bluuebunny/crossref_metadata_2025 huggingface dataset:
No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis
Authors: Mensah-Kane Josephine , Schmidt Amand F. , Hingorani Aroon D. , Finan Chris , Chen Yutang , van Duijvenboden Stefan , Orini Michele , Lambiase Pier D. , Tinker Andrew , Marouli Eirini , Munroe Patricia B. , Ramírez Julia
Published: February 2021

Background

Reduced heart rate (HR) increase (HRI), recovery (HRR), and higher resting HR are associated with cardiovascular (CV) disease, but causal inferences have not been deduced. We investigated causal effects of HRI, HRR, and resting HR on CV risk, all-cause mortality (ACM), atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke (IS) using Mendelian Randomization.

Methods

11 variants for HRI, 11 for HRR, and two sets of 46 and 414 variants for resting HR were obtained from four genome-wide association studies (GWASs) on UK Biobank. We performed a lookup on GWASs for CV risk and ACM in UK Biobank (N = 375,367, 5.4% cases and N = 393,165, 4.4% cases, respectively). For CAD, AF, and IS, we used publicly available summary statistics. We used a random-effects inverse-variance weighted (IVW) method and sensitivity analyses to estimate causality.

Results

IVW showed a nominally significant effect of HRI on CV events (odds ratio [OR] = 1.0012, P = 4.11 × 10–2) and on CAD and AF. Regarding HRR, IVW was not significant for any outcome. The IVW method indicated statistically significant associations of resting HR with AF (OR = 0.9825, P = 9.8 × 10–6), supported by all sensitivity analyses, and a nominally significant association with IS (OR = 0.9926, P = 9.82 × 10–3).

Conclusion

Our findings suggest no strong evidence of an association between HRI and HRR and any outcome and confirm prior work reporting a highly significant effect of resting HR on AF. Future research is required to explore HRI and HRR associations further using more powerful predictors, when available.
Single-Cell Transcriptional Profiling Reveals Sex and Age Diversity of Gene Expression in Mouse Endothelial Cells
Authors: Huang Xianxi , Shen Wenjun , Veizades Stefan , Liang Grace , Sayed Nazish , Nguyen Patricia K.
Published: February 2021

Although it is well-known that sex and age are important factors regulating endothelial cell (EC) function, the impact of sex and age on the gene expression of ECs has not been systematically analyzed at the single cell level. In this study, we performed an integrated characterization of the EC transcriptome of five major organs (e.g., fat, heart-aorta, lung, limb muscle, and kidney) isolated from male and female C57BL/6 mice at 3 and 18 months of age. A total of 590 and 252 differentially expressed genes (DEGS) were identified between females and males in the 3- and 18-month subgroups, respectively. Within the younger and older group, there were 177 vs. 178 DEGS in fat, 305 vs. 469 DEGS in heart/aorta, 22 vs. 37 DEGS in kidney, 26 vs. 439 DEGS in limb muscle, and 880 vs. 274 DEGS in lung. Interestingly, LARS2, a mitochondrial leucyl tRNA synthase, involved in the translation of mitochondrially encoded genes was differentially expressed in all organs in males compared to females in the 3-month group while S100a8 and S100a9, which are calcium binding proteins that are increased in inflammatory and autoimmune states, were upregulated in all organs in males at 18 months. Importantly, findings from RNAseq were confirmed by qPCR and Western blot. Gene enrichment analysis found genes enriched in protein targeting, catabolism, mitochondrial electron transport, IL 1- and IL 2- signaling, and Wnt signaling in males vs. angiogenesis and chemotaxis in females at 3 months. In contrast, ECs from males and females at 18-months had up-regulation in similar pathways involved in inflammation and apoptosis. Taken together, our findings suggest that gene expression is largely similar between males and females in both age groups. Compared to younger mice, however, older mice have increased expression of genes involved in inflammation in endothelial cells, which may contribute to the development of chronic, non-communicable diseases like atherosclerosis, hypertension, and Alzheimer's disease with age.
Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Disturbances
Authors: Cerminara Maria , Spirito Giovanni , Pisciotta Livia , Squillario Margherita , Servetti Martina , Divizia Maria Teresa , Lerone Margherita , Berloco Bianca , Boeri Silvia , Nobili Lino , Vozzi Diego , Sanges Remo , Gustincich Stefano , Puliti Aldamaria
Published: February 2021

Autism Spectrum Disorder (ASD) refers to a broad range of conditions characterized by difficulties in communication, social interaction and behavior, and may be accompanied by other medical or psychiatric conditions. Patients with ASD and comorbidities are often difficult to diagnose because of the tendency to consider the multiple symptoms as the presentation of a complicated syndromic form. This view influences variant filtering which might ignore causative variants for specific clinical features shown by the patient. Here we report on a male child diagnosed with ASD, showing cognitive and motor impairments, stereotypies, hyperactivity, sleep, and gastrointestinal disturbances. The analysis of whole exome sequencing (WES) data with bioinformatic tools for oligogenic diseases helped us to identify two major previously unreported pathogenetic variants: a maternally inherited missense variant (p.R4122H) in HUWE1, an ubiquitin protein ligase associated to X-linked intellectual disability and ASD; and a de novo stop variant (p.Q259X) in TPH2, encoding the tryptophan hydroxylase 2 enzyme involved in serotonin synthesis and associated with susceptibility to attention deficit-hyperactivity disorder (ADHD). TPH2, expressed in central and peripheral nervous tissues, modulates various physiological functions, including gut motility and sleep. To the best of our knowledge, this is the first case presenting with ASD, cognitive impairment, sleep, and gastrointestinal disturbances linked to both HUWE1 and TPH2 genes. Our findings could contribute to the existing knowledge on clinical and genetic diagnosis of patients with ASD presentation with comorbidities.
Assessment of Causal Direction Between Gut Microbiota and Inflammatory Bowel Disease: A Mendelian Randomization Analysis
Authors: Zhang Zi-Jia , Qu Hong-Lei , Zhao Na , Wang Jing , Wang Xiu-Yan , Hai Rong , Li Bin
Published: February 2021

Background

Recent studies have shown that the gut microbiota is closely related to the pathogenesis of Inflammatory Bowel Disease (IBD), but the causal nature is largely unknown. The purpose of this study was to assess the causal relationship between intestinal bacteria and IBD and to identify specific pathogenic bacterial taxa via the Mendelian randomization (MR) analysis.

Materials and Methods

MR analysis was performed on genome-wide association study (GWAS) summary statistics of gut microbiota and IBD. Specifically, the TwinsUK microbiota GWAS (N = 1,126 twin pairs) was used as exposure. The UK inflammatory bowel disease (UKIBD) and the Understanding Social Program (USP) study GWAS (N = 48,328) was used as discovery outcome, and the British IBD study (N = 35,289) was used as replication outcome. SNPs associated with bacteria abundance at the suggestive significance level (α = 1.0 × 10–5) were used as instrumental variables. Bacteria were grouped into families and genera.

Results

In the discovery sample, a total of 30 features were available for analysis, including 15 families and 15 genera. Three features were nominally significant, including one family (Verrucomicrobiaceae, 2 IVs, beta = −0.04, p = 0.05) and two genera (Akkermansia, 2 IVs, beta = 0.04, p = 0.05; Dorea, 2 IVs, beta = −0.07, p = 0.04). All of them were successfully replicated in the replication sample (Verrucomicrobiaceae and Akkermansia Preplication = 0.02, Dorea Preplication = 0.01) with consistent effect direction.

Conclusion

We identified specific pathogenic bacteria features that were causally associated with the risk of IBD, thus offering new insights into the prevention and diagnosis of IBD.
CCR5 Promoter Polymorphisms Associated With Pulmonary Tuberculosis in a Chinese Han Population
Authors: Liu Shuyuan , Liu Nannan , Wang Hui , Zhang Xinwen , Yao Yufeng , Zhang Shuqiong , Shi Li
Published: February 2021

Background

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, is a major public health concern. Chemokines and their receptors, such as RANTES, CXCR3, and CCR5, have been reported to play important roles in cell activation and migration in immune responses against TB infection.

Methods

To understand the correlations involving CCR5 gene variations, M. tuberculosis infection, and TB disease progression, a case-control study comprising 450 patients with TB and 306 healthy controls from a Chinese Han population was conducted, along with the detection of polymorphisms in the CCR5 promoter using a sequencing method.

Results

After adjustment for age and gender, the results of logistic analysis indicated that the frequency of rs2734648-G was significantly higher in the TB patient group (P = 0.002, OR = 1.38, 95% CI: 1.123–1.696); meanwhile, rs2734648-GG showed notable susceptibility to TB (P = 6.32E-06, OR = 2.173, 95% CI: 1.546–3.056 in a recessive model). The genotypic frequency of rs1799987 also varied between the TB and control groups (P = 0.008). In stratified analysis, rs2734648-GG significantly increased susceptibility to pulmonary TB in a recessive model (P < 0.0001, OR = 2.382, 95% CI: 1.663–3.413), and the rs2734648-G allele significantly increased susceptibility to TB recurrence in a dominant model (P = 0.0032, OR = 1.936, 95% CI: 1.221–3.068), whereas rs1799987-AA was associated with susceptibility to pulmonary TB (P = 0.0078, OR = 1.678, 95% CI: 1.141–2.495 in a recessive model) but not with extra-pulmonary TB and TB recurrence. A haplotype constructed with the major alleles of the eight SNPs in the CCR5 promoter (rs2227010-rs2856758-rs2734648-rs1799987-rs1799988-rs41469351-rs1800023-rs1800024: A-A-G-G-T-C-G-C) exhibited extraordinarily increased risk of susceptibility to TB and pulmonary TB (P = 6.33E-11, OR = 24.887, 95% CI: 6.081–101.841).

Conclusion

In conclusion, CCR5 promoter polymorphisms were found to be associated with pulmonary TB and TB progression in Chinese Han people.
Altered Gut Microbiota Related to Inflammatory Responses in Patients With Huntington’s Disease
Authors: Du Gang , Dong Wei , Yang Qing , Yu Xueying , Ma Jinghong , Gu Weihong , Huang Yue
Published: February 2021

Emerging evidence indicates that gut dysbiosis may play a regulatory role in the onset and progression of Huntington’s disease (HD). However, any alterations in the fecal microbiome of HD patients and its relation to the host cytokine response remain unknown. The present study investigated alterations and host cytokine responses in patients with HD. We enrolled 33 HD patients and 33 sex- and age- matched healthy controls. Fecal microbiota communities were determined through 16S ribosomal DNA gene sequencing, from which we analyzed fecal microbial richness, evenness, structure, and differential abundance of individual taxa between HD patients and healthy controls. HD patients were evaluated for their clinical characteristics, and the relationships of fecal microbiota with these clinical characteristics were analyzed. Plasma concentrations of interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were measured by Meso Scale Discovery (MSD) assays, and relationships between microbiota and cytokine levels were analyzed in the HD group. HD patients showed increased α-diversity (richness), β-diversity (structure), and altered relative abundances of several taxa compared to those in healthy controls. HD-associated clinical characteristics correlated with the abundances of components of fecal microbiota at the genus level. Genus Intestinimonas was correlated with total functional capacity scores and IL-4 levels. Our present study also revealed that genus Bilophila were negatively correlated with proinflammatory IL-6 levels. Taken together, our present study represents the first to demonstrate alterations in fecal microbiota and inflammatory cytokine responses in HD patients. Further elucidation of interactions between microbial and host immune responses may help to better understand the pathogenesis of HD.
GM-CSF Expression and Macrophage Polarization in Joints of Undifferentiated Arthritis Patients Evolving to Rheumatoid Arthritis or Psoriatic Arthritis
Authors: Fuentelsaz-Romero Sara , Cuervo Andrea , Estrada-Capetillo Lizbeth , Celis Raquel , García-Campos Raquel , Ramírez Julio , Sastre Sergi , Samaniego Rafael , Puig-Kröger Amaya , Cañete Juan D.
Published: February 2021

Background and Aims

GM-CSF-dependent macrophage polarization has been demonstrated in rheumatoid arthritis (RA). Our aim was to seek diagnostic/prognostic biomarkers for undifferentiated arthritis (UA) by analyzing GM-CSF expression and source, macrophage polarization and density in joints of patients with UA evolving to RA or PsA compared with established RA or PsA, respectively.

Methods

Synovial tissue (ST) from patients with UA evolving to RA (UA>RA, n=8), PsA (UA>PsA, n=9), persistent UA (UA, n=16), established RA (n=12) and PsA (n=10), and healthy controls (n=6), were analyzed. Cell source and quantitative expression of GM-CSF and proteins associated with pro-inflammatory (GM-CSF-driven) and anti-inflammatory (M-CSF-driven) macrophage polarization (activin A, TNFα, MMP12, and CD209, respectively) were assessed in ST CD163+ macrophages by multicolor immunofluorescence. GM-CSF and activin A levels were also quantified in paired synovial fluid samples. CD163+ macrophage density was determined in all groups by immunofluorescence.

Results

Synovial stromal cells (FAP+ CD90+ fibroblast, CD90+ endothelial cells) and CD163+ sublining macrophages were the sources of GM-CSF. ST CD163+ macrophages from all groups expressed pro-inflammatory polarization markers (activin A, TNFα, and MMP12). Expression of the M-CSF-dependent anti-inflammatory marker CD209 identified two macrophage subsets (CD163+ CD209high and CD163+ CD209low/-). CD209+ macrophages were more abundant in ST from healthy controls and PsA patients, although both macrophage subtypes showed similar levels of pro-inflammatory markers in all groups. In paired synovial fluid samples, activin A was detected in all patients, with higher levels in UA>RA and RA, while GM-CSF was infrequently detected. ST CD163+ macrophage density was comparable between UA>RA and UA>PsA patients, but significantly higher than in persistent UA.

Conclusions

GM-CSF is highly expressed by sublining CD90+ FAP+ synovial fibroblasts, CD90+ activated endothelium and CD163+ macrophages in different types of arthritis. The polarization state of ST macrophages was similar in all UA and established arthritis groups, with a predominance of pro-inflammatory GM-CSF-associated markers. CD163+ macrophage density was significantly higher in the UA phases of RA and PsA compared with persistent UA. Taken together, our findings support the idea that GM-CSF is a strong driver of macrophage polarization and a potential therapeutic target not only in RA but also in PsA and all types of UA.
Pathogenicity of Proteinase 3-Anti-Neutrophil Cytoplasmic Antibody in Granulomatosis With Polyangiitis: Implications as Biomarker and Future Therapies
Authors: Granel Jérôme , Korkmaz Brice , Nouar Dalila , Weiss Stefanie A. I. , Jenne Dieter E. , Lemoine Roxane , Hoarau Cyrille
Published: February 2021

Granulomatosis with polyangiitis (GPA) is a rare but serious necrotizing auto-immune vasculitis. GPA is mostly associated with the presence of Anti-Neutrophil Cytoplasmic Antibody (ANCA) targeting proteinase 3 (PR3-ANCA), a serine protease contained in neutrophil granules but also exposed at the membrane. PR3-ANCAs have a proven fundamental role in GPA: they bind neutrophils allowing their auto-immune activation responsible for vasculitis lesions. PR3-ANCAs bind neutrophil surface on the one hand by their Fab binding PR3 and on the other by their Fc binding Fc gamma receptors. Despite current therapies, GPA is still a serious disease with an important mortality and a high risk of relapse. Furthermore, although PR3-ANCAs are a consistent biomarker for GPA diagnosis, relapse management currently based on their level is inconsistent. Indeed, PR3-ANCA level is not correlated with disease activity in 25% of patients suggesting that not all PR3-ANCAs are pathogenic. Therefore, the development of new biomarkers to evaluate disease activity and predict relapse and new therapies is necessary. Understanding factors influencing PR3-ANCA pathogenicity,i.e.their potential to induce auto-immune activation of neutrophils, offers interesting perspectives in order to improve GPA management. Most relevant factors influencing PR3-ANCA pathogenicity are involved in their interaction with neutrophils: level of PR3 autoantigen at neutrophil surface, epitope of PR3 recognized by PR3-ANCA, isotype and glycosylation of PR3-ANCA. We detailed in this review the advances in understanding these factors influencing PR3-ANCA pathogenicity in order to use them as biomarkers and develop new therapies in GPA as part of a personalized approach.
In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy
Authors: Giehl Esther , Kosaka Hiromichi , Liu Zuqiang , Feist Mathilde , Kammula Udai S. , Lotze Michael T. , Ma Congrong , Guo Zong Sheng , Bartlett David L.
Published: February 2021

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8+T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8+T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8+T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rαin vivopriming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.
Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives
Authors: Bogale Tizibt Ashine , Faustini Gaia , Longhena Francesca , Mitola Stefania , Pizzi Marina , Bellucci Arianna
Published: February 2021

Misfolded proteins, inflammation, and vascular alterations are common pathological hallmarks of neurodegenerative diseases. Alpha-synuclein is a small synaptic protein that was identified as a major component of Lewy bodies and Lewy neurites in the brain of patients affected by Parkinson's disease (PD), Lewy body dementia (LBD), and other synucleinopathies. It is mainly involved in the regulation of synaptic vesicle trafficking but can also control mitochondrial/endoplasmic reticulum (ER) homeostasis, lysosome/phagosome function, and cytoskeleton organization. Recent evidence supports that the pathological forms of α-synuclein can also reduce the release of vasoactive and inflammatory mediators from endothelial cells (ECs) and modulates the expression of tight junction (TJ) proteins important for maintaining the blood–brain barrier (BBB). This hints that α-synuclein deposition can affect BBB integrity. Border associated macrophages (BAMs) are brain resident macrophages found in association with the vasculature (PVMs), meninges (MAMs), and choroid plexus (CPMs). Recent findings indicate that these cells play distinct roles in stroke and neurodegenerative disorders. Although many studies have addressed how α-synuclein may modulate microglia, its effect on BAMs has been scarcely investigated. This review aims at summarizing the main findings supporting how α-synuclein can affect ECs and/or BAMs function as well as their interplay and effect on other cells in the brain perivascular environment in physiological and pathological conditions. Gaps of knowledge and new perspectives on how this protein can contribute to neurodegeneration by inducing BBB homeostatic changes in different neurological conditions are highlighted.
Macrophage-Targeted Lung Delivery of Dexamethasone Improves Pulmonary Fibrosis Therapy via Regulating the Immune Microenvironment
Authors: Sang Xiaoqing , Wang Yuanyuan , Xue Zhifeng , Qi Dawei , Fan Guanwei , Tian Fei , Zhu Yan , Yang Jian
Published: February 2021

Idiopathic pulmonary fibrosis (IPF) is serious chronic lung disease with limited therapeutic approaches. Inflammation and immune disorders are considered as the main factors in the initiation and development of pulmonary fibrosis. Inspired by the key roles of macrophages during the processes of inflammation and immune disorders, here, we report a new method for direct drug delivery into the in-situ fibrotic tissue sites in vitro and in vivo. First, liposomes containing dexamethasone (Dex-L) are prepared and designed to entry into the macrophages in the early hours, forming the macrophages loaded Dex-L delivery system (Dex-L-MV). Chemokine and cytokine factors such as IL-6, IL-10, Arg-1 are measured to show the effect of Dex-L to the various subtypes of macrophages. Next, we mimic the inflammatory and anti-inflammatory microenvironment by co-culture of polarized/inactive macrophage and fibroblast cells to show the acute inflammation response of Dex-L-MV. Further, we confirm the targeted delivery of Dex-L-MV into the inflammatory sites in vivo, and surprisingly found that injected macrophage containing Dex can reduce the level of macrophage infiltration and expression of the markers of collagen deposition during the fibrotic stage, while causing little systematic toxicity. These data demonstrated the suitability and immune regulation effect of Dex-L-MV for the anti-pulmonary process. It is envisaged that these findings are a step forward toward endogenous immune targeting systems as a tool for clinical drug delivery.
Endogenous Long Pentraxin 3 Exerts a Protective Role in a Murine Model of Pulmonary Fibrosis
Authors: Maccarinelli Federica , Bugatti Mattia , Churruca Schuind Ander , Ganzerla Sara , Vermi William , Presta Marco , Ronca Roberto
Published: February 2021

Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient Ptx3−/− animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, Ptx3-null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease.
Platelets in Multiple Sclerosis: Early and Central Mediators of Inflammation and Neurodegeneration and Attractive Targets for Molecular Imaging and Site-Directed Therapy
Authors: Orian Jacqueline M. , D'Souza Claretta S. , Kocovski Pece , Krippner Guy , Hale Matthew W. , Wang Xiaowei , Peter Karlheinz
Published: February 2021

Platelets are clearly central to thrombosis and hemostasis. In addition, more recently, evidence has emerged for non-hemostatic roles of platelets including inflammatory and immune reactions/responses. Platelets express immunologically relevant ligands and receptors, demonstrate adhesive interactions with endothelial cells, monocytes and neutrophils, and toll-like receptor (TLR) mediated responses. These properties make platelets central to innate and adaptive immunity and potential candidate key mediators of autoimmune disorders. Multiple sclerosis (MS) is the most common chronic autoimmune central nervous system (CNS) disease. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells. This was followed by reports identifying structural and functional changes of platelets, their chronic activation in the peripheral blood of MS patients, platelet presence in MS lesions and the more recent revelation that these structural and functional abnormalities are associated with all MS forms and stages. Investigations based on the murine experimental autoimmune encephalomyelitis (EAE) MS model first revealed a contribution to EAE pathogenesis by exacerbation of CNS inflammation and an early role for platelets in EAE development via platelet-neuron and platelet-astrocyte associations, through sialated gangliosides in lipid rafts. Our own studies refined and extended these findings by identifying the critical timing of platelet accumulation in pre-clinical EAE and establishing an initiating and central rather than merely exacerbating role for platelets in disease development. Furthermore, we demonstrated platelet-neuron associations in EAE, coincident with behavioral changes, but preceding the earliest detectable autoreactive T cell accumulation. In combination, these findings establish a new paradigm by asserting that platelets play a neurodegenerative as well as a neuroinflammatory role in MS and therefore, that these two pathological processes are causally linked. This review will discuss the implications of these findings for our understanding of MS, for future applications for imaging toward early detection of MS, and for novel strategies for platelet-targeted treatment of MS.
Lactobacillus acidipiscis Induced Regulatory Gamma Delta T Cells and Attenuated Experimental Autoimmune Encephalomyelitis
Authors: Ren Saisai , Zhang Xiaorong , Guan Hongbing , Wu Lihong , Yu Miao , Hou Dan , Yan Yongyong , Fang Xuechun
Published: February 2021

Multiple sclerosis is a chronic autoimmune disease involving the central nervous system, and shows a high disability rate. Its pathogenesis is complicated, and there is no good treatment. In recent years, with in-depth studies on the regulation of gastrointestinal flora, the relationship between the mammalian immune system and the intestinal flora has been extensively explored. Changes in the composition and structure of the gastrointestinal flora can affect the characteristics and development of the host immune system and even induce a series of central nervous system inflammation events. The occurrence and development of multiple sclerosis are closely related to the continuous destruction of the intestinal barrier caused by intestinal dysbacteriosis. In this study, we analyzed Lactobacillus acidipiscis in a mouse model of experimental autoimmune encephalomyelitis (EAE). We found that the amount of L. acidipiscis in the intestinal tract was inversely proportional to the progress of EAE development. In addition, the number of CD4+ FOXP3+ regulatory T cells in the mesenteric lymph nodes of mice increased significantly after the mice were fed with L. acidipiscis, and the differentiation of CD4+ T cells to Th1 and Th17 cells was inhibited. However, the protective effect of L. acidipiscis was lost in γδ T cell-deficient mice and hence was concluded to depend on the presence of regulatory γδ T cells in the intestinal epithelium. Moreover, including L. acidipiscis enhanced the development of Vγ1+γδ T cells but suppressed that of Vγ4+γδ T cells. In summary, our results demonstrated the ability of L. acidipiscis to induce generation of regulatory γδ T cells that suppress the development of the encephalomyelitic Th1 and Th17 cells and the progress of EAE.
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells
Authors: Ortutay Zsuzsanna , Grönholm Anna , Laitinen Melina , Keresztes-Andrei Melinda , Hermelo Ismail , Pesu Marko
Published: February 2021

The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specificFuringene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream ofFuringene was identified. When this region was deleted with CRISPR/Cas9 the production ofFurinmRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novelFurinregulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally,Furingenetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence ofFurinexpression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.
Malaria and Early Life Immunity: Competence in Context
Authors: Callaway Perri C. , Farrington Lila A. , Feeney Margaret E.
Published: February 2021

Childhood vaccines have been the cornerstone tool of public health over the past century. A major barrier to neonatal vaccination is the “immaturity” of the infant immune system and the inefficiency of conventional vaccine approaches at inducing immunity at birth. While much of the literature on fetal and neonatal immunity has focused on the early life propensity toward immune tolerance, recent studies indicate that the fetus is more immunologically capable than previously thought, and can, in some circumstances, mount adaptive B and T cell responses to perinatal pathogens in utero. Although significant hurdles remain before these findings can be translated into vaccines and other protective strategies, they should lend optimism to the prospect that neonatal and even fetal vaccination is achievable. Next steps toward this goal should include efforts to define the conditions for optimal stimulation of infant immune responses, including antigen timing, dose, and route of delivery, as well as antigen presentation pathways and co-stimulatory requirements. A better understanding of these factors will enable optimal deployment of vaccines against malaria and other pathogens to protect infants during their period of greatest vulnerability.
Establishment of Humanized Mice for the Study of HBV
Authors: Lai Fritz , Wee Cherry Yong Yi , Chen Qingfeng
Published: February 2021

Viral hepatitis particularly Hepatitis B Virus (HBV) is still an ongoing health issue worldwide. Despite the vast technological advancements in research and development, only HBV vaccines, typically given during early years, are currently available as a preventive measure against acquiring the disease from a secondary source. In general, HBV can be cleared naturally by the human immune system if detected at low levels early. However, long term circulation of HBV in the peripheral blood may be detrimental to the human liver, specifically targeting human hepatocytes for cccDNA integration which inevitably supports HBV life cycle for the purpose of reinfection in healthy cells. Although there is some success in using nucleoside analogs or polyclonal antibodies targeting HBV surface antigens (HBsAg) in patients with acute or chronic HBV+ (CHB), majority of them would either respond only partially or succumb to the disease entirely unless they undergo liver transplants from a fully matched healthy donor and even so may not necessarily guarantee a 100% chance of survival. Indeed, in vitro/ex vivo cultures and various transgenic animal models have already provided us with a good understanding of HBV but they primarily lack human specificity or virus-host interactions in the presence of human immune surveillance. Therefore, the demand of utilizing humanized mice has increased over the last decade as a pre-clinical platform for investigating human-specific immune responses against HBV as well as identifying potential immunotherapeutic strategies in eradicating the virus. Basically, this review covers some of the recent developments and key advantages of humanized mouse models over other conventional transgenic mice platforms.
Novel Bispecific Antibody for Synovial-Specific Target Delivery of Anti-TNF Therapy in Rheumatoid Arthritis
Authors: Ferrari Mathieu , Onuoha Shimobi C. , Fossati-Jimack Liliane , Nerviani Alessandra , Alves Pedro L. , Pagani Sara , Deantonio Cecilia , Colombo Federico , Santoro Claudio , Sblattero Daniele , Pitzalis Costantino
Published: February 2021

Biologic drugs, especially anti-TNF, are considered as the gold standard therapy in rheumatoid arthritis. However, non-uniform efficacy, incidence of infections, and high costs are major concerns. Novel tissue-specific agents may overcome the current limitations of systemic administration, providing improved potency, and safety. We developed a bispecific antibody (BsAb), combining human arthritic joint targeting, via the synovial-specific single-chain variable fragment (scFv)-A7 antibody, and TNFα neutralization, via the scFv-anti-TNFα of adalimumab, with the binding/blocking capacity comparable to adalimumab -immunoglobulin G (IgG). Tissue-targeting capacity of the BsAb was confirmed on the human arthritic synovium in vitro and in a synovium xenograft Severe combined immune deficient (SCID) mouse model. Peak graft accumulation occurred at 48 h after injection with sustained levels over adalimumab-IgG for 7 days and increased therapeutic effect, efficiently decreasing tissue cellularity, and markers of inflammation with higher potency compared to the standard treatment. This study provides the first description of a BsAb capable of drug delivery, specifically to the disease tissue, and a strong evidence of improved therapeutic effect on the human arthritic synovium, with applications to other existing biologics.
Natural Killer-Like B Cells Secreting Interleukin-18 Induces a Proinflammatory Response in Periodontitis
Authors: Zhang Ye , Kuang Wei , Li Danfeng , Li Yu , Feng Yi , Lyu Xinwei , Huang Gao-Bo , Lian Jian-Qi , Yang Xiao-Fei , Hu Cheng , Xie Yajuan , Xue Song , Tan Jiali
Published: February 2021

Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3−CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.
Tolerogenic Immunotherapy: Targeting DC Surface Receptors to Induce Antigen-Specific Tolerance
Authors: Castenmiller Charlotte , Keumatio-Doungtsop Brigitte-Carole , van Ree Ronald , de Jong Esther C. , van Kooyk Yvette
Published: February 2021

Dendritic cells (DCs) are well-established as major players in the regulation of immune responses. They either induce inflammatory or tolerogenic responses, depending on the DC-subtype and stimuli they receive from the local environment. This dual capacity of DCs has raised therapeutic interest for their use to modify immune-activation via the generation of tolerogenic DCs (tolDCs). Several compounds such as vitamin D3, retinoic acid, dexamethasone, or IL-10 and TGF-β have shown potency in the induction of tolDCs. However, an increasing interest exists in defining tolerance inducing receptors on DCs for new targeting strategies aimed to develop tolerance inducing immunotherapies, on which we focus particular in this review. Ligation of specific cell surface molecules on DCs can result in antigen presentation to T cells in the presence of inhibitory costimulatory molecules and tolerogenic cytokines, giving rise to regulatory T cells. The combination of factors such as antigen structure and conformation, delivery method, and receptor specificity is of paramount importance. During the last decades, research provided many tools that can specifically target various receptors on DCs to induce a tolerogenic phenotype. Based on advances in the knowledge of pathogen recognition receptor expression profiles in human DC subsets, the most promising cell surface receptors that are currently being explored as possible targets for the induction of tolerance in DCs will be discussed. We also review the different strategies that are being tested to target DC receptors such as antigen-carbohydrate conjugates, antibody-antigen fusion proteins and antigen-adjuvant conjugates.
Accounting for Seasonal Growth in Per-Recruit Analyses: A Case Study of Four Commercial Fish in Coastal China Seas
Authors: Liu Yiwen , Zhang Chongliang , Xu Binduo , Xue Ying , Ren Yiping , Chen Yong
Published: February 2021

Biological reference points (BRPs) derived from per-recruit analyses are commonly used in inferring stock status and serve as the target or threshold in fisheries management. However, the estimation of BRPs may be impacted by the variability in life history processes, and particularly, individual growth rates often display substantial seasonal oscillations but are seldomly considered in per-recruit analyses. Using four commercial fish species Lophius litulon, Saurida elongata, Hexagrammos otakii, and Larimichthys polyactis in coastal China Seas as examples, this study examined the effects of seasonal growth variability on per-recruit analyses and on the estimation of BRPs. We developed an individual-based modeling framework to simulate growth patterns with and without variations at the seasonal and the individual levels and adopted two common assessment methods, age-based analysis and length-frequency analysis, to estimate growth parameters regarding data availability in data-rich or data-poor fisheries, respectively. We found that ignoring seasonality could lead to substantial errors in the estimation of BRPs for the small-size species H. otakii and L. polyactis in our evaluation; when seasonal growth was considered, the estimation could be largely improved. Length-frequency analysis might yield considerably less reliable estimations than age-based method. The time of year when fast growth occurs determines positive or negative bias in estimation, and the amplitude of seasonal growth determines the degree of biases. In general, ignoring the seasonality of growth when there is can lead to underestimated growth parameter K and trigger biases that propagate in stock assessment and management, whereas incorporating seasonality falsely in assessment when there is no seasonal variation will have little influences on the estimation of BRPs. This study contributes to demonstrate the risk of ignoring seasonality in stock assessment and the approaches accounting for seasonal variability in fishery management.
Whole Community Metatranscriptomes and Lipidomes Reveal Diverse Responses Among Antarctic Phytoplankton to Changing Ice Conditions
Authors: Bowman Jeff S. , Van Mooy Benjamin A. S. , Lowenstein Daniel P. , Fredricks Helen F. , Hansel Colleen M. , Gast Rebecca , Collins James R. , Couto Nicole , Ducklow Hugh W.
Published: February 2021

The transition from winter to spring represents a major shift in the basal energy source for the Antarctic marine ecosystem from lipids and other sources of stored energy to sunlight. Because sea ice imposes a strong control on the transmission of sunlight into the water column during the polar spring, we hypothesized that the timing of the sea ice retreat influences the timing of the transition from stored energy to photosynthesis. To test the influence of sea ice on water column microbial energy utilization we took advantage of unique sea ice conditions in Arthur Harbor, an embayment near Palmer Station on the western Antarctic Peninsula, during the 2015 spring–summer seasonal transition. Over a 5-week period we sampled water from below land-fast sea ice, in the marginal ice zone at nearby Palmer Station B, and conducted an ice removal experiment with incubations of water collected below the land-fast ice. Whole-community metatranscriptomes were paired with lipidomics to better understand how lipid production and utilization was influenced by light conditions. We identified several different phytoplankton taxa that responded similarly to light by the number of genes up-regulated, and in the transcriptional complexity of this response. We applied a principal components analysis to these data to reduce their dimensionality, revealing that each of these taxa exhibited a strikingly different pattern of gene up-regulation. By correlating the changes in lipid concentration to the first principal component of log fold-change for each taxa we could make predictions about which taxa were associated with different changes in the community lipidome. We found that genes coding for the catabolism of triacylglycerol storage lipids were expressed early on in phytoplankton associated with a Fragilariopsis kerguelensis reference transcriptome. Phytoplankton associated with a Corethron pennatum reference transcriptome occupied an adjacent niche, responding favorably to higher light conditions than F. kerguelensis. Other diatom and dinoflagellate taxa had distinct transcriptional profiles and correlations to lipids, suggesting diverse ecological strategies during the polar winter–spring transition.
Structural and Mechanical Properties of Silica Mesoporous Films Synthesized Using Deep X-Rays: Implications in the Construction of Devices
Authors: Steinberg Paula Y. , Lionello Diego F. , Medone Acosta Daiana E. , Zalduendo M. Mercedes , Amenitsch Heinz , Granja Leticia P. , Marmiroli Benedetta , Angelomé Paula C. , Fuertes M. Cecilia
Published: February 2021

In recent years, the use of X-Rays (XR) irradiation for the production of ordered mesoporous thin films has been well established. This technique allows obtaining porous materials that contain thermal sensitive moieties or nanoparticles. Additionally, in combination with lithographic masks, the generation of high aspect ratio patterns of several geometrical shapes with micrometric resolution is possible. In this work, the structural and mechanical properties of porous silica thin films obtained by sol-gel method along with the exposure to high intensity XR is presented. Two templates (CTAB and Brij 58) and several irradiation doses and post-synthesis treatments were evaluated by a combination of characterization techniques, including grazing incidence small-angle XR scattering, electronic microscopies, XR reflectometry and nanoindentation. The results demonstrate that all the irradiated oxides presented a highly ordered mesoporous structure, independently of the XR dose and post thermal treatment. Their mechanical properties, on the other hand, clearly depend on the irradiation dose; high hardness values were measured on samples irradiated at low doses but higher doses are necessary to obtain films with indentation modulus values similar to the obtained for thermally treated coatings. The accessible porosity, essential for the application of these films in devices for micro- and nanofluidics, is also dependent on the dose and the thermal treatment performed afterward. The same tendency is observed for the films contraction and rigidity. After this characterization, it was concluded that thermal treatments are needed after the consolidation with XR to increase the accessibility and structural integrity of these porous oxides. Finally, the production of composites with metallic (Au and Ag) nanoparticles was tested which envisioned their applications in sensing and catalysis. Moreover, diverse geometrical patterns of both pure and Ag nanoparticles doped silica mesostructured films were obtained, demonstrating the feasibility of the proposed approach. The results presented in this work are of great importance to understand the transport mechanisms that operate in these silica porous films, in order to integrate them in different devices for lab-on-a-chip applications.