bluuebunny/crossref_metadata_2025 huggingface dataset:
Remifentanil Promotes PDIA3 Expression by Activating p38MAPK to Inhibit Intestinal Ischemia/Reperfusion-Induced Oxidative and Endoplasmic Reticulum Stress
Authors: Shen Jiantong , Zhan Yaqing , He Qiulan , Deng Qiwen , Li Kunhe , Wen Shihong , Huang Wenqi
Published: January 2022

Background: Remifentanil protects against intestinal ischemia/reperfusion (I/R) injury; however, its exact mechanism remains to be elucidated. The objective of this study was to investigate the underlying molecular mechanism of remifentanil in intestinal I/R injury in mice.

Methods: We evaluated the intestine-protective effect of remifentanil in adult male mice with 45 min superior mesenteric artery occlusion followed by 4 h reperfusion by determining the following: intestinal Chiu’s scores, diamine oxidase, and intestinal fatty acid binding protein in serum; the apoptotic index, lipid peroxidation product malondialdehyde (MDA), and superoxide dismutase (SOD) activity in the intestinal mucosa; and the intestinal mRNA and protein expressions of Bip, CHOP, caspase-12, and cleaved caspase-3, reflecting endoplasmic reticulum (ER) stress. Furthermore, conditional knockout mice, in which the protein disulfide isomerase A3 (PDIA3) gene was deleted from the intestinal epithelium, and SB203580 (a selective p38MAPK inhibitor) were used to determine the role of PDIA3 and p38MAPK in I/R progression and intestinal protection by remifentanil.

Results: Our data showed that intestinal I/R induced obvious oxidative stress and endoplasmic reticulum stress–related cell apoptosis, as evidenced by an increase in the intestinal mucosal malondialdehyde, a decrease in the intestinal mucosal SOD, and an increase in the apoptotic index and the mRNA and protein expression of Bip, CHOP, caspase-12, and cleaved caspase-3. Remifentanil significantly improved these changes. Moreover, the deletion of intestinal epithelium PDIA3 blocked the protective effects of remifentanil. SB203580 also abolished the intestinal protection of remifentanil and downregulated the mRNA and protein expression of PDIA3.

Conclusion: Remifentanil appears to act via p38MAPK to protect the small intestine from intestinal I/R injury by its PDIA3-mediated antioxidant and anti-ER stress properties.
Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma
Authors: Zhang Shichao , Xiong Yu , Zheng Chaochao , Long Jinhua , Zhou Houming , Zeng Zhu , Ouyang Yan , Tang Fuzhou
Published: January 2022

The “writers” of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification “writers” in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification “writer” scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these “writers” essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.
The Effect of Ticagrelor on Endothelial Function Compared to Prasugrel, Clopidogrel, and Placebo: A Systematic Review and Meta-Analysis
Authors: Guan Baoyi , Zhao Lin , Ma Dan , Fan Yixuan , Zhang He , Wang Anlu , Xu Hao
Published: January 2022

Background/Objective

Endothelial dysfunction is associated with the long-term outcomes in patients with coronary artery disease (CAD). Recent evidence suggests that ticagrelor, a potent antiplatelet agent, improves endothelial function. However, several studies demonstrated contrasting results. The objective of this meta-analysis was to determine the efficacy of ticagrelor treatment on endothelial function.

Materials and Methods

A systematic literature study was conducted on databases including PubMed, Web of Science, EMBASE, Scopus, and the Cochrane Library. A historical search was performed for a reference list of the selected studies as of August 2021. The randomized controlled trials (RCTs) were assessed using the Cochrane tool. The weighted mean difference (WMD) 95% CI was treated as the overall effect size, and data were pooled using the fixed-effect model or random-effect model according to the heterogeneity. Subgroup and sensitivity analyses were performed to measure the effects of potential confounders.

Results

A total of 21 studies were included. The meta-analysis indicated that ticagrelor resulted in a significant increase of flow-mediated dilation (FMD) (WMD: 1.48; 95% CI: 0.36, 2.60), reactive hyperemia index (RHI) (WMD: 0.06; 95% CI: 0.00, 0.13), and circulating progenitor endothelial cells (CEPCs) (WMD: 13.84; 95% CI: 5.70, 21.98), and a reduction in the index of microvascular resistance (IMR) (WMD: −15.39; 95% CI: −25.11, −5.68).

Conclusion

Ticagrelor has a significant effect on some markers of endothelial function in patients with CAD. However, the results should be interpreted with caution due to the heterogeneity and limited studies.
Effect of Thermoelastic Properties of the Pyrope-Almandine Solid Solutions on the Entrapment Pressure of Garnet-Related Elastic Geobarometer
Authors: Li Bo , Jiang Junjie , Xu Jingui , Tkachev Sergey N. , Ye Zhilin , Huang Shijie , Guo Weihua , Zeng Yongjun , Prakapenka Vitali B. , Fan Dawei , Zhou Wenge
Published: January 2022

The pyrope (Prp)–almandine (Alm) solid solutions are the most fundamental garnet components on the Earth, and both the quartz inclusions in garnet (QuiG) barometry and the garnet inclusions in diamond barometry need to be constrained by the thermoelastic parameters of Prp-Alm solid solution garnets. Here, we report the thermoelastic properties of a series of synthetic Prp-Alm solid solutions based on the high-pressure and high-temperature (HP–HT)in situsynchrotron single-crystal x-ray diffraction (SCXRD) experiments up to ∼20 GPa and 700 K, using diamond anvil cell (DAC). Fitting the SCXRD data by the Birch-Murnaghan equation of state (BM-EoS) and the thermal-pressure EoS, we obtain the thermoelastic parameters of Prp-Alm solid solution garnets, including bulk modulus (K0), its pressure derivative (K′0), and the thermal expansion coefficient (α0). TheK0along the Prp-Alm solid solution changes linearly with Prp content within their uncertainties and can be expressed byK0(GPa) = 181.0(8) – 0.11(1)Xprp(R2= 0.91,Xprpis the Prp mole fraction andK′0fixed at 4). Our result indicates that the compressibility of the Prp-Alm solid solution increases with the increasing Prp content. However, the thermal expansion coefficient of Prp-Alm solid solution at ambient pressure shows a non-linear trend with Prp content and can be expressed byα0(10−5K−1) = 2.7 (1) + 3.0 (5)XPrp−3.2 (4)X2Prp(R2= 0.985). It shows that the Prp-Alm solid solution with intermediate composition has a larger thermal expansion coefficient than those close to the endmembers at ambient conditions. Furthermore, we also evaluated the influence of thermoelastic properties of the Prp-Alm solid solution on the entrapment pressure (Pe) estimation for two types of elastic geobarometers. Our results indicate that the garnet component may significantly influence entrapment pressure, and among the thermoelastic parameters of garnet, the thermal expansion coefficient has the main effect on the estimation ofPe.
The Efficacy of Alendronate Versus Denosumab on Major Osteoporotic Fracture Risk in Elderly Patients With Diabetes Mellitus: A Danish Retrospective Cohort Study
Authors: Viggers Rikke , Al-Mashhadi Zheer , Starup-Linde Jakob , Vestergaard Peter
Published: January 2022

Objective

Patients with diabetes mellitus have an increased risk of fractures; however, the underlying mechanism is largely unknown. We aimed to investigate whether the risk of major osteoporotic fractures in diabetes patients differs between subjects initiated with alendronate and denosumab, respectively.

Methods and Research Design

We conducted a retrospective nationwide cohort study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. We identified all subjects with a diabetes diagnosis between 2000 and 2018 and collected data on the first new prescription of anti-osteoporotic treatment between 2011 and 2018. Exposure was defined as either alendronate or denosumab treatment initiated after diabetes diagnosis. Outcome information was collected by identification of all major osteoporotic fracture (MOF) diagnoses, i.e., hip, spine, forearm, and humerus, from exposure until 2018 or censoring by emigration or death. The risk of fracture was calculated as hazard ratios (HR) using multiply adjusted Cox proportional models with death as a competing risk.

Results

We included 8,745 subjects initiated with either alendronate (n = 8,255) or denosumab (n = 490). The cohort consisted of subjects with a mean age of 73.62 (SD ± 9.27) years, primarily females (69%) and suffering mainly from type 2 diabetes (98.22%) with a median diabetes duration at baseline of 5.45 years (IQR 2.41–9.19). Those in the denosumab group were older (mean 75.60 [SD ± 9.72] versus 73.51 [SD ± 9.23] years), had a higher proportion of women (81% versus 68%, RR 1.18 [95% CI 1.13–1.24], and were more comorbid (mean CCI 2.68 [95% CI 2.47–2.88] versus 1.98 [95% CI 1.93–2.02]) compared to alendronate initiators. In addition, denosumab users had a higher prevalence of previous fractures (64% versus 46%, RR 1.38 [95% CI 1.28–1.48]). The adjusted HR for any MOF after treatment initiation with denosumab was 0.89 (95% CI 0.78–1.02) compared to initiation with alendronate.

Conclusion

The risk of incident MOF among subjects with diabetes was similar between those initially treated with alendronate and denosumab. These findings indicate that the two treatment strategies are equally effective in preventing osteoporotic fractures in subjects with diabetes.
Single-Cell RNA Sequencing Atlas From a Bivalve Larva Enhances Classical Cell Lineage Studies
Authors: Salamanca-Díaz David A. , Schulreich Stephan M. , Cole Alison G. , Wanninger Andreas
Published: January 2022

Ciliated trochophore-type larvae are widespread among protostome animals with spiral cleavage. The respective phyla are often united into the superclade Spiralia or Lophotrochozoa that includes, for example, mollusks, annelids, and platyhelminths. Mollusks (bivalves, gastropods, cephalopods, polyplacophorans, and their kin) in particular are known for their morphological innovations and lineage-specific plasticity of homologous characters (e.g., radula, shell, foot, neuromuscular systems), raising questions concerning the cell types and the molecular toolkit that underlie this variation. Here, we report on the gene expression profile of individual cells of the trochophore larva of the invasive freshwater bivalve Dreissena rostriformis as inferred from single cell RNA sequencing. We generated transcriptomes of 632 individual cells and identified seven transcriptionally distinct cell populations. Developmental trajectory analyses identify cell populations that, for example, share an ectodermal origin such as the nervous system, the shell field, and the prototroch. To annotate these cell populations, we examined ontology terms from the gene sets that characterize each individual cluster. These were compared to gene expression data previously reported from other lophotrochozoans. Genes expected to be specific to certain tissues, such as Hox1 (in the shell field), Caveolin (in prototrochal cells), or FoxJ (in other cillia-bearing cells) provide evidence that the recovered cell populations contribute to various distinct tissues and organs known from morphological studies. This dataset provides the first molecular atlas of gene expression underlying bivalve organogenesis and generates an important framework for future comparative studies into cell and tissue type development in Mollusca and Metazoa as a whole.
Regional Patterns of Late Medieval and Early Modern European Building Activity Revealed by Felling Dates
Authors: Ljungqvist Fredrik Charpentier , Seim Andrea , Tegel Willy , Krusic Paul J. , Baittinger Claudia , Belingard Christelle , Bernabei Mauro , Bonde Niels , Borghaerts Paul , Couturier Yann , Crone Anne , van Daalen Sjoerd , Daly Aoife , Doeve Petra , Domínguez-Delmás Marta , Edouard Jean-Louis , Frank Thomas , Ginzler Christian , Grabner Michael , Gschwind Friederike M. , Haneca Kristof , Hansson Anton , Herzig Franz , Heussner Karl-Uwe , Hofmann Jutta , Houbrechts David , Kaczka Ryszard J. , Kolář Tomáš , Kontic Raymond , Kyncl Tomáš , Labbas Vincent , Lagerås Per , Le Digol Yannick , Le Roy Melaine , Leuschner Hanns Hubert , Linderson Hans , Ludlow Francis , Marais Axel , Mills Coralie M. , Neyses-Eiden Mechthild , Nicolussi Kurt , Perrault Christophe , Pfeifer Klaus , Rybníček Michal , Rzepecki Andreas , Schmidhalter Martin , Seifert Mathias , Shindo Lisa , Spyt Barbara , Susperregi Josué , Svarva Helene Løvstrand , Thun Terje , Walder Felix , Ważny Tomasz , Werthe Elise , Westphal Thorsten , Wilson Rob , Büntgen Ulf
Published: January 2022

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europec. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.
Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment
Authors: Xie Jieqiong , Jiang Jiayang , Guo Qiwei
Published: January 2022

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.
BGN May be a Potential Prognostic Biomarker and Associated With Immune Cell Enrichment of Gastric Cancer
Authors: Zhang Shiyu , Yang Huiying , Xiang Xuelian , Liu Li , Huang Huali , Tang Guodu
Published: January 2022

Background: Biglycan (BGN) plays a role in the occurrence and progression of several malignant tumors, though its role in gastric cancer (GC) remains unclear. The objective of this study was to investigate BGN expression, its role in GC prognosis, and immune infiltration.

Material and Methods: Gene expression data and corresponding clinical information were downloaded from TCGA and GTEx, respectively. We compared the expression of BGN in GC and normal tissues and verified the differential expression via Real-Time PCR and immunohistochemistry. BGN-related differentially expressed genes (DEGs) were identified. Additionally, the relationships between BGN gene expression and clinicopathological variables and survival in patients with GC were also investigated through univariate and multivariate Cox regression analyses. Finally, we established a predictive model that could well predict the probability of 1-, 3-, and 5-years survival in GC.

Results: We found a significantly higher expression of BGN in GC than that in normal tissues (p < 0.001), which was verified by Real-Time PCR (p < 0.01) and immunohistochemistry (p < 0.001). The 492 identified DEGs were primarily enriched in pathways related to tumor genesis and metastasis, including extracellular matrix (ECM)-receptor interaction, focal adhesion pathway, Wnt signaling, and signaling by VEGF. BGN expression was positively correlated with the enrichment of the NK cells (r = 0.620, p < 0.001) and macrophages (r = 0.550, p < 0.001), but negatively correlated with the enrichment of Th17 cells (r = 0.250, p < 0.001). BGN expression was also significantly correlated with histologic grade (GI&G2 vs. G3, p < 0.001), histologic type (Diffuse type vs. Tubular type, p < 0.001), histologic stage (stage I vs. stage II and stage I vs. stage III, p < 0.001), T stage (T1 vs. T2, T1 vs. T3, and T1 vs. T4, p < 0.001) and Helicobacter pylori (HP) infection (yes vs. no, p < 0.05) in GC. High BGN expression showed significant association with poor overall survival (OS) in GC patients (HR = 1.53 (1.09–2.14), p = 0.013). The constructed nomogram can well predict the 1-, 3-, and 5-years overall survival probability of GC patients (C-index = 0.728).

Conclusion: BGN plays an important role in the occurrence and progression of GC and is a potential biomarker for the diagnosis and treatment of GC.
Perceptions of People with Special Needs Regarding Autonomous Vehicles and Implication on the Design of Mobility as a Service to Foster Social Inclusion
Authors: Nanchen Benjamin , Ramseyer Randolf , Grèzes Sandra , Wyer Mélanie , Gervaix Alain , Juon Dominic , Fragnière Emmanuel
Published: January 2022

Worldwide, more than one billion people live with disabilities. People with disabilities (PWD) have needs in terms of autonomy, social participation and inclusion. Mobility is one condition for them to be included in society and participate in social life. Autonomous vehicles (AVs) can be part of the concept of Mobility as a Service (MaaS) that enables us to rethink the policy of mobility. However, the way these new autonomous mobility services are designed could exclude PWD. To prevent that, universal design principles and inclusive design could help policymakers and public transport companies design new means of transport that are accessible to all. However, perceptions of PWD regarding MaaS in general and AVs are not well documented. This article presents qualitative research about these perceptions. Eight semi-directive interviews were thus carried out on the subject. Based on these findings, we developed an integrative model to accompany and orchestrate such AV design developments. This integrative model will help policymakers and public transport companies rethink mobility concepts while incorporating AVs and make them accessible to ensure the social inclusion of PWD.
Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum
Authors: Del’Arco Ana Elisa , Argolo Deivison Silva , Guillemin Gilles , Costa Maria de Fátima Dias , Costa Silvia Lima , Pinheiro Alexandre Moraes
Published: January 2022

Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection Neospora caninum could be used as a relevant model to study the role of the kynurenine pathway in the neuroinflammatory response and the subset of cells involved.
Genetic Influence on Frequencies of Myeloid-Derived Cell Subpopulations in Mouse
Authors: Krayem Imtissal , Sohrabi Yahya , Javorková Eliška , Volkova Valeriya , Strnad Hynek , Havelková Helena , Vojtíšková Jarmila , Aidarova Aigerim , Holáň Vladimír , Demant Peter , Lipoldová Marie
Published: January 2022

Differences in frequencies of blood cell subpopulations were reported to influence the course of infections, atopic and autoimmune diseases, and cancer. We have discovered a unique mouse strain B10.O20 containing extremely high frequency of myeloid-derived cells (MDC) in spleen. B10.O20 carries 3.6% of genes of the strain O20 on the C57BL/10 genetic background. It contains much higher frequency of CD11b+Gr1+ cells in spleen than both its parents. B10.O20 carries O20-derived segments on chromosomes 1, 15, 17, and 18. Their linkage with frequencies of blood cell subpopulations in spleen was tested in F2 hybrids between B10.O20 and C57BL/10. We found 3 novel loci controlling MDC frequencies: Mydc1, 2, and 3 on chromosomes 1, 15, and 17, respectively, and a locus controlling relative spleen weight (Rsw1) that co-localizes with Mydc3 and also influences proportion of white and red pulp in spleen. Mydc1 controls numbers of CD11b+Gr1+ cells. Interaction of Mydc2 and Mydc3 regulates frequency of CD11b+Gr1+ cells and neutrophils (Gr1+Siglec-F- cells from CD11b+ cells). Interestingly, Mydc3/Rsw1 is orthologous with human segment 6q21 that was shown previously to determine counts of white blood cells. Bioinformatics analysis of genomic sequence of the chromosomal segments bearing these loci revealed polymorphisms between O20 and C57BL/10 that change RNA stability and genes’ functions, and we examined expression of relevant genes. This identified potential candidate genes Smap1, Vps52, Tnxb, and Rab44. Definition of genetic control of MDC can help to personalize therapy of diseases influenced by these cells.
A Targeted Complement Inhibitor CRIg/FH Protects Against Experimental Autoimmune Myasthenia Gravis in Rats via Immune Modulation
Authors: Song Jie , Zhao Rui , Yan Chong , Luo Sushan , Xi Jianying , Ding Peipei , Li Ling , Hu Weiguo , Zhao Chongbo
Published: January 2022

Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgGin vitro. Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verifiedin vitro. Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MGviaimmune modulation.
Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
Authors: Ormsby Thomas J. R. , Owens Sian E. , Clement Liam , Mills Tom J. , Cronin James G. , Bromfield John J. , Sheldon Iain Martin
Published: January 2022

Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune responses to bacteria. Whether oxysterols also influence the protection of cells against pore-forming toxins is unresolved. Here we tested the hypothesis that oxysterols stimulate the intrinsic protection of epithelial cells against damage caused by cholesterol-dependent cytolysins. We treated epithelial cells with oxysterols and then challenged them with the cholesterol-dependent cytolysin, pyolysin. Treating HeLa cells with 27-hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol, or 7β-hydroxycholesterol reduced pyolysin-induced leakage of lactate dehydrogenase and reduced pyolysin-induced cytolysis. Specifically, treatment with 10 ng/ml 27-hydroxycholesterol for 24 h reduced pyolysin-induced lactate dehydrogenase leakage by 88%, and reduced cytolysis from 74% to 1%. Treating HeLa cells with 27-hydroxycholesterol also reduced pyolysin-induced leakage of potassium ions, prevented mitogen-activated protein kinase cell stress responses, and limited alterations in the cytoskeleton. Furthermore, 27-hydroxycholesterol reduced pyolysin-induced damage in lung and liver epithelial cells, and protected against the cytolysins streptolysin O and Staphylococcus aureus α-hemolysin. Although oxysterols regulate cellular cholesterol by activating liver X receptors, cytoprotection did not depend on liver X receptors or changes in total cellular cholesterol. However, oxysterol cytoprotection was partially dependent on acyl-CoA:cholesterol acyltransferase (ACAT) reducing accessible cholesterol in cell membranes. Collectively, these findings imply that oxysterols stimulate the intrinsic protection of epithelial cells against pore-forming toxins and may help protect tissues against pathogenic bacteria.
SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision
Authors: Ji Ce , Bao Li , Yuan Shunzong , Qi Zhihong , Wang Fang , You Menghao , Yu Guotao , Liu Jingjing , Cui Xiao , Wang Zhao , Liu Juanjuan , Guo Wenhui , Feng Mingxia , Chen Feng , Kang Youmin , Yu Shuyang
Published: January 2022

The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulating the T cell regulatory gene networks post-transcriptionally, which are critical in response to type I interferon signaling for supporting thymocyte maturation. Here, we report SRSF1 also contributes to the determination of the CD8+T cell fate. By specific ablation of SRSF1 in CD4+CD8+double positive (DP) thymocytes, we found that SRSF1 deficiency impaired the maturation of late thymocytes and diminished the output of both CD4+and CD8+single positive T cells. Interestingly, the ratio of mature CD4+to CD8+cells was notably altered and more severe defects were exhibited in CD8+lineage than those in CD4+lineage, reflecting the specific function of SRSF1 in CD8+T cell fate decision. Mechanistically, SRSF1-deficient cells downregulate their expression ofRunx3, which is a crucial transcriptional regulator in sustaining CD8+single positive (SP) thymocyte development and lineage choice. Moreover, forced expression of Runx3 partially rectified the defects in SRSF1-deficient CD8+thymocyte maturation. Thus, our data uncovered the previous unknown role of SRSF1 in establishment of CD8+cell identity.
Biogeography and Biodiversity of the Intertidal Barnacle Tetraclita Species in the Gulf of Thailand and Andaman Sea – Influences of Oceanographic Currents and Pleistocene Glaciations
Authors: Chan Benny K. K. , Tsao Yao-Feng , Wangkulangkul Kringpaka , Amjud Kittipong , Sukparangsi Woranop
Published: January 2022

The present study investigated the phylogeography of the intertidal barnacle Tetraclita in the Gulf of Thailand ecoregion (Sunda Shelf Province in the Pacific) and the Andaman Sea Coral Coast ecoregion (Andaman Province in the Indian Ocean) in Thailand’s waters. Tetraclita species were identified by a combined morphological and molecular approach using mitochondrial gene fragments (CO1 and 12S rRNA). Tetraclita singaporensis is a major occupiers on the Andaman coast but is sparse in the western Gulf of Thailand. Tetraclita squamosa inhabits almost all of our collection sites in the Gulf of Thailand but has a very low abundance in the Andaman Sea. Tetraclita kuroshioensis has two genetically distinct populations, one in the Andaman Sea and the other in the West Pacific region. S-DIVA analysis showed that the most recent common ancestor (MRCA) of T. kuroshioensis was distributed in both the Andaman Sea and West Pacific region, with a relative probability of 63%; the analysis further identified two molecular subclades, one on each side of the Sunda Shelf by vicariance about 0.53 million years ago, far before the Last Glacial Maximum (LGM). The MRCA of T. squamosa was based in the West Pacific region (relative probability: 90%), and dispersed into the Andaman Sea after the LGM. The MRCA of T. singaporensis was in the Andaman Sea (relative probability: 89.5%) and dispersed into the Gulf of Thailand via monsoonal currents through the Malacca Strait after the LGM. Presently, T. singaporensis is absent from the West Pacific region, further supporting its origin in the Andaman Sea. The distribution of intertidal barnacles in the Sunda Shelf and Andaman provinces is a result of the interplay between geological events and present day oceanographic currents.
The Sources and Burial of Marine Organic Carbon in the Eastern China Marginal Seas
Authors: Cao Yali , Bi Rong , Wang Xingchen , Chen Xi , Hu Jingwen , Wang Yaoyao , Jiang Yiqing , Zhang Hailong , Xing Lei , Zhao Meixun
Published: January 2022

The ecological functions and biogeochemical processes of continental marginal seas are important for the global carbon cycle. In the eastern China marginal seas (ECMS), phytoplankton productivity has increased significantly in recent decades, but the sources and burial processes of marine organic carbon (OC) remain under-studied. We analyzed the contents of marine lipid biomarkers (brassicasterol, dinosterol, and C37 alkenones) in surface suspended particles obtained from seven cruises between 2010 and 2015, and in surface sediments from eight cruises between 2006 and 2012 in the ECMS, to estimate marine OC sources and burial. The correlations between lipid biomarkers and environmental factors were quantified to reveal controlling factors. The study area was divided into four regions according to cluster analysis conducted based on sediment parameters. Our results showed that the concentrations of marine lipid biomarkers in surface water were high near large estuaries such as the Changjiang River Estuary and the Yellow River Estuary, but those in surface sediments were high in mud areas. Nutrient concentration was a key factor controlling phytoplankton biomass in surface water, with high nutrients enhancing the growth of diatoms and dinoflagellates, while haptophytes were more abundant in low-nutrient, high-salinity and cold environments. High marine OC contents calculated from total OC δ13C were mainly associated with fine sediments transported by coastal currents, and finally deposited in mud areas. The proto-burial efficiency of marine OC in the ECMS (7–19%) was markedly higher than the mean value in global marginal seas, with high values being located in the western coast of the ECMS. The proto-burial efficiency of total marine lipid biomarkers (6–24%) was quantified for the first time in our study, with overall values and spatial patterns similar to that of marine OC. A key parameter for marine OC and marine biomarker proto-burial efficiency was sediment grain size. The smaller the sediment grain size was, the better the marine OC and marine biomarker were retained. Our study provides an important basis to elucidate spatial distribution patterns and forcing mechanisms of marine OC in surface water (production process) and surface sediments (burial process), and to estimate carbon budgets in large marginal seas.
Effect of Ridge Width on the Lasing Characteristics of Triangular and Rectangular InAs/In0.53Ga0.47As Quantum Well Lasers
Authors: Jiao Zhejing , Gu Yi , Zhang Yonggang , Hu Anduo , Gong Qian , Wang Shumin , Li Tao , Li Xue
Published: January 2022

The lasing characteristics of InP-based InAs/In0.53Ga0.47As quantum well (QW) lasers with different ridge widths are investigated. Two groups of lasers are grown for comparison, one with active triangular QW regions and the other with rectangular QW regions. Their output powers, characteristic temperatures (T0), external differential quantum efficiencies (ηd) and junction temperatures (Tj) are analyzed and compared. The parameter of ridge width is found to play an important role in the performance of the lasers. In triangular QW lasers, by broadening the ridge width from 8 to 12 μm, output power and ηd of the lasers are decreased for the temperature range of 100–320 K due to heating effect. But by broadening the ridge width from 8 to 100 μm in rectangular QW lasers, output power has about 3.5 time increase at 100 K and ηd also has a little increase for temperatures from 100 to 180 K due to much larger emission area and much faster heat dissipation. Tj, the real temperature of the active region, is also found to have accelerated increase at high injection current and heat sink temperature. Besides, compared to the rectangular QW laser of the same ridge width, the improved thermal performance of triangular QW laser is also demonstrated.
Intravoxel Incoherent Motion Imaging on Sacroiliitis in Patients With Axial Spondyloarthritis: Correlation With Perfusion Characteristics Based on Dynamic Contrast-Enhanced Magnetic Resonance Imaging
Authors: Guo Chang , Zheng Kai , Ye Qiang , Lu Zixiao , Xie Zhuoyao , Li Xin , Zhao Yinghua
Published: January 2022

Background

To prospectively explore the relationship between intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) parameters of sacroiliitis in patients with axial spondyloarthritis (axSpA).

Methods

Patients with initially diagnosed axSpA prospectively underwent on 3.0 T MRI of sacroiliac joint (SIJ). The IVIM parameters (D, f, D*) were calculated using biexponential analysis. Ktrans, Kep, Ve, and Vp from DCE-MRI were obtained in SIJ. The uni-variable and multi-variable linear regression analyses were used to evaluate the correlation between the parameters from these two imaging methods after controlling confounders, such as bone marrow edema (BME), age, agenda, scopes, and localization of lesions, and course of the disease. Then, their correlations were measured by calculating the Pearson's correlation coefficient (r).

Results

The study eventually enrolled 234 patients (178 men, 56 women; mean age, 28.51 ± 9.50 years) with axSpA. With controlling confounders, D was independently related to Ktrans (regression coefficient [b] = 27.593, p < 0.001), Kep (b = −6.707, p = 0.021), and Ve (b = 131.074, p = 0.003), whereas f and D* had no independent correlation with the parameters from DCE MRI. The correlations above were exhibited with Pearson's correlation coefficients (r) (r = 0.662, −0.408, and 0.396, respectively, all p < 0.001).

Conclusion

There were independent correlations between D derived from IVIM DWI and Ktrans, Kep, and Ve derived from DCE-MRI. The factors which affect their correlations mainly included BME, gender, and scopes of lesions.
Ethnic Disparities in Hepatitis B Virus Infection Among 1 Million Reproductive-Age Couples Preparing for Pregnancy in the Rural Yunnan, China: A Population-Based Cross-Sectional Study
Authors: Jing Wenzhan , Yuan Yanling , Liu Min , Ye Hanfeng , Kong Cai , Liu Jue , Wu Yu
Published: January 2022

Introduction

Hepatitis B is a potentially life-threatening liver infection caused by hepatitis B virus (HBV) and China has the largest disease burden. We aim to understand the ethnic disparities in HBV infection among the married reproductive-age couples planning for pregnancy in Yunnan, a multiethnic province in Southwest China, to increase the health equities within the hepatitis response in China.

Methods

A population-based cross-sectional study was performed. Couples aged 20–49 years in rural Yunnan were enrolled through the National Free Preconception Health Examination Project from Jan 2014 to Dec 2019. HBsAg-positive couples were defined as couples in which one or both were HBsAg-positive, and HBsAg- and HBeAg-positive couples were defined as couples in which one or both were HBsAg- and HBeAg-positive. The HBV prevalence of positive couples was estimated by ethnicity. Multivariate logistic regression analyses were used to assess the association between ethnicity and HBsAg status.

Results

Overall, 63,513 of 1,060,643 couples (5.99%, 95% CI, 5.94%−6.03%) were HBsAg-positive, and 15,898 of 63,513 HBsAg-positive couples (25.03%, 95% CI 24.69%−25.37%) were HBsAg- and HBeAg-positive couples in rural Yunnan. The highest prevalence of HBsAg-positive couples was in the Miao and Miao ethnicity (12.04%) and Zhuang and Zhuang ethnicity (9.76%), and the risk of HBV infection of wives/husbands in these ethnic groups was significantly higher than that in the Han and Han ethnicity. Additionally, the HBsAg prevalence in wives/husbands has increased with the positive status of HBsAg and HBeAg of their spouses.

Conclusion

The HBV prevalence in reproductive-age couples was intermediate (6% of 1 million couples) in rural Yunnan, China, with the highest in the Miao and Zhuang ethnicities. There are still large ethnic disparities in HBV infection in China. Therefore, China should make great efforts, especially giving priority to ethnic minorities and taking positive couples as an important unit of care, to equitably eliminate the HBV intrafamilial transmission.
The Prognostic Impact of Serum Uric Acid on Disease Severity and 5-Year Mortality in Patients With Idiopathic Pulmonary Artery Hypertension
Authors: Yan Lu , Huang Zhihua , Zhao Zhihui , Zhao Qing , Tang Yi , Zhang Yi , Li Xin , Duan Anqi , Luo Qin , Liu Zhihong
Published: January 2022

Background

Serum uric acid (UA) has long been identified as a prognostic factor of adverse outcomes in pulmonary hypertension. However, there remains a paucity of evidence on patients with idiopathic pulmonary artery hypertension (IPAH) in the era of targeted drug therapy. This study aims to explore the impact of serum UA levels on the disease severity and mortality in patients with IPAH.

Methods

Consecutive patients diagnosed with IPAH were enrolled, from which UA levels at baseline and the first follow-up were collected. Patients were divided into groups of “hyperuricemia,” which is defined as serum UA level ≥357 μmol/L in women and ≥420 μmol/L in men, and otherwise “normouricemia.” The potential relationship between UA and hemodynamics at right heart catheterization was investigated. Associations between UA and survival were evaluated by Kaplan-Meier analysis and Cox proportional hazard modeling.

Results

Of 207 patients with IPAH, 121 (58.5%) had hyperuricemia. Higher serum UA levels were associated with lower cardiac index (r = 0.47, p < 0.001) and higher pulmonary vascular resistance (r = 0.36, p < 0.001). During a median follow-up of 34 months, there were 32 deaths recorded, accounting for a 15.5% mortality rate. Patients with hyperuricemia had a significantly lower survival rate than those with normouricemia (log-rank test, p = 0.002). Hyperuricemia at baseline was independently associated with a 2.6-fold increased risk of 5-year death, which was consistent across different subgroups, especially in females and those aged ≥30 years (each p < 0.05). Individuals with higher variability in UA had a higher mortality than those with stable UA (log-rank test, p = 0.024).

Conclusions

Baseline hyperuricemia and high variability in serum UA at first follow-up were related to a higher rate of 5-year mortality in patients with IPAH. Closely detecting the UA levels may aid in the early recognition of IPAH patients at higher mortality risk.
Probiotics Exhibit Strain-Specific Protective Effects in T84 Cells Challenged With Clostridioides difficile-Infected Fecal Water
Authors: Gaisawat Mohd Baasir , Lopez-Escalera Silvia , MacPherson Chad W. , Iskandar Michèle M. , Tompkins Thomas A. , Kubow Stan
Published: January 2022

Clostridioides difficile infection (CDI) is frequently associated with intestinal injury and mucosal barrier dysfunction, leading to an inflammatory response involving neutrophil localization and upregulation of pro-inflammatory cytokines. The severity of clinical manifestations is associated with the extent of the immune response, which requires mitigation for better clinical management. Probiotics could play a protective role in this disorder due to their immunomodulatory ability in gastrointestinal disorders. We assessed five single-strain and three multi-strain probiotics for their ability to modulate CDI fecal water (FW)-induced effects on T84 cells. The CDI-FW significantly (p < 0.05) decreased T84 cell viability. The CDI-FW-exposed cells also exhibited increased pro-inflammatory cytokine production as characterized by interleukin (IL)-8, C-X-C motif chemokine 5, macrophage inhibitory factor (MIF), IL-32, and tumor necrosis factor (TNF) ligand superfamily member 8. Probiotics were associated with strain-specific attenuation of the CDI-FW mediated effects, whereby Saccharomyces boulardii CNCM I-1079 and Lacticaseibacillus rhamnosus R0011 were most effective in reducing pro-inflammatory cytokine production and in increasing T84 cell viability. ProtecFlor™, Lactobacillus helveticus R0052, and Bifidobacterium longum R0175 showed moderate effectiveness, and L. rhamnosus GG R0343 along with the two other multi-strain combinations were the least effective. Overall, the findings showed that probiotic strains possess the capability to modulate the CDI-mediated inflammatory response in the gut lumen.
Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats
Authors: Fernández-Quintero Monica L. , Quoika Patrick K. , Wedl Florian S. , Seidler Clarissa A. , Kroell Katharina B. , Loeffler Johannes R. , Pomarici Nancy D. , Hoerschinger Valentin J. , Bujotzek Alexander , Georges Guy , Kettenberger Hubert , Liedl Klaus R.
Published: January 2022

As the current biotherapeutic market is dominated by antibodies, the design of different antibody formats, like bispecific antibodies and other new formats, represent a key component in advancing antibody therapy. When designing new formats, a targeted modulation of pairing preferences is key. Several existing approaches are successful, but expanding the repertoire of design possibilities would be desirable. Cognate immunoglobulin G antibodies depend on homodimerization of the fragment crystallizable regions of two identical heavy chains. By modifying the dimeric interface of the third constant domain (CH3-CH3), with different mutations on each domain, the engineered Fc fragments form rather heterodimers than homodimers. The first constant domain (CH1-CL) shares a very similar fold and interdomain orientation with the CH3-CH3 dimer. Thus, numerous well-established design efforts for CH3-CH3 interfaces, have also been applied to CH1-CL dimers to reduce the number of mispairings in the Fabs. Given the high structural similarity of the CH3-CH3 and CH1-CL domains we want to identify additional opportunities in comparing the differences and overlapping interaction profiles. Our vision is to facilitate a toolkit that allows for the interchangeable usage of different design tools from crosslinking the knowledge between these two interface types. As a starting point, here, we use classical molecular dynamics simulations to identify differences of the CH3-CH3 and CH1-CL interfaces and already find unexpected features of these interfaces shedding new light on possible design variations. Apart from identifying clear differences between the similar CH3-CH3 and CH1-CL dimers, we structurally characterize the effects of point-mutations in the CH3-CH3 interface on the respective dynamics and interface interaction patterns. Thus, this study has broad implications in the field of antibody engineering as it provides a structural and mechanistical understanding of antibody interfaces and thereby presents a crucial aspect for the design of bispecific antibodies.