bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Important Modules and Biomarkers That Are Related to Immune Infiltration Cells in Severe Burns Based on Weighted Gene Co-Expression Network Analysis
Authors: Zhang Zexin , He Yan , Lin Rongjie , Lan Junhong , Fan Yueying , Wang Peng , Jia Chiyu
Published: June 2022

Background: Immunosuppression is an important trigger for infection and a significant cause of death in patients with severe burns. Nevertheless, the prognostic value of immune-related genes remains unclear. This study aimed to identify the biomarkers related to immunosuppression in severe burns.

Methods: The gene expression profile and clinical data of 185 burn and 75 healthy samples were obtained from the GEO database. Immune infiltration analysis and gene set variation analysis were utilized to identify the disorder of circulating immune cells. A weighted gene co-expression network analysis (WGCNA) was carried out to select immune-related gene modules. Enrichment analysis and protein–protein interaction (PPI) network were performed to select hub genes. Next, LASSO and logistic regression were utilized to construct the hazard regression model with a survival state. Finally, we investigated the correlation between high- and low-risk patients in total burn surface area (TBSA), age, and inhalation injury.

Results: Gene set variation analysis (GSVA) and immune infiltration analysis showed that neutrophils increased and T cells decreased in severe burns. In WGCNA, four modular differently expressed in burns and controls were related to immune cells. Based on PPI and enrichment analysis, 210 immune-related genes were identified, mainly involved in T-cell inhibition and neutrophil activation. In LASSO and logistic regression, we screened out key genes, including LCK, SKAP1 and GZMB, and LY9. In the ROC analysis, the area under the curve (AUC) of key genes was 0.945, indicating that the key genes had excellent diagnostic value. Finally, we discovered that the key genes were related to T cells, and the regression model performed well when accompanied by TBSA and age.

Conclusion: We identified LCK, SKAP1, GZMB, and LY9 as good prognostic biomarkers that may play a role in post-burn immunosuppression against T-cell dysfunction and as potential immunotherapeutic targets for transformed T-cell dysfunction.
Promoter Specific Methylation of SSTR4 is Associated With Alcohol Dependence in Han Chinese Males
Authors: Zhao Rongrong , Shi Huihui , Yin Jiajun , Sun Zhen , Xu Yahui
Published: June 2022

Alcohol dependence (AD), a disease can be affected by environmental factors with epigenetic modification like DNA methylation changes, is one of the most serious and complex public health problems in China and worldwide. Previous findings from our laboratory using the Illumina Infinium Human Methylation450 BeadChip suggested that methylation at the promoter of SSTR4 was one of the major form of DNA modification in alcohol-dependent populations. To investigate whether DNA methylation levels of the SSTR4 promoter influence alcohol-dependent behaviors, genomic DNA was extracted from the peripheral blood sample of 63 subjects with AD and 65 healthy controls, and pyrosequencing was used to verify the results of BeadChip array. Linear regression was used to analyze the correlation between the methylation levels of SSTR4 promoter and the scores of alcohol dependence scales. Gene expression of SSTR4 in brain tissue was obtained from the Genotype-Tissue Expression (GTEx) project and Human Brain Transcriptome database (HBT). We found the methylation levels of SSTR4 in AD group were significantly lower than healthy controls (two-tailed t-test, t = 14.723, p < 0.001). In addition, only weak to moderate correlations between the methylation levels of the SSTR4 promoter region and scale scores of Alcohol Use Disorders Identification Test (AUDIT), Life Events Scale (LES) and Wheatley Stress Profile (WSS) based on linear regression analyses (AUDIT: R2= 0.35, p < 0.001; LES: R2 = 0.27, p < 0.001; WSS: R2 = 0.49, p < 0.001). The hypomethylated status of SSTR4 may involve in the development of AD and increase the risk of AD persistence in Han Chinese males.
The Association Between Breast Cancer and Blood-Based Methylation of CD160, ISYNA1 and RAD51B in the Chinese Population
Authors: Liu Chunlan , Zhou Xiajie , Jin Jialie , Zhu Qiang , Li Lixi , Yin Qiming , Xu Tian , Gu Wanjian , Ma Fei , Yang Rongxi
Published: June 2022

Recent studies have identified DNA methylation signatures in the white blood cells as potential biomarkers for breast cancer (BC) in the European population. Here, we investigated the association between BC and blood-based methylation of cluster of differentiation 160 (CD160), inositol-3-phosphate synthase 1 (ISYNA1) and RAD51 paralog B (RAD51B) genes in the Chinese population. Peripheral blood samples were collected from two independent case-control studies with a total of 272 sporadic early-stage BC cases (76.5% at stage I&II) and 272 cancer-free female controls. Mass spectrometry was applied to quantitatively measure the levels of DNA methylation. The logistic regression and non-parametric tests were used for the statistical analyses. In contrast to the protective effects reported in European women, we reported the blood-based hypomethylation in CD160, ISYNA1 and RAD51B as risk factors for BC in the Chinese population (CD160_CpG_3, CD160_CpG_4/cg20975414, ISYNA1_CpG_2, RAD51B_CpG_3 and RAD51B_CpG_4; odds ratios (ORs) per -10% methylation ranging from 1.08 to 1.67, p < 0.05 for all). Moreover, hypomethylation of CD160, ISYNA1 and RAD51B was significantly correlated with age, BC subtypes including estrogen receptor (ER)-negative BC tumors, triple negative tumors, BC cases with larger size, advanced stages and more lymph node involvement. Our results supported the report in European women that BC is associated with altered methylation of CD160, ISYNA1 and RAD51B in the peripheral blood, although the effects are opposite in the Chinese population. The difference between the two populations may be due to variant genetic background or life styles, implicating that the validations of epigenetic biomarkers in variant ethnic groups are warranted.
The Nuclear Envelope as a Regulator of Immune Cell Function
Authors: Selezneva Anna , Gibb Alasdair J. , Willis Dean
Published: June 2022

The traditional view of the nuclear envelope (NE) was that it represented a relatively inert physical barrier within the cell, whose main purpose was to separate the nucleoplasm from the cytoplasm. However, recent research suggests that this is far from the case, with new and important cellular functions being attributed to this organelle. In this review we describe research suggesting an important contribution of the NE and its constituents in regulating the functions of cells of the innate and adaptive immune system. One of the standout properties of immune cells is their ability to migrate around the body, allowing them to carry out their physiological/pathophysiology cellular role at the appropriate location. This together with the physiological role of the tissue, changes in tissue matrix composition due to disease and aging, and the activation status of the immune cell, all result in immune cells being subjected to different mechanical forces. We report research which suggests that the NE may be an important sensor/transducer of these mechanical signals and propose that the NE is an integrator of both mechanical and chemical signals, allowing the cells of the innate immune system to precisely regulate gene transcription and functionality. By presenting this overview we hope to stimulate the interests of researchers into this often-overlooked organelle and propose it should join the ranks of mitochondria and phagosome, which are important organelles contributing to immune cell function.
ILC2s Control Microfilaremia During Litomosoides sigmodontis Infection in Rag2-/- Mice
Authors: Reichwald Julia J. , Risch Frederic , Neumann Anna-Lena , Frohberger Stefan J. , Scheunemann Johanna F. , Lenz Benjamin , Ehrens Alexandra , Strutz Wiebke , Schumak Beatrix , Hoerauf Achim , Hübner Marc P.
Published: June 2022

Group 2 innate lymphoid cells (ILC2s) are inducers of type 2 immune responses, but their role during filarial infection remains unclear. In the present study, we used the Litomosoides sigmodontis rodent model of filariasis to analyze ILC2s during infection in susceptible BALB/c mice that develop a chronic infection with microfilaremia and semi-susceptible C57BL/6 mice that eliminate the filariae shortly after the molt into adult worms and thus do not develop microfilaremia. ILC2s (CD45+ Lineage- TCRβ- CD90.2+ Sca-1+ IL-33R+ GATA-3+) were analyzed in the pleural cavity, the site of L. sigmodontis infection, after the infective L3 larvae reached the pleural cavity (9 days post infection, dpi), after the molt into adult worms (30dpi) and during the peak of microfilaremia (70dpi). C57BL/6 mice had significantly increased ILC2 numbers compared to BALB/c mice at 30dpi, accompanied by substantially higher IL-5 and IL-13 levels, indicating a stronger type 2 immune response in C57BL/6 mice upon L. sigmodontis infection. At this time point the ILC2 numbers positively correlated with the worm burden in both mouse strains. ILC2s and GATA-3+ CD4+ T cells were the dominant source of IL-5 in L. sigmodontis-infected C57BL/6 mice with ILC2s showing a significantly higher IL-5 expression than CD4+ T cells. To investigate the importance of ILC2s during L. sigmodontis infection, ILC2s were depleted with anti-CD90.2 antibodies in T and B cell-deficient Rag2-/- C57BL/6 mice on 26-28dpi and the outcome of infection was compared to isotype controls. Rag2-/- mice were per se susceptible to L. sigmodontis infection with significantly higher worm burden than C57BL/6 mice and developed microfilaremia. Depletion of ILC2s did not result in an increased worm burden in Rag2-/- mice, but led to significantly higher microfilariae numbers compared to isotype controls. In conclusion, our data demonstrate that ILC2s are essentially involved in the control of microfilaremia in Rag2-/- C57BL/6 mice.
ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain
Authors: Zhang Tianshu , Lin Cong , Wu Siru , Jin Sha , Li Xiaodong , Peng Yinghua , Wang Xiaohui
Published: June 2022

Neuropathic pain is a common and challenging neurological disease, which renders an unmet need for safe and effective new therapies. Toll-like receptor 4 (TLR4) expressed on immune cells in the central nervous system arises as a novel target for treating neuropathic pain. In this study, ACT001, an orphan drug currently in clinical trials for the treatment of glioblastoma, was identified as a TLR4 antagonist. In vitro quenching titrations of intrinsic protein fluorescence and saturation transfer difference (STD)-NMR showed the direct binding of ACT001 to TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that ACT001 binding affected the MD2 stability, which implies that MD2 is the endogenous target of ACT001. In silico simulations showed that ACT001 binding decreased the percentage of hydrophobic area in the buried solvent-accessible surface areas (SASA) of MD2 and rendered most regions of MD2 to be more flexible, which is consistent with experimental data that ACT001 binding decreased MD2 stability. In keeping with targeting MD2, ACT001 was found to restrain the formation of TLR4/MD2/MyD88 complex and the activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO, IL-6, TNF-α, and IL-1β. Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.
Exposure of Keratinocytes to Candida Albicans in the Context of Atopic Milieu Induces Changes in the Surface Glycosylation Pattern of Small Extracellular Vesicles to Enhance Their Propensity to Interact With Inhibitory Siglec Receptors
Authors: Kobiela Adrian , Frackowiak Joanna E. , Biernacka Anna , Hovhannisyan Lilit , Bogucka Aleksandra E. , Panek Kinga , Paul Argho Aninda , Lukomska Joanna , Wang Xinwen , Giannoulatou Eleni , Krolicka Aleksandra , Zielinski Jacek , Deptula Milena , Pikula Michal , Gabrielsson Susanne , Ogg Graham S. , Gutowska-Owsiak Danuta
Published: June 2022

Candida albicans (C. albicans) infection is a potential complication in the individuals with atopic dermatitis (AD) and can affect clinical course of the disease. Here, using primary keratinocytes we determined that atopic milieu promotes changes in the interaction of small extracellular vesicles (sEVs) with dendritic cells and that this is further enhanced by the presence of C. albicans. sEV uptake is largely dependent on the expression of glycans on their surface; modelling of the protein interactions indicated that recognition of this pathogen through C. albicans-relevant pattern recognition receptors (PRRs) is linked to several glycosylation enzymes which may in turn affect the expression of sEV glycans. Here, significant changes in the surface glycosylation pattern, as determined by lectin array, could be observed in sEVs upon a combined exposure of keratinocytes to AD cytokines and C. albicans. This included enhanced expression of multiple types of glycans, for which several dendritic cell receptors could be proposed as binding partners. Blocking experiments showed predominant involvement of the inhibitory Siglec-7 and -9 receptors in the sEV-cell interaction and the engagement of sialic acid-containing carbohydrate moieties on the surface of sEVs. This pointed on ST6 β-Galactoside α-2,6-Sialyltransferase 1 (ST6GAL1) and Core 1 β,3-Galactosyltransferase 1 (C1GALT1) as potential enzymes involved in the process of remodelling of the sEV surface glycans upon C. albicans exposure. Our results suggest that, in combination with atopic dermatitis milieu, C. albicans promotes alterations in the glycosylation pattern of keratinocyte-derived sEVs to interact with inhibitory Siglecs on antigen presenting cells. Hence, a strategy aiming at this pathway to enhance antifungal responses and restrict pathogen spread could offer novel therapeutic options for skin candidiasis in AD.
Tissue-Specific Diversity of Group 2 Innate Lymphoid Cells in the Skin
Authors: Kobayashi Tetsuro , Moro Kazuyo
Published: June 2022

Since the discovery of group 2 innate lymphoid cells (ILC2s), their developmental pathways, mechanisms of activation and regulation, and immunological roles in the steady state and in disease have been reported in various organs. ILC2s, which produce large amounts of IL-5 and IL-13 in response to tissue-derived factors and are essential in inducing and promoting allergic inflammation, have also been found to play multifaceted roles in maintaining tissue homeostasis. While T cells respond to foreign antigens, the activation of ILC2s is regulated by various tissue-derived factors, including cytokines, lipids, hormones, and neurotransmitters, and ILC2s show different phenotypes depending on the tissue in which they are present. In this review, we discuss tissue-specific characteristics of ILC2s in the skin. ILC2s, as defined in the lungs, intestinal tract, and adipose tissue, cannot be directly applied to cutaneous ILC biology, because skin ILC2s exhibit different aspects in the expression patterns of cell surface markers, the response to tissue-derived cytokines and the functions in both steady-state and inflammation. The skin contains ILCs with features of both ILC2s and ILC3s, and the plasticity between ILCs complicates their characters. Furthermore, the epidermis, dermis, and subcutaneous tissues contain ILCs with different characteristics; their localization has expanded our understanding of ILC function. Single-cell RNA-seq technology has further elucidated the role of ILCs in human skin and disease pathogenesis. Overall, this review discusses the phenotypical and functional heterogeneity of skin ILCs reported in recent years and highlights future directions within the field of ILC biology.
Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection
Authors: Wiech Milena , Chroscicki Piotr , Swatler Julian , Stepnik Dawid , De Biasi Sara , Hampel Michal , Brewinska-Olchowik Marta , Maliszewska Anna , Sklinda Katarzyna , Durlik Marek , Wierzba Waldemar , Cossarizza Andrea , Piwocka Katarzyna
Published: June 2022

Several COVID-19 convalescents suffer from the post-acute COVID-syndrome (PACS)/long COVID, with symptoms that include fatigue, dyspnea, pulmonary fibrosis, cognitive dysfunctions or even stroke. Given the scale of the worldwide infections, the long-term recovery and the integrative health-care in the nearest future, it is critical to understand the cellular and molecular mechanisms as well as possible predictors of the longitudinal post-COVID-19 responses in convalescent individuals. The immune system and T cell alterations are proposed as drivers of post-acute COVID syndrome. However, despite the number of studies on COVID-19, many of them addressed only the severe convalescents or the short-term responses. Here, we performed longitudinal studies of mild, moderate and severe COVID-19-convalescent patients, at two time points (3 and 6 months from the infection), to assess the dynamics of T cells immune landscape, integrated with patients-reported symptoms. We show that alterations among T cell subsets exhibit different, severity- and time-dependent dynamics, that in severe convalescents result in a polarization towards an exhausted/senescent state of CD4+ and CD8+ T cells and perturbances in CD4+ Tregs. In particular, CD8+ T cells exhibit a high proportion of CD57+ terminal effector cells, together with significant decrease of naïve cell population, augmented granzyme B and IFN-γ production and unresolved inflammation 6 months after infection. Mild convalescents showed increased naïve, and decreased central memory and effector memory CD4+ Treg subsets. Patients from all severity groups can be predisposed to the long COVID symptoms, and fatigue and cognitive dysfunctions are not necessarily related to exhausted/senescent state and T cell dysfunctions, as well as unresolved inflammation that was found only in severe convalescents. In conclusion, the post-COVID-19 functional remodeling of T cells could be seen as a two-step process, leading to distinct convalescent immune states at 6 months after infection. Our data imply that attenuation of the functional polarization together with blocking granzyme B and IFN-γ in CD8+ cells might influence post-COVID alterations in severe convalescents. However, either the search for long COVID predictors or any treatment to prevent PACS and further complications is mandatory in all patients with SARS-CoV-2 infection, and not only in those suffering from severe COVID-19.
IL-17 Induces Autophagy Dysfunction to Promote Inflammatory Cell Death and Fibrosis in Keloid Fibroblasts via the STAT3 and HIF-1α Dependent Signaling Pathways
Authors: Lee Seon-Yeong , Lee A Ram , Choi Jeong Won , Lee Chae Rim , Cho Keun-Hyung , Lee Jung Ho , Cho Mi-La
Published: June 2022

Keloid is an abnormal fibrotic disease after cutaneous injury characterized by exaggerated scar tissue formation, which often extends beyond the boundaries of the original wound. Although chronic inflammation is known to be associated with the excessive inflammation in keloid tissue, there are few studies on the role of autophagy in the pathogenesis of keloid. In this study, we evaluated the pattern of autophagy in keloid fibroblasts (KF) and normal fibroblasts (NF). Expression of HIF-1α, STAT3 and autophagic flux markers were evaluated in KF and NF. Defective autophagy caused by IL-17 was evaluated, and the relationship between defective autophagy and necroptosis was also examined. The expression of IL-17, HIF-1α and STAT3 was significantly increased in keloid tissue, and autophagosome-to autophagolysosome conversion was defective in KF. IL-17 treatment significantly elevated the expression of STAT3 and HIF-1α in NF and caused defective autophagy, which was reversed by HIF-1α inhibitor. In addition, the defective autophagy was associated with the increased necroptosis and fibrosis. In keloid tissue, the elevated necroptosis marker was confirmed, and with the HIF-1α inhibitor, the defective autophagy, necroptosis and fibrosis was decreased in KF. In conclusion, autophagy was defective in keloid tissue, which was associated with increased necroptosis and fibrosis. The IL-17-STAT3-HIF-1α axis was involved in defective autophagy in KF, and this suggests that targeting the axis could alleviate chronic inflammation in keloid disease.
Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison
Authors: Romo-González Marta , Ijurko Carla , Hernández-Hernández Ángel
Published: June 2022

Reactive oxygen species (ROS), previously considered toxic by-products of aerobic metabolism, are increasingly recognized as regulators of cellular signaling. Keeping ROS levels low is essential to safeguard the self-renewal capacity of hematopoietic stem cells (HSC). HSC reside in a hypoxic environment and have been shown to be highly dependent on the glycolytic pathway to meet their energy requirements. However, when the differentiation machinery is activated, there is an essential enhancement of ROS together with a metabolic shift toward oxidative metabolism. Initiating and sustaining leukemia depend on the activity of leukemic stem cells (LSC). LSC also show low ROS levels, but unlike HSC, LSC rely on oxygen to meet their metabolic energetic requirements through mitochondrial respiration. In contrast, leukemic blasts show high ROS levels and great metabolic plasticity, both of which seem to sustain their invasiveness. Oxidative stress and metabolism rewiring are recognized as hallmarks of cancer that are intimately intermingled. Here we present a detailed overview of these two features, sustained at different levels, that support a two-way relationship in leukemia. Modifying ROS levels and targeting metabolism are interesting therapeutic approaches. Therefore, we provide the most recent evidence on the modulation of oxidative stress and metabolism as a suitable anti-leukemic approach.
Increased Risk of Acute Coronary Syndrome in Ankylosing Spondylitis Patients With Uveitis: A Population-Based Cohort Study
Authors: Feng Kathy Ming , Chien Wu-Chien , Chen Yi-Hao , Sun Chien-An , Chung Chi-Hsiang , Chen Jiann-Torng , Chen Ching-Long
Published: June 2022

Background

Uveitis, a sight-threatening ocular inflammatory state, is associated with autoimmune diseases and systemic inflammation. This prolonged systemic inflammation may cause plaque formation in coronary arteries, subsequently resulting in acute coronary syndrome (ACS).

Methods

This retrospective, population-based study (15-year period) used the Longitudinal Health Insurance Database based on the National Health Insurance Research Database in Taiwan. Chi-square and Student’s t-tests were used to examine differences between the study and comparison cohorts for categorical and continuous variables, respectively. Fine and Gray’s competing risk model was used to determine the hazard ratio of the risk of ACS. Furthermore, the cumulative risk of ACS was determined using Kaplan-Meier analysis.

Results

A total of 1,111 patients with AS and uveitis were enrolled in this study cohort, and 4,444 patients with AS without uveitis were enrolled in the comparison cohort. After adjustment for age, sex, and comorbidities, patients with AS and uveitis demonstrated an increased risk of ACS compared to those without uveitis (adjusted hazard ratio: 1.675, p<0.001). In addition, Kaplan-Meier analysis revealed that patients with AS and uveitis had a significantly higher risk of ACS than those without uveitis (p<0.001). Age, diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, asthma, and systemic steroids were significant risk factors for ACS. Both anterior uveitis and posterior segment involvement were associated with an increased risk of ACS in patients with AS. All-cause mortality was higher in the uveitis group (9.81%) than in the non-uveitis group (8.10%) (p=0.015).

Conclusion

Our analysis revealed that uveitis could potentially be a predictor of ACS in patients with AS. However, further prospective controlled studies are required to assess the association between uveitis and ACS in patients with AS.
The Emerging Role of Plant-Derived Exosomes-Like Nanoparticles in Immune Regulation and Periodontitis Treatment
Authors: Zhang Zeyu , Yu Yang , Zhu Guanxiong , Zeng Liting , Xu Shaofen , Cheng Haoyu , Ouyang Zhaoguang , Chen Jianwei , Pathak Janak L. , Wu Lihong , Yu Lina
Published: June 2022

Periodontitis is an infectious oral disease, which leads to the destruction of periodontal tissues and tooth loss. Although the treatment of periodontitis has improved recently, the effective treatment of periodontitis and the periodontitis-affected periodontal tissues is still a challenge. Therefore, it is urgent to explore new therapeutic strategies for periodontitis. Natural products show anti-microbial, anti-inflammatory, anti-oxidant and bone protective effects to periodontitis and most of these natural products are safe and cost-effective. Among these, the plant-derived exosome-like nanoparticles (PELNs), a type of natural nanocarriers repleted with lipids, proteins, RNAs, and other active molecules, show the ability to enter mammalian cells and regulate cellular activities. Reports from the literature indicate the great potential of PELNs in the regulation of immune functions, inflammation, microbiome, and tissue regeneration. Moreover, PELNs can also be used as drug carriers to enhance drug stability and cellular uptakein vivo. Since regulation of immune function, inflammation, microbiome, and tissue regeneration are the key phenomena usually targeted during periodontitis treatment, the PELNs hold the promising potential for periodontitis treatment. This review summarizes the recent advances in PELNs-related research that are related to the treatment of periodontitis and regeneration of periodontitis-destructed tissues and the underlying mechanisms. We also discuss the existing challenges and prospects of the application of PELNs-based therapeutic approaches for periodontitis treatment.
Xenotransplantation: A New Era
Authors: Carrier Amber N. , Verma Anjali , Mohiuddin Muhammad , Pascual Manuel , Muller Yannick D. , Longchamp Alban , Bhati Chandra , Buhler Leo H. , Maluf Daniel G. , Meier Raphael P. H.
Published: June 2022

Organ allotransplantation has now reached an impassable ceiling inherent to the limited supply of human donor organs. In the United States, there are currently over 100,000 individuals on the national transplant waiting list awaiting a kidney, heart, and/or liver transplant. This is in contrast with only a fraction of them receiving a living or deceased donor allograft. Given the morbidity, mortality, costs, or absence of supportive treatments, xenotransplant has the potential to address the critical shortage in organ grafts. Last decade research efforts focused on creation of donor organs from pigs with various genes edited out using CRISPR technologies and utilizing non-human primates for trial. Three groups in the United States have recently moved forward with trials in human subjects and obtained initial successful results with pig-to-human heart and kidney xenotransplantation. This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.
Low Serum Calcium Concentration in Patients With Systemic Lupus Erythematosus Accompanied by the Enhanced Peripheral Cellular Immunity
Authors: Du Xue , Zhao Di , Wang Ying , Sun Zhengyi , Yu Qiuyang , Jiang Hongyu , Wang Liying
Published: June 2022

Objective

This study aims to explore the relationship between serum calcium concentration and peripheral lymphocyte status/Th1/Th2 cytokine levels in SLE patients, and the effect of glucocorticoids (GCs) on the calcium concentration and immune cell activation.

Methods

The peripheral blood TBNK lymphocyte subsets and Th1/Th2 cytokines in SLE patients with low or normal serum calcium concentration and healthy people were analyzed and compared retrospectively. Peripheral white blood cells (PWBCs) from SLE patients or healthy people were stimulated with PMA or GCs in vitro to test their extracellular calcium concentration and CD8+ T cell activation.

Results

The percentages of CD8+ T in SLE patients increased, but the increase of the number of CD8+ T cells only occurred in the SLE patients with low serum calcium concentration, and the number of CD45hiCD8+ T cells also increased, suggesting that SLE patients with hypocalcemia tend to possess an enhanced cellular immunity. The results of Th1/Th2 cytokines in peripheral blood showed that the levels of serum IL-2, IL-10, IL-6 and IFN-γ in SLE patients with hypocalcemia were significantly increased. Although the serum levels of TNF-α in SLE patients were –similar to that in healthy people, it was significantly higher than that in SLE patients with normal serum calcium. When comparing the results of Th1/Th2 cytokines in two times of one patient, the serum levels of TNF-α in SLE patients increased while serum calcium levels decreased. The in vitro experiments showed that the decrease of serum calcium concentration in SLE patients was affected by the immune cell activation and the application of GCs, but GCs did not promote the immune cell activation.

Conclusions

Low serum calcium may make SLE patients in an enhanced cellular immune status and GCs aggravates the decrease of serum calcium levels but has no role on the immune cell activation. It suggests that hypocalcemia possibly promotes the disease activity of SLE patient, which should be paid attention to clinically.
Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing
Authors: Hoft Stella G. , Pherson Michelle D. , DiPaolo Richard J.
Published: June 2022

Single-cell RNA sequencing (scRNAseq) technology is still relatively new in the field of gastric cancer immunology but gaining significant traction. This technology now provides unprecedented insights into the intratumoral and intertumoral heterogeneities at the immunological, cellular, and molecular levels. Within the last few years, a volume of publications reported the usefulness of scRNAseq technology in identifying thus far elusive immunological mechanisms that may promote and impede gastric cancer development. These studies analyzed datasets generated from primary human gastric cancer tissues, metastatic ascites fluid from gastric cancer patients, and laboratory-generated data fromin vitroandin vivomodels of gastric diseases. In this review, we overview the exciting findings from scRNAseq datasets that uncovered the role of critical immune cells, including T cells, B cells, myeloid cells, mast cells, ILC2s, and other inflammatory stromal cells, like fibroblasts and endothelial cells. In addition, we also provide a synopsis of the initial scRNAseq findings on the interesting epithelial cell responses to inflammation. In summary, these new studies have implicated roles for T and B cells and subsets like NKT cells in tumor development and progression. The current studies identified diverse subsets of macrophages and mast cells in the tumor microenvironment, however, additional studies to determine their roles in promoting cancer growth are needed. Some groups specifically focus on the less prevalent ILC2 cell type that may contribute to early cancer development. ScRNAseq analysis also reveals that stromal cells, e.g., fibroblasts and endothelial cells, regulate inflammation and promote metastasis, making them key targets for future investigations. While evaluating the outcomes, we also highlight the gaps in the current findings and provide an assessment of what this technology holds for gastric cancer research in the coming years. With scRNAseq technology expanding rapidly, we stress the need for periodic review of the findings and assess the available scRNAseq analytical tools to guide future work on immunological mechanisms of gastric carcinogenesis.
Harnessing the B Cell Response in Kidney Transplantation – Current State and Future Directions
Authors: Anwar Imran J. , DeLaura Isabel F. , Gao Qimeng , Ladowski Joseph , Jackson Annette M. , Kwun Jean , Knechtle Stuart J.
Published: June 2022

Despite dramatic improvement in kidney transplantation outcomes over the last decades due to advent of modern immunosuppressive agents, long-term outcomes remain poor. Antibody-mediated rejection (ABMR), a B cell driven process, accounts for the majority of chronic graft failures. There are currently no FDA-approved regimens for ABMR; however, several clinical trials are currently on-going. In this review, we present current mechanisms of B cell response in kidney transplantation, the clinical impact of sensitization and ABMR, the B cell response under current immunosuppressive regimens, and ongoing clinical trials for ABMR and desensitization treatment.
Schizophrenia and Inflammation Research: A Bibliometric Analysis
Authors: Sun He-Li , Bai Wei , Li Xiao-Hong , Huang Huanhuan , Cui Xi-Ling , Cheung Teris , Su Zhao-Hui , Yuan Zhen , Ng Chee H. , Xiang Yu-Tao
Published: June 2022

Background

Schizophrenia (SCZ) is a severe psychiatric disorder that involves inflammatory processes. The aim of this study was to explore the field of inflammation-related research in SCZ from a bibliometric perspective.

Methods

Regular and review articles on SCZ- and inflammation-related research were obtained from the Web of Science Core Collection (WOSCC) database from its inception to February 19, 2022. R package “bibliometrix” was used to summarize the main findings, count the occurrences of the top keywords, visualize the collaboration network between countries, and generate a three-field plot. VOSviewer software was applied to conduct both co-authorship and co-occurrence analyses. CiteSpace was used to identify the top references and keywords with the strongest citation burst.

Results

A total of 3,596 publications on SCZ and inflammation were included. Publications were mainly from the USA, China, and Germany. The highest number of publications was found in a list of relevant journals. Apart from “schizophrenia” and “inflammatory”, the terms “bipolar disorder,” “brain,” and “meta-analysis” were also the most frequently used keywords.

Conclusions

This bibliometric study mapped out a fundamental knowledge structure consisting of countries, institutions, authors, journals, and articles in the research field of SCZ and inflammation over the past 30 years. The results provide a comprehensive perspective about the wider landscape of this research area.
Current Status and Future Directions of Bacteria-Based Immunotherapy
Authors: Tang Quan , Peng Xian , Xu Bo , Zhou Xuedong , Chen Jing , Cheng Lei
Published: June 2022

With the in-depth understanding of the anti-cancer immunity, immunotherapy has become a promising cancer treatment after surgery, radiotherapy, and chemotherapy. As natural immunogenicity substances, some bacteria can preferentially colonize and proliferate inside tumor tissues to interact with the host and exert anti-tumor effect. However, further research is hampered by the infection-associated toxicity and their unpredictable behaviors in vivo. Due to modern advances in genetic engineering, synthetic biology, and material science, modifying bacteria to minimize the toxicity and constructing a bacteria-based immunotherapy platform has become a hotspot in recent research. This review will cover the inherent advantages of unedited bacteria, highlight how bacteria can be engineered to provide greater tumor-targeting properties, enhanced immune-modulation effect, and improved safety. Successful applications of engineered bacteria in cancer immunotherapy or as part of the combination therapy are discussed as well as the bacteria based immunotherapy in different cancer types. In the end, we highlight the future directions and potential opportunities of this emerging field.
Sertoli Cell Immune Regulation: A Double-Edged Sword
Authors: Washburn Rachel L. , Hibler Taylor , Kaur Gurvinder , Dufour Jannette M.
Published: June 2022

The testis must create and maintain an immune privileged environment to protect maturing germ cells from autoimmune destruction. The establishment of this protective environment is due, at least in part, to Sertoli cells. Sertoli cells line the seminiferous tubules and form the blood-testis barrier (BTB), a barrier between advanced germ cells and the immune system. The BTB compartmentalizes the germ cells and facilitates the appropriate microenvironment necessary for spermatogenesis. Further, Sertoli cells modulate innate and adaptive immune processes through production of immunoregulatory compounds. Sertoli cells, when transplanted ectopically (outside the testis), can also protect transplanted tissue from the recipient’s immune system and reduce immune complications in autoimmune diseases primarily by immune regulation. These properties make Sertoli cells an attractive candidate for inflammatory disease treatments and cell-based therapies. Conversely, the same properties that protect the germ cells also allow the testis to act as a reservoir site for infections. Interestingly, Sertoli cells also have the ability to mount an antimicrobial response, if necessary, as in the case of infections. This review aims to explore how Sertoli cells act as a double-edged sword to both protect germ cells from an autoimmune response and activate innate and adaptive immune responses to fight off infections.
Relapses of Anti-NMDAR, Anti-GABABR and Anti-LGI1 Encephalitis: A Retrospective Cohort Study
Authors: Zhong Rui , Chen Qingling , Zhang Xinyue , Zhang Hanyu , Lin Weihong
Published: June 2022

Objective

To investigate the relapse rate and study the factors that may predict the subsequent relapse in anti-NMDAR, anti-GABABR and anti-LGI1 encephalitis in Northeast China.

Methods

In the retrospective cohort study, we consecutively enrolled patients with anti-N1MDAR, anti-GABABR and anti-LGI1 encephalitis between March 2015 and November 2021. The patients were followed up for at least 6 months. The outcome variable was a binary variable of relapse or not. Predictors of relapse were identified.

Results

A total of 100 patients were enrolled. Relapse occurred in 26 (26%) patients after a median follow-up of 18 months since the first event. The relapse rates of anti - NMDAR, anti - GABABR and anti - LGI1 encephalitis were 25%, 33.3%, and 28.6%, respectively. The multivariable analysis results suggested that immunotherapy delay at the acute phase was independently associated with an increased risk of relapse in total patients (HR = 2.447, 95% CI = 1.027 - 5.832; P = 0.043). Subgroup analysis results showed that antibody titer was associated with the likelihood of relapse in anti-LGI1 encephalitis. The higher the concentration, the more likely it was for patients to have relapse (p=0.019).

Conclusion

The general relapse rate of anti-NMDAR, anti-GABABR and anti-LGI1 encephalitis was 26%. The risk of subsequent relapse was elevated in those with delayed immunotherapy in the first episode. In subgroup of anti-LGI1 encephalitis, higher antibody titer was the risk factors of relapse. Thus, timely and aggressive immunotherapy may be beneficial for patients to prevent subsequent relapse.
CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges
Authors: Zhang Xiaomin , Zhu Lingling , Zhang Hui , Chen Shanshan , Xiao Yang
Published: June 2022

Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.
Physical Process Controlling the Surface Bacterial Community Composition in the Ulleung Basin of East Sea
Authors: Kim Hyo-Ryeon , Lim Jae-Hyun , Kim Ju-Hyoung , Thangaraj Satheeswaran , Kim Il-Nam
Published: June 2022

Although environmental drivers are known to shape the abundance and distribution of bacterial communities in the East Sea, the effects of physical processes have not been directly studied. Here, we aimed to examine the influences of water mass mixing (summer) and eddy circulation (winter) on the surface bacterial communities of the Ulleung Basin (UB), East Sea, based on the metagenomic approach. Overall, 490,087 operational taxonomic units (OTUs) were identified from five stations, and prokaryotic abundance was dominant at all stations in both seasons. Among the prokaryotes, most OTUs were affiliated with Proteobacteria, Cyanobacteria, Flavobacteria, and Actinobacteria during summer and winter. Bacterial communities were found to differ with water masses (Changjiang, Tsushima, and North Korea surface water) and eddy circulation, and were strongly correlated with environmental variables, suggesting specific bacterial community responses with specific seasonal physicochemical parameters. Our investigation indicates that together with distance and environment, advection shapes the UB bacterial community composition, helping us better understand the physical cues related to biological composition in the East Sea. However, further studies are needed to ascertain the role of microbial functional genes along with the advection of oceanographic processes in the East Sea to better understand the regional biogeochemical processes.
Estimating the Impact of a Seasonal Fishing Moratorium on the East China Sea Ecosystem From 1997 to 2018
Authors: Xu Lingyan , Song Puqing , Wang Yuyu , Xie Bin , Huang Lingfeng , Li Yuan , Zheng Xinqing , Lin Longshan
Published: June 2022

Fisheries management policies (FMPs) have been implemented in coastal countries to ensure a sustainable supply of seafood and the recovery of species diversity. Because of the depletion of fishery stocks, China has introduced a series of FMPs since 1995, including a seasonal fishing moratorium (SFM), a zero-growth strategy, and a minimum mesh size for fishing nets. Here, we built two mass balance models for 1997–2000 (M1997) and 2018–2019 (M2018) using Ecopath with Ecosim 6.6 to illustrate the interannual changes over the past two decades in the East China Sea (ECS). We then simulated two dynamic scenarios from 1997 to 2018, SFM (M2018SFM) and no SFM (M2018no-SFM), to test the role of the SFM under fishing pressure in the ECS. Ecopath showed that the ECS ecosystem is becoming more mature, although it is still unstable, featuring lower total primary production/total respiration, longer cycles, faster organic material circulation speed, and a higher omnivorous degree. This suggests a slow recovery for the ECS ecosystem in the past two decades. The biomass of fish in the ECS—especially the planktivores, dominated by small-sized Benthosema pterotum—significantly increased in M2018 versus M1997, but there were fewer medium- and large-sized fish. The keystone species switched from the planktivores/piscivores dominated by Decapterus maruadsi in M1997 to planktivores in M2018. Ecosim illustrated that the SFM has positive effects on fishery resources recovery, especially for commercial fishes (i.e., large yellow croakers and hairtails), as reflected by the significantly higher predicted biomass of fish in M2018SFM compared to M2018no-SFM and M1997, although the bioaccumulation was consumed by the intense fishing pressure after the SFM. However, the M2018SFM prediction for nektons was still lower than the actual value, especially for planktivores, which display a sharp increase in biomass. This should be partly attributable to the policy of the minimum mesh size (<5 cm was banned), which benefits B. pterotum due to its 3.5 cm maximum body size. Therefore, a series of FMPs, rather than only the SFM, functioned together in the ECS ecosystem. However, the mixed trophic impact indicated a negative impact if the fisheries were further developed. Fishery management in the ECS needs to be strengthened by extending the SFM and reducing fishing pressure after the SFM.
Holocene Environmental Evolution Response to the Human Activities and East Asian Summer Monsoon Variation in the Liangzhu Ancient City Complex, Eastern China
Authors: Zou Chunhui , Mao Longjiang , Shan Siwei , Zhaocheng Shuangping , Mo Duowen
Published: June 2022

The Liangzhu Ancient City Complex is located in a low-lying coastal delta area, and its environmental evolution would have had a significant impact on the human-environment interactions. In this study, element geochemistry and grain size of the sediment sequence from a dam section in Ganggongling (GGL) reveal crucial aspects of sedimentary dynamics, environmental evolution, human activities, and East Asian Summer Monsoon(EASM) variation in the Liangzhu area since 5500 a. Starting from the middle-to-late Holocene, the GGL section shows an overall transition from warm humidity to cold-dry, which is consistent with the climate record dimension in southern China. Through comprehensive analysis of the sedimentary environment before and after the dam’s completion, it can be found that the Ganggongling dam has played a positive role in regulating mountain torrents and met the needs of production and domestic water, such as rice planting through water storage. Further applications on the multi-decadal to centennial time scale demonstrate that variations in solar activity may control the EASM intensity mainly in southern China, which is subject to ENSO intensity changes.
Temperature and Pressure Effects on HMX/Graphene via ReaxFF Molecular Dynamics Simulations
Authors: Yun Xiaopeng , Zhang Li
Published: June 2022

Studying the thermal decomposition of energetic materials at high temperatures can provide detailed reaction and mechanistic information, which is critical for understanding the reactivity of energetic materials, designing mixed explosives, and achieving improved safety. In this work, the effects of temperature and pressure on graphene (Gr)-based HMX crystals were investigated using ReaxFF molecular dynamics simulations. The thermal decomposition processes of perfect HMX crystals, HMX crystals with (001), (010), or (100) crystal planes, and HMX/Gr mixed systems were studied at high temperatures and pressures. In the mixed systems, different configurations of HMX molecules adsorbed on the Gr surface were confirmed by theoretical calculation methods. With the pressure ranging from atmospheric pressure to 31 GPa, 3, 5, and 3 configurations of HMX adsorbed on the Gr surface were identified for the (001)/Gr, (010)/Gr, and (100)/Gr systems, respectively. The time-dependent curves for the evolution of fragments, intermediates, and pyrolysis products were analyzed. The rate constant for the thermal decomposition of HMX was found to be significantly affected by the addition of Gr. In particular, the thermal decomposition reaction was strongly inhibited in the (010)/Gr system. This result indicates that Gr promotes an anisotropic thermal effect, resulting from the steric hindrance of the NO2 functional groups and the interaction between Gr and HMX molecules. Gr also affected the initial reaction pathway of homolytic N–NO2 bond cleavage, with C=O, C–OH, and C–OC bonds on the Gr surface participating in the formation of nitro radicals and HONO.