wiens Gregory D. , Leeds Timothy D. , Martin Kyle E. , Palti Yniv
Published: February 2021

Genomic structural variants (SVs) are a major source of genetic and phenotypic variation but have not been investigated systematically in rainbow trout (Oncorhynchus mykiss), an important aquaculture species of cold freshwater. The objectives of this study were 1) to identify and validate high-confidence SVs in rainbow trout using whole-genome re-sequencing; and 2) to examine the contribution of transposable elements (TEs) to SVs in rainbow trout. A total of 96 rainbow trout, including 11 homozygous lines and 85 outbred fish from three breeding populations, were whole-genome sequenced with an average genome coverage of 17.2×. Putative SVs were identified using the program Smoove which integrates LUMPY and other associated tools into one package. After rigorous filtering, 13,863 high-confidence SVs were identified. Pacific Biosciences long-reads of Arlee, one of the homozygous lines used for SV detection, validated 98% (3,948 of 4,030) of the high-confidence SVs identified in the Arlee homozygous line. Based on principal component analysis, the 85 outbred fish clustered into three groups consistent with their populations of origin, further indicating that the high-confidence SVs identified in this study are robust. The repetitive DNA content of the high-confidence SV sequences was 86.5%, which is much higher than the 57.1% repetitive DNA content of the reference genome, and is also higher than the repetitive DNA content of Atlantic salmon SVs reported previously. TEs thus contribute substantially to SVs in rainbow trout as TEs make up the majority of repetitive sequences. Hundreds of the high-confidence SVs were annotated as exon-loss or gene-fusion variants, and may have phenotypic effects. The high-confidence SVs reported in this study provide a foundation for further rainbow trout SV studies.
Renal Involvement and HBV Infection Are Common in Chinese Patients With Cryoglobulinemia
Authors: Bai Wei , Zhang Lixia , Zhao Jiuliang , Zhang Shangzhu , Zhou Jiaxin , Leng Xiaomei , Liu Zhengyin , Ye Wenling , Han Bing , Tian Xinping , Li Mengtao , Zhao Yan , Zeng Xiaofeng
Published: February 2021

Objectives: This study aimed to describe the main characteristics of Chinese patients with cryoglobulinemia, especially the characteristics of patients with different causes of cryoglobulinemia.

Methods: Eighty inpatients diagnosed with cryoglobulinemia from different wards in Peking Union Medical College Hospital were included in this study. Demographic, clinical, biological, and renal pathological data were collected. We analyzed the characteristics of 61 patients with different causes of cryoglobulinemia.

Results: Most patients (36/80, 45%) were diagnosed between 40 and 60 years of age. The male: female ratio was 1:1.5. Mixed (II + III) cryoglobulinemia accounted for the majority (43.8%) of cases. Renal involvement (87.5%), cutaneous involvement (57.5%), and fever (27.5%) were the most common clinical manifestations, while other manifestations included serositis and pulmonary and gastrointestinal involvement. The most common renal histopathological pattern was membranoproliferative glomerulonephritis (25/42, 59.5%). The secondary causes of cryoglobulinemia included infectious diseases (26/61, 32.5%), such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and connective tissue diseases (22/61, 27.5%), such as lupus and hematologic tumors (13/61, 16.3%). Patients with hematologic tumors were diagnosed at an older age (P = 0.044) and mostly had type I cryoglobulinemia (P < 0.001). No significant difference in clinical or biological manifestations was found among patients with different causes of cryoglobulinemia.

Conclusions: This is the largest cohort of Chinese patients with cryoglobulinemia. We found that renal involvement and HBV infection might be more common in Chinese patients with cryoglobulinemia.
Association of PTPN22-C1858T Polymorphism With Susceptibility to Mycobacterium tuberculosis and Mycobacterium leprae Infection: A Meta-Analysis
Authors: Li Shuping , Wang Xiaohua , Zhao Yuming , Yang Juan , Cui Tianjiao , Zhao Zhizhuang Joe , Chen Yun , Zheng Zhihua
Published: February 2021

It was previously published that single-nucleotide polymorphism rs2476601 (PTPN22 [protein tyrosine phosphatase non-receptor type 22]-C1858T) might be related to increased sensibility to Mycobacterium tuberculosis and M. leprae infection. However, the results were inconclusive despite a high degree of similarity between both parameters. Herein, we carried out this meta-analysis to systematically summarize and articulate the correlation between PTPN22-C1858T polymorphism and mycobacterial infection. The susceptibility of PTPN22-C1858T carriers with autoimmune conditions receiving immunosuppressive therapy to M. tuberculosis and M. leprae infection was determined. A systematic retrieval of studies on relevance of PTPN22-C1858T polymorphism to susceptibility of M. tuberculosis or M. leprae infection was performed in Chinese National Knowledge Infrastructure, PubMed and Embase databases. We regarded Odds ratios (ORs) and 95% confidence intervals (CIs) as the determined effect size. Finally, four and two case-control studies on tuberculosis and leprosy, respectively, were included. In all genetic models, without indicated association between PTPN22-C1858T polymorphism and tuberculosis’s susceptibility. [C versus T: OR = 0.22 (95% CI: 0.09–0.50, PH = 0.887); CT versus CC: OR = 0.21 (95% CI: 0.09–0.49, PH = 0.889); TT+CT versus CC: OR = 0.21 (95% CI: 0.09–0.49, PH = 0.889)]. A significantly increased risk of leprosy was perceived in patients with the PTPN22-C1858T polymorphism [C versus T: OR = 2.82 (95% CI: 1.02–7.81, PH = 0.108)]. While the PTPN22-C1858T polymorphism is irrelevant to higher susceptibility to the infection of M. tuberculosis in Caucasians and Asians, it is relevant to increased susceptibility to the infection of M. leprae. However, the results of M. leprae are supposed to interpreted with prudence owing to the limited quantity of studies and heterogeneity. Further well-designed studies with sufficient populations are required to verify our conclusions.
A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population
Authors: Zhang Yue-miao , Liu Xing-zi , Zhou Xu-jie , Liu Li-jun , Shi Su-fang , Hou Ping , Lv Ji-cheng , Zhang Hong
Published: February 2021

C-C chemokine receptor 6 (CCR6) is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN). In this study, we aimed to identify the functional variants. First, we analyzed the associations ofCCR6common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region. Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15,P= 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P= 1.45 × 10−3). It was independently replicated (rs3093023-A, OR = 1.18,P= 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17,P= 6.14 × 10−7). Although rs3093023 was in a strong linkage disequilibrium with the reportedCCR6functional variant dinucleotide polymorphism,CCR6DNP, the alleles of rs3093023 (G>A) rather than ofCCR6DNPwere shown differential nuclear protein binding effect by electrophoretic mobility shift assay. The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated withCCR6mRNA (r= −0.60,P= 3.94 × 10−9). At the mRNA level, the eQTL effect ofCCR6was validated (P= 4.39 × 10−2), andCCR6was positively associated with the expression ofCCR4andIL-17Arather than that ofCXCR3andIFNG. At the protein level, a higher CCR6+cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P= 3.57 × 10−2), CD3+T cells (P= 4.54 × 10−2), and CD4+T cells (P= 1.32 × 10−2), but not in CD8+T cells. Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis. Overall, the rs3093023 was prioritized as the function variant inCCR6, which may contribute to IgAN susceptibility by regulating Th17 cells.
The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw
Authors: Zhang Weidong , Gao Ling , Ren Wenhao , Li Shaoming , Zheng Jingjing , Li Shasha , Jiang Chunmiao , Yang Shuying , Zhi Keqian
Published: February 2021

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug effect. There are multiple hypotheses to explain the development of MRONJ. Reduced bone remodeling and infection or inflammation are considered central to the pathogenesis of MRONJ. In recent years, increasing evidence has shown that bisphosphonates (BPs)-mediated immunity dysfunction is associated with the pathophysiology of MRONJ. In a healthy state, mucosal immunity provides the first line of protection against pathogens and oral mucosal immune cells defense against potentially invading pathogens by mediating the generation of protective immunoinflammatory responses. In addition, the immune system takes part in the process of bone remodeling and tissue repair. However, the treatment of BPs disturbs the mucosal and osteo immune homeostasis and thus impairs the body's ability to resist infection and repair from injury, thereby adding to the development of MRONJ. Here, we present the current knowledge about immunity dysfunction to shed light on the role of local immune disorder in the development of MRONJ.
Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1
Authors: Renrick Ariana N. , Thounaojam Menaka C. , de Aquino Maria Teresa P. , Chaudhuri Evan , Pandhare Jui , Dash Chandravanu , Shanker Anil
Published: February 2021

Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor–bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8+T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8+T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib–induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8+T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1+phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155–dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1–mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib–mediated lymphocyte–stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment.
Clusterin and Its Role in Insulin Resistance and the Cardiometabolic Syndrome
Authors: Wittwer Jennifer , Bradley David
Published: February 2021

The cardiometabolic syndrome involves a clustering of metabolic and cardiovascular factors which increase the risk of patients developing both Type 2 Diabetes Mellitus and cardio/cerebrovascular disease. Although the mechanistic underpinnings of this link remain uncertain, key factors include insulin resistance, excess visceral adiposity, atherogenic dyslipidemia, and endothelial dysfunction. Of these, a state of resistance to insulin action in overweight/obese patients appears to be central to the pathophysiologic process. Given the increasing prevalence of obesity-related Type 2 Diabetes, coupled with the fact that cardiovascular disease is the number one cause of mortality in this patient population, a more thorough understanding of the cardiometabolic syndrome and potential options to mitigate its risk is imperative. Inherent in the pathogenesis of insulin resistance is an underlying state of chronic inflammation, at least partly in response to excess adiposity. Within obese adipose tissue, an immunomodulatory shift occurs, involving a preponderance of pro-inflammatory immune cells and cytokines/adipokines, along with antigen presentation by adipocytes. Therefore, various adipokines differentially expressed by obese adipocytes may have a significant effect on cardiometabolism. Clusterin is a molecular chaperone that is widely produced by many tissues throughout the body, but is also preferentially overexpressed by obese compared lean adipocytes and relates strongly to multiple components of the cardiometabolic syndrome. Herein, we summarize the known and potential roles of circulating and adipocyte-specific clusterin in cardiometabolism and discuss potential further investigations to determine if clusterin is a viable target to attenuate both metabolic and cardiovascular disease.
Berberine Prolongs Mouse Heart Allograft Survival by Activating T Cell Apoptosis via the Mitochondrial Pathway
Authors: Ma Yunhan , Yan Guoliang , Guo Junjun , Li Fujun , Zheng Haiping , Wang Chenxi , Chen Yingyu , Ye Yuhan , Dai Helong , Qi Zhongquan , Zhuang Guohong
Published: February 2021

Berberine, which is a traditional Chinese medicine can inhibit tumorigenesis by inducing tumor cell apoptosis. However, the immunoregulatory of effects berberine on T cells remains poorly understood. Here, we first examined whether berberine can prolong allograft survival by regulating the recruitment and function of T cells. Using a major histocompatibility complex complete mismatch mouse heterotopic cardiac transplantation model, we found that the administration of moderate doses (5 mg/kg) of berberine significantly prolonged heart allograft survival to 19 days and elicited no obvious berberine-related toxicity. Compared to that with normal saline treatment, berberine treatment decreased alloreactive T cells in recipient splenocytes and lymph node cells. It also inhibited the activation, proliferation, and function of alloreactive T cells. Most importantly, berberine treatment protected myocardial cells by decreasing CD4+and CD8+T cell infiltration and by inhibiting T cell function in allografts.In vivoandin vitroassays revealed that berberine treatment eliminated alloreactive T lymphocytesviathe mitochondrial apoptosis pathway, which was validated by transcriptome sequencing. Taken together, we demonstrated that berberine prolongs allograft survival by inducing apoptosis of alloreactive T cells. Thus, our study provides more evidence supporting the potential use of berberine in translational medicine.
Multi-Source Pathways of T Follicular Helper Cell Differentiation
Authors: Ma Xiaoxue , Nakayamada Shingo , Wang Jun
Published: February 2021

T follicular helper (Tfh) cells participate in humoral immune by promoting inflammation and aiding B cells survival, proliferation, maturation, and generation autoantibodies. The plasticity of Tfh cells enables the immune system to adjust the direction of differentiation according to the degree of the immune response, regulate the germinal center (GC) response and maintain homeostasis. Tfh differentiation involves several signaling factors, including multiple cytokines, receptors, transcription factors and genes. The signal transducer and activator of transcription (STAT) family signaling pathways are crucial for Tfh formation. However, because of the multi-factorial and multi-stage features of Tfh differentiation, every STAT member plays a role in Tfh differentiation, but is not completely depended on. With the gradual recognition of different Tfh subsets (Tfh1, Tfh2, Tfh17), the process of Tfh differentiation can no longer be explained by straight-line derivation models. In this review, we summarize the roles of different STATs in mediating Tfh subsets, analyze the contributions of mutual restraint and cooperation among cytokine-STAT signals to terminal Tfh differentiation, and clarify the multi-source pathways of Tfh differentiation with a three-dimensional illustration.
Major Role of the IL17/23 Axis in Psoriasis Supports the Development of New Targeted Therapies
Authors: Bugaut Hélène , Aractingi Sélim
Published: February 2021

Psoriasis is a frequent, chronic disease characterized by cutaneous inflammatory plaques and/or arthritis. It may be associated with few other diseases, mainly Crohn’s disease and metabolic syndrome. The medical and psychosocial burden of psoriasis remains high even since biological treatments arose, stressing that efforts to decipher its physiopathology are constantly needed. Tumor-necrosis factor α, interleukin (IL) 12 and IL17 have been previously associated with psoriasis and successfully targeted by monoclonal antibodies. IL17 in particular has been initially described as a T helper (Th) 17—produced cytokine, but it is now established that other cell types, such as γδ T lymphocytes, Mucosal-Associated Invariant T (MAIT) cells and Innate Lymphoïd Cells (ILC) 3 are also important sources of IL17 in the skin in response to inflammatory stimuli. Th17 phenotype has been shown to be stabilized by IL23, which is synthetized by macrophages and dendritic cells in response to Toll Like Receptors and C-type Lectin Receptors stimulation. Recent data also reported a crucial role for IL23 in MAIT17 and ILC3 homeostasis. Genome-wide association studies have found a significant link between IL23 receptor polymorphism and psoriasis susceptibility. IL23 signals through Janus kinase 2 and Tyrosine kinase 2, against which specific inhibitors are currently being tested. Monoclonal antibodies against IL17 and IL23 are only the beginning of a new avenue in psoriasis treatment. This review focuses on the molecular basis underlying IL23/IL17 axis blockade in psoriasis, and on future targets in this pathway.
Biomarkers for Chimeric Antigen Receptor T Cell Therapy in Acute Lymphoblastic Leukemia: Prospects for Personalized Management and Prognostic Prediction
Authors: Hong Ruimin , Hu Yongxian , Huang He
Published: February 2021

Chimeric antigen receptor (CAR) T cell therapy represents a breakthrough in immunotherapy with the potential of ushering in a new era in cancer treatment. Remarkable therapeutic response and complete remission of this innovative management have been observed in patients with relapse/refractory acute lymphoblastic leukemia. With CAR-T cell therapy becoming widely used both in multicenter clinical trials and as a commercial treatment, therapeutic efficacy monitoring and management of toxicities will be indispensable for ensuring safety and improving overall survival. Biomarkers can act not only as effective indicators reflecting patients’ baseline characteristics, CAR-T cell potency, and the immune microenvironment, but can also assess side effects during treatment. In this review, we will elaborate on a series of biomarkers associated with therapeutic response as well as treatment-related toxicities, and present their current condition and latent value with respect to the clinical utility. The combination of biomarker research and CAR-T cell therapy will contribute to establishing a safer and more powerful monitoring system and prolonging the event-free survival of patients.
Current Understanding of Circular RNAs in Systemic Lupus Erythematosus
Authors: Liu Hongjiang , Zou Yundong , Chen Chen , Tang Yundi , Guo Jianping
Published: February 2021

Systemic lupus erythematosus (SLE) is a common and potentially fatal autoimmune disease that affects multiple organs. To date, its etiology and pathogenesis remains elusive. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs with covalently closed loop structure. Growing evidence has demonstrated that circRNAs may play an essential role in regulation of gene expression and transcription by acting as microRNA (miRNA) sponges, impacting cell survival and proliferation by interacting with RNA binding proteins (RBPs), and strengthening mRNA stability by forming RNA-protein complexes duplex structures. The expression patterns of circRNAs exhibit tissue-specific and pathogenesis-related manner. CircRNAs have implicated in the development of multiple autoimmune diseases, including SLE. In this review, we summarize the characteristics, biogenesis, and potential functions of circRNAs, its impact on immune responses and highlight current understanding of circRNAs in the pathogenesis of SLE.
The Crucial Role of PPARγ-Egr-1-Pro-Inflammatory Mediators Axis in IgG Immune Complex-Induced Acute Lung Injury
Authors: Yan Chunguang , Chen Jing , Ding Yue , Zhou Zetian , Li Bingyu , Deng Chunmin , Yuan Dong , Zhang Qi , Wang Ximo
Published: February 2021

Background

The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. However, during IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown.

Objectives

The study is designed to determine the effect of PPARγ on IgG-IC-triggered acute lung inflammation, and the underlying mechanisms, which might provide theoretical basis for therapy of acute lung inflammation.

Setting

Department of Pathogenic Biology and Immunology, Medical School of Southeast University

Subjects

Mice with down-regulated/up-regulated PPARγ activity or down-regulation of Early growth response protein 1 (Egr-1) expression, and the corresponding controls.

Interventions

Acute lung inflammation is induced in the mice by airway deposition of IgG-IC. Activation of PPARγ is achieved by using its agonist Rosiglitazone or adenoviral vectors that could mediate overexpression of PPARγ. PPARγ activity is suppressed by application of its antagonist GW9662 or shRNA. Egr-1 expression is down-regulated by using the gene specific shRNA.

Measures and Main Results

We find that during IgG-IC-induced acute lung inflammation, PPARγ expression at both RNA and protein levels is repressed, which is consistent with the results obtained from macrophages treated with IgG-IC. Furthermore, both in vivo and in vitro data show that PPARγ activation reduces IgG-IC-mediated pro-inflammatory mediators’ production, thereby alleviating lung injury. In terms of mechanism, we observe that the generation of Egr-1 elicited by IgG-IC is inhibited by PPARγ. As an important transcription factor, Egr-1 transcription is substantially increased by IgG-IC in both in vivo and in vitro studies, leading to augmented protein expression, thus amplifying IgG-IC-triggered expressions of inflammatory factors via association with their promoters.

Conclusion

During IgG-IC-stimulated acute lung inflammation, PPARγ activation can relieve the inflammatory response by suppressing the expression of its downstream target Egr-1 that directly binds to the promoter regions of several inflammation-associated genes. Therefore, regulation of PPARγ-Egr-1-pro-inflammatory mediators axis by PPARγ agonist Rosiglitazone may represent a novel strategy for blockade of acute lung injury.
Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance
Authors: Xu Ling , Li Yanhong , Sang Yifei , Li Da-Jin , Du Meirong
Published: February 2021

The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal–fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell–cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts–DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal–fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal–fetal immune tolerance mediated by trophoblasts–DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.
Reflections on the Use of an Invertebrate Chordate Model System for Studies of Gut Microbial Immune Interactions
Authors: Liberti Assunta , Natarajan Ojas , Atkinson Celine Grace F. , Sordino Paolo , Dishaw Larry J.
Published: February 2021

The functional ecology of the gastrointestinal tract impacts host physiology, and its dysregulation is at the center of various diseases. The immune system, and specifically innate immunity, plays a fundamental role in modulating the interface of host and microbes in the gut. While humans remain a primary focus of research in this field, the use of diverse model systems help inform us of the fundamental principles legislating homeostasis in the gut. Invertebrates, which lack vertebrate-style adaptive immunity, can help define conserved features of innate immunity that shape the gut ecosystem. In this context, we previously proposed the use of a marine invertebrate, the protochordate Ciona robusta, as a novel tractable model system for studies of host-microbiome interactions. Significant progress, reviewed herein, has been made to fulfill that vision. We examine and review discoveries from Ciona that include roles for a secreted immune effector interacting with elements of the microbiota, as well as chitin-rich mucus lining the gut epithelium, the gut-associated microbiome of adults, and the establishment of a large catalog of cultured isolates with which juveniles can be colonized. Also discussed is the establishment of methods to rear the animals germ-free, an essential technology for dissecting the symbiotic interactions at play. As the foundation is now set to extend these studies into the future, broadening our comprehension of how host effectors shape the ecology of these microbial communities in ways that establish and maintain homeostasis will require full utilization of “multi-omics” approaches to merge computational sciences, modeling, and experimental biology in hypothesis-driven investigations.