bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters
Authors: Bose Shroddha , He Hailan , Stauber Tobias
Published: February 2021

The regulation of luminal ion concentrations is critical for the function of, and transport between intracellular organelles. The importance of the acidic pH in the compartments of the endosomal-lysosomal pathway has been well-known for decades. Besides the V-ATPase, which pumps protons into their lumen, a variety of ion transporters and channels is involved in the regulation of the organelles' complex ion homeostasis. Amongst these are the intracellular members of the CLC family, ClC-3 through ClC-7. They localize to distinct but overlapping compartments of the endosomal-lysosomal pathway, partially with tissue-specific expression. Functioning as 2Cl−/H+ exchangers, they can support the vesicular acidification and accumulate luminal Cl−. Mutations in the encoding genes in patients and mouse models underlie severe phenotypes including kidney stones with CLCN5 and osteopetrosis or hypopigmentation with CLCN7. Dysfunction of those intracellular CLCs that are expressed in neurons lead to neuronal defects. Loss of endosomal ClC-3, which heteromerizes with ClC-4, results in neurodegeneration. Mutations in ClC-4 are associated with epileptic encephalopathy and intellectual disability. Mice lacking the late endosomal ClC-6 develop a lysosomal storage disease with reduced pain sensitivity. Human gene variants have been associated with epilepsy, and a gain-of-function mutation causes early-onset neurodegeneration. Dysfunction of the lysosomal ClC-7 leads to a lysosomal storage disease and neurodegeneration in mice and humans. Reduced luminal chloride, as well as altered calcium regulation, has been associated with lysosomal storage diseases in general. This review discusses the properties of endosomal and lysosomal Cl−/H+ exchange by CLCs and how various alterations of ion transport by CLCs impact organellar ion homeostasis and function in neurodegenerative disorders.
TBL1XR1 Ensures Balanced Neural Development Through NCOR Complex-Mediated Regulation of the MAPK Pathway
Authors: Mastrototaro Giuseppina , Zaghi Mattia , Massimino Luca , Moneta Matteo , Mohammadi Neda , Banfi Federica , Bellini Edoardo , Indrigo Marzia , Fagnocchi Giulia , Bagliani Anna , Taverna Stefano , Rohm Maria , Herzig Stephan , Sessa Alessandro
Published: February 2021

TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in the modulation of important cellular pathways and master regulators of transcriptional output, including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in a neurological context, leaving a knowledge gap in the mechanisms at the basis of the diseases. Here, we show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1 or its point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to a failure in the regulation of the MAPK cascade. Taken together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
Cardiovascular Risk Factors and Social Development Index
Authors: Martínez-García Mireya , Gutiérrez-Esparza Guadalupe O. , Roblero-Godinez Juan Carlos , Marín-Pérez Diana Vianey , Montes-Ruiz Cindy Lucia , Vallejo Maite , Hernández-Lemus Enrique
Published: February 2021

Cardiovascular diseases (CVD) are the leading causes of morbidity and mortality worldwide. The complex etiology of CVD is known to be significantly affected by environmental and social factors. There is, however, a lag in our understanding of how population level components may be related to the onset and severity of CVD, and how some indicators of unsatisfied basic needs might be related to known risk factors. Here, we present a cross-sectional study aimed to analyze the association between cardiovascular risk factors (CVRF) and Social Development Index (SDI) in adult individuals within a metropolitan urban environment. The six components of SDI as well as socioeconomic, anthropometric, clinical, biochemical, and risk behavior parameters were explored within the study population. As a result, several CVRF (waist circumference, waist-to-height ratio, body mass index, systolic blood pressure, glucose, lower high-density lipoprotein cholesterol, triglycerides, and sodium) were found in a higher proportion in the low or very low levels of the SDI, and this pattern occurs more in women than in men. Canonical analysis indicates a correlation between other socioeconomic features and anthropometric, clinical, and biochemical factors (canonical coefficient = 0.8030). Further studies along these lines are needed to fully establish how to insert such associations into the design of health policy and interventions with a view to lessen the burden of cardiovascular diseases, particularly in metropolitan urban environments.
Geological Structure of the Sylmar Basin: Implications for Slip Distribution Along the Santa Susana/Hospital and Mission Hills Fault System in the San Fernando Valley, CA, U.S.A.
Authors: Levy Yuval , Rockwell Thomas , Minas Shant , Hughes Alex , Rood Dylan
Published: February 2021

We developed a forward model using the Trishear module in MOVE to better understand the structure of the northwestern San Fernando Valley and the relationship among the Santa Susana, Hospital, Mission Hills and Northridge Hills faults. This study was motivated by the 1971 San Fernando earthquake and previous work that inferred a high slip rate on the Santa Susana fault, which is in apparent contrast to the lack of significant geomorphic expression of the fault in the Sylmar Basin region. We trenched the Mission Hills anticline from the crest to the base of slope and demonstrate that the Mission Hills anticline is an actively growing fault propagation fold. The associated thrust tip is either deeper than 15 m or sufficiently far to the south that the fault was not encountered in large diameter borings, but the minimum structural relief across the Mission Hills fault since the late Pleistocene is on the order of 37 m, suggesting a minimum uplift rate of 0.5 mm/yr. Our work presents a structural analysis that demonstrates how the Santa Susana fault system evolved in time, with the frontal thrust progressively migrating southward to the Mission Hills fault, and farther south to the Northridge Hills blind thrust. The progression of faulting towards the direction of vergence is compatible with the observed thrust front migration in the western Transverse Ranges of California, and other trust belts around the world.
A Sensitive Plasma Insulin Immunoassay to Establish the Diagnosis of Congenital Hyperinsulinism
Authors: Siersbæk Julie , Larsen Annette Rønholt , Nybo Mads , Christesen Henrik Thybo
Published: February 2021

Background

The diagnosis of congenital hyperinsulinism (CHI) may be hampered by a plasma (p-) insulin detection limit of 12–18 pmol/L (2–3 mU/L).

Objective

To evaluate the diagnostic performance of a sensitive insulin immunoassay and to find the optimal p-insulin cut-off for the diagnosis of CHI.

Methods

Diagnostic fasting tests, performed without medication or i.v.-glucose, were investigated in children with a clinical diagnosis of CHI, or idiopathic ketotic hypoglycemia (IKH). The CHI diagnosis was either clinical or by the alternative, p-insulin-free criteria; hypoglycemia plus disease-causing genetic mutations and/or CHI-compatible pancreatic histopathology. We included diagnostic p-insulin samples with simultaneous p-glucose <3.2 mmol/L and used a sensitive insulin assay (Cobas e411 immunoassay analyzer; lower detection limit 1.2 pmol/L; normal range 15.1–147.1 pmol/L). Receiver operating characteristics area under the curve (ROC AUC) values and optimal cut-offs were analyzed for the performance of p-insulin to diagnose CHI.

Results

In 61 CHI patients, the median (range) p-insulin was 76.5 (17–644) pmol/L compared to 1.5 (1.5–7.7) pmol/L in IKH patients (n=15). The ROC AUC was 1.0 for the diagnosis of CHI defined both by the clinical diagnosis (n=61) and by alternative criteria (n=57). The optimal p-insulin cut-offs were 12.3 pmol/L, and 10.6 pmol/L, at p-glucose <3.2 mmol/L (n=61), and <3.0 mmol/L (n=49), respectively.

Conclusions

The sensitive insulin assay performed excellent in diagnosing CHI with optimal p-insulin cut-offs at 12.3 pmol/L (2.0 mU/L), and 10.6 pmol/L (1.8 mU/L), at p-glucose <3.2 mmol/L, and <3.0 mmol/L, respectively. A sensitive insulin assay may serve to simplify the diagnosis of CHI.
Exploring the Stress Impact in the Paternal Germ Cells Epigenome: Can Catecholamines Induce Epigenetic Reprogramming?
Authors: González Candela R. , González Betina
Published: February 2021

Spermatogenesis is characterized by unique epigenetic programs that enable chromatin remodeling and transcriptional regulation for proper meiotic divisions and germ cells maturation. Paternal lifestyle stressors such as diet, drug abuse, or psychological trauma can directly impact the germ cell epigenome and transmit phenotypes to the next generation, pointing to the importance of epigenetic regulation during spermatogenesis. It is established that environmental perturbations can affect the development and behavior of the offspring through epigenetic inheritance, including changes in small non-coding RNAs, DNA methylation, and histones post-translational modifications. But how male germ cells react to lifestyle stressors and encode them in the paternal epigenome is still a research gap. Most lifestyle stressors activate catecholamine circuits leading to both acute and long-term changes in neural functions, and epigenetic mechanisms show strong links to both long-term and rapid, dynamic gene expression regulation during stress. Importantly, the testis shares a molecular and transcriptional signature with the brain tissue, including a rich expression of catecholaminergic elements in germ cells that seem to respond to stressors with similar epigenetic and transcriptional profiles. In this minireview, we put on stage the action of catecholamines as possible mediators between paternal stress responses and epigenetic marks alterations during spermatogenesis. Understanding the epigenetic regulation in spermatogenesis will contribute to unravel the coding mechanisms in the transmission of the biological impacts of stress between generations.
Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency
Authors: Fujita Yasunori , Bando Hironori , Iguchi Genzo , Iida Keiji , Nishizawa Hitoshi , Kanie Keitaro , Yoshida Kenichi , Matsumoto Ryusaku , Suda Kentaro , Fukuoka Hidenori , Ogawa Wataru , Takahashi Yutaka
Published: February 2021

Objective

Heterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies.

Design and Methods

We analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies.

Results

Immunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high.

Conclusions

Patients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.
Construction and Comprehensive Analyses of a METTL5-Associated Prognostic Signature With Immune Implication in Lung Adenocarcinomas
Authors: Sun Sijin , Fei Kailun , Zhang Guochao , Wang Juhong , Yang Yannan , Guo Wei , Yang Zhenlin , Wang Jie , Xue Qi , Gao Yibo , He Jie
Published: February 2021

For lung adenocarcinoma (LUAD), patients of different stages have strong heterogeneity, and their overall prognosis varies greatly. Thus, exploration of novel biomarkers to better clarify the characteristics of LUAD is urgent. Multi-omics information of LUAD patients were collected form TCGA. Three independent LUAD cohorts were obtained from gene expression omnibus (GEO). A multi-omics correlation analysis of METTL5 was performed in TCGA dataset. To build a METTL5-associated prognostic score (MAPS). Spathial and random forest methods were first applied for feature selection. Then, LASSO was implemented to develop the model in TCGA cohort. The prognostic value of MAPS was validated in three independent GEO datasets. Finally, functional annotation was conducted using gene set enrichment analysis (GSEA) and the abundances of infiltrated immune cells were estimated by ImmuCellAI algorithm. A total of 901 LUAD patients were included. The expression of METTL5 in LUAD was significantly higher than that in normal lung tissue. And high expression of METTL5 indicated poor prognosis in all different stages (P < 0.001, HR = 1.81). Five genes (RAC1, C11of24, METTL5, RCCD1, and SLC7A5) were used to construct MAPS and MAPS was significantly correlated with poor prognosis (P < 0.001, HR = 2.15). Furthermore, multivariate Cox regression analysis suggested MAPS as an independent prognostic factor. Functional enrichment revealed significant association between MAPS and several immune components and pathways. This study provides insights into the potential significance of METTL5 in LUAD and MAPS can serve as a promising biomarker for LUAD.
Selective Sweeps Uncovering the Genetic Basis of Horn and Adaptability Traits on Fine-Wool Sheep in China
Authors: Guo Tingting , Zhao Hongchang , Yuan Chao , Huang Shuhong , Zhou Shiwei , Lu Zengkui , Niu Chun’e , Liu Jianbin , Zhu Shaohua , Yue Yaojing , Yang Yuxin , Wang Xiaolong , Chen Yulin , Yang Bohui
Published: February 2021

Long-term natural and artificial selection leads to change in certain regions of the genome, resulting in selection signatures that can reveal genes associated with selected traits, such as horns (i.e., polled/horned), high-quality wool traits, and high-altitude hypoxia adaptability. These are complex traits determined by multiple genes, regulatory pathways, and environmental factors. A list of genes with considerable effects on horn and adaptability traits has not been found, although multiple quantitative trait loci (QTL) have been identified. Selection signatures could be identified using genetic differentiation (FST), polymorphism levels θπ, and Tajima’s D. This study aimed to identify selection signatures in fine-wool sheep and to investigate the genes annotated in these regions, as well as the biological pathways involved in horn and adaptability traits. For this purpose, the whole-genome sequence of 120 individuals from four breeds, which come from different elevations and habitats in China, was used to analyze selection signatures for horn and adaptability traits. Annotation of the consensus regions of FST and θπ ratios revealed a list of identified genes associated with polled/horned and high-altitude hypoxia adaptability traits, such as RXPF2, EERFC4, MSH6, PP1R12A, THBS1, ATP1B2, RYR2, and PLA2G2E. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified genes related primarily to mismatch repair, metabolism, vascular smooth muscle contraction, and cardiac muscle contraction. This is the first study to demonstrate that selection signatures play an important role in the polled/horned and high-altitude hypoxia adaptability traits of fine-wool sheep breeds that have undergone high-intensity selection and adapted to different ecological environments in China. Changes observed in the genome of fine-wool sheep may have acted on genomic regions that affect performance traits and provide a reference for genome design and breeding.
Joint Lp-Norm and L2,1-Norm Constrained Graph Laplacian PCA for Robust Tumor Sample Clustering and Gene Network Module Discovery
Authors: Kong Xiang-Zhen , Song Yu , Liu Jin-Xing , Zheng Chun-Hou , Yuan Sha-Sha , Wang Juan , Dai Ling-Yun
Published: February 2021

The dimensionality reduction method accompanied by different norm constraints plays an important role in mining useful information from large-scale gene expression data. In this article, a novel method named Lp-norm and L2,1-norm constrained graph Laplacian principal component analysis (PL21GPCA) based on traditional principal component analysis (PCA) is proposed for robust tumor sample clustering and gene network module discovery. Three aspects are highlighted in the PL21GPCA method. First, to degrade the high sensitivity to outliers and noise, the non-convex proximal Lp-norm (0 < p < 1)constraint is applied on the loss function. Second, to enhance the sparsity of gene expression in cancer samples, the L2,1-norm constraint is used on one of the regularization terms. Third, to retain the geometric structure of the data, we introduce the graph Laplacian regularization item to the PL21GPCA optimization model. Extensive experiments on five gene expression datasets, including one benchmark dataset, two single-cancer datasets from The Cancer Genome Atlas (TCGA), and two integrated datasets of multiple cancers from TCGA, are performed to validate the effectiveness of our method. The experimental results demonstrate that the PL21GPCA method performs better than many other methods in terms of tumor sample clustering. Additionally, this method is used to discover the gene network modules for the purpose of finding key genes that may be associated with some cancers.
Commercial Versus Volunteer: Comparing User Perceptions of Toxicity and Transparency in Content Moderation Across Social Media Platforms
Authors: Cook Christine L. , Patel Aashka , Wohn Donghee Yvette
Published: February 2021

Content moderation is a critical service performed by a variety of people on social media, protecting users from offensive or harmful content by reviewing and removing either the content or the perpetrator. These moderators fall into one of two categories: employees or volunteers. Prior research has suggested that there are differences in the effectiveness of these two types of moderators, with the more transparent user-based moderation being useful for educating users. However, direct comparisons between commercially-moderated and user-moderated platforms are rare, and apart from the difference in transparency, we still know little about what other disparities in user experience these two moderator types may create. To explore this, we conducted cross-platform surveys of over 900 users of commercially-moderated (Facebook, Instagram, Twitter, and YouTube) and user-moderated (Reddit and Twitch) social media platforms. Our results indicated that although user-moderated platforms did seem to be more transparent than commercially-moderated ones, this did not lead to user-moderated platforms being perceived as less toxic. In addition, commercially-moderated platform users want companies to take more responsibility for content moderation than they currently do, while user-moderated platform users want designated moderators and those who post on the site to take more responsibility. Across platforms, users seem to feel powerless and want to be taken care of when it comes to content moderation as opposed to engaging themselves.
Evolution of Fc Receptor-Like Scavenger in Mammals
Authors: Matos Maria Carolina , Pinheiro Ana , Melo-Ferreira José , Davis Randall S. , Esteves Pedro José
Published: February 2021

Fc receptor-like (FCRL) molecules comprise a large family of receptors, homologous to the receptors for the Fc portion of immunoglobulins (FCR). Within this family, an unusual gene known to exist in mice, rats and dogs, termedFCRLS, encodes a chimeric protein with both Ig-like FCRL and type B scavenger-receptor cysteine-rich (SRCR)-like domains. In mice,FCRLSis located next to theCD5LandKIRREL1genes. Here, we show that the curiousFCRLSgene is actually present across major mammalian groups, but its annotation is generally incorrect or absent. Anchored on mouseFCRLSandFCRL2genomic sequence alignments, phylogenetic analyses demonstrated that many mammalian sequences currently annotated asFCRL2cluster withFCRLS, supported by a conserved genetic synteny among organisms. This analysis shows thatFCRLSis present in Rodentia, some Carnivora (Canidae and Ursidae), Chiroptera, Arctiodactyla, Proboscidae, and some Primata. Thus, theFCRLSmost likely originated in a eutherian mammal ancestor since it is not present in Monotremata or Marsupialia.FCRLShas a peculiar distribution pattern across mammalian lineages, being present in some species, but absent in others from the same family, as in carnivores for example. The most parsimonious hypothesis to explain thisFCRLSevolution is that it was convergently lost in several independent mammalian lineages. Analyses of branch-specific nucleotide evolutionary rates, show thatFCRL2andFCRLShave similar ranges of rates across mammals, suggesting that both genes have crucial, but separate functions in the immune system. Bayesian estimates of evolutionary rates forFCRLSin mammalian lineages revealed that carnivores display the highest mutation rate after rodents. Additionally, positive diversifying selection was detected for bothFCRL2andFCRLS. Our results show that the presence of theFCRLSgene is older and more widespread across mammals than previously thought and appears to be functional, being under positive selection. Its precise physiologic role should thus be investigated.
STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
Authors: Safarzadeh Elham , Mohammadi Ali , Mansoori Behzad , Duijf Pascal H. G. , Hashemzadeh Shahryar , Khaze Vahid , Kazemi Tohid , Derakhshani Afshin , Silvestris Nicola , Baradaran Behzad
Published: February 2021

Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR-CD33+ MDSCs and CD3+ T cells from BC patients’ peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities in vitro. Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DR-CD33+ MDSCs. These cells strongly suppress both autologous and analogous CD3+ T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3+ T cells and, importantly, reduces breast cancer cells’ proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs’ level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy.
VJ Segment Usage of TCR-Beta Repertoire in Monozygotic Cystic Fibrosis Twins
Authors: Fischer Sebastian , Stanke Frauke , Tümmler Burkhard
Published: February 2021

Sixteen monozygotic cystic fibrosis (CF) twin pairs of whom 14 pairs were homozygous for the most common p.Phe508del CFTR mutation were selected from the European Cystic Fibrosis Twin and Sibling Study Cohort. The monozygotic twins were examined in their T cell receptor (TCR) repertoire in peripheral blood by amplicon sequencing of the CDR3 variable region of the ß-chain. The recruitment of TCR J and V genes for recombination and selection in the thymus showed a strong genetic influence in the CF twin cohort as indicated by the shortest Jensen-Shannon distance to the twin individual. Exceptions were the clinically most discordant and/or most severely affected twin pairs where clonal expansion probably caused by recurrent pulmonary infections overshadowed the impact of the identical genomic blueprint. In general the Simpson clonality was low indicating that the population of TCRß clonotypes of the CF twins was dominated by the naïve T-cell repertoire. Intrapair sharing of clonotypes was significantly more frequent among monozygotic CF twins than among pairs of unrelated CF patients. Complete nucleotide sequence identity was observed in about 0.11% of CDR3 sequences which partially should represent persisting fetal clones derived from the same progenitor T cells. Complete amino acid sequence identity was noted in 0.59% of clonotypes. Of the nearly 40,000 frequent amino acid clonotypes shared by at least two twin siblings 99.8% were already known within the immuneACCESS database and only 73 had yet not been detected indicating that the CDR3ß repertoire of CF children and adolescents does not carry a disease-specific signature but rather shares public clones with that of the non-CF community. Clonotypes shared within twin pairs and between unrelated CF siblings were highly abundant among healthy non-CF people, less represented in individuals with infectious disease and uncommon in patients with cancer. This subset of shared CF clonotypes defines CDR3 amino acid sequences that are more common in health than in disease.
Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer
Authors: Wu Jing , Cheng Hang , Wang Helei , Zang Guoxia , Qi Lingli , Lv Xinping , Liu Chunyan , Zhu Shan , Zhang Mingyou , Cui Jiuwei , Ueno Hideki , Liu Yong-Jun , Suo Jian , Chen Jingtao
Published: February 2021

Background

Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumor types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear.

Methods

We characterized ILCs and pDCs in the tumor microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing.

Results

ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological stage. There was a negative correlation between the numbers of ILC3s and pDCs in tumor tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumor immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumor-like microenvironment.

Conclusions

One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.
Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation
Authors: Tukaj Stefan , Mantej Jagoda , Sobala Michał , Potrykus Katarzyna , Tukaj Zbigniew , Zillikens Detlef , Ludwig Ralf J. , Bieber Katja , Kasperkiewicz Michael
Published: February 2021

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.
Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?
Authors: Gianchecchi Elena , Delfino Domenico V. , Fierabracci Alessandra
Published: February 2021

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hiNK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.
The “Gum–Gut” Axis in Inflammatory Bowel Diseases: A Hypothesis-Driven Review of Associations and Advances
Authors: Byrd Kevin M. , Gulati Ajay S.
Published: February 2021

In modern medicine, the oral cavity has often been viewed as a passive conduit to the upper airways and gastrointestinal tract; however, its connection to the rest of the body has been increasingly explored over the last 40 years. For several diseases, the periodontium and gingiva are at the center of this oral-systemic link. Over 50 systemic conditions have been specifically associated with gingival and periodontal inflammation, including inflammatory bowel diseases (IBD), which have recently been elevated from simple “associations” to elegant, mechanistic investigations. IBD and periodontitis have been reported to impact each other’s progression via a bidirectional relationship whereby chronic oral or intestinal inflammation can impact the other; however, the precise mechanisms for how this occurs remain unclear. Classically, the etiology of gingival inflammation (gingivitis) is oral microbial dysbiosis in the subgingival crevice that can lead to destructive periodontal disease (periodontitis); however, the current understanding of gingival involvement in IBD is that it may represent a separate disease entity from classical gingivitis, arising from mechanisms related to systemic inflammatory activation of niche-resident immune cells. Synthesizing available evidence, we hypothesize that once established, IBD can be driven by microbiomial and inflammatory changes originating specifically from the gingival niche through saliva, thereby worsening IBD outcomes and thus perpetuating a vicious cycle. In this review, we introduce the concept of the “gum–gut axis” as a framework for examining this reciprocal relationship between the periodontium and the gastrointestinal tract. To support and explore this gum–gut axis, we 1) provide a narrative review of historical studies reporting gingival and periodontal manifestations in IBD, 2) describe the current understanding and advances for the gum–gut axis, and 3) underscore the importance of collaborative treatment and research plans between oral and GI practitioners to benefit this patient population.
PSGL-1 Immune Checkpoint Inhibition for CD4+ T Cell Cancer Immunotherapy
Authors: DeRogatis Julia M. , Viramontes Karla M. , Neubert Emily N. , Tinoco Roberto
Published: February 2021

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+T cells may represent a new cancer therapy approach to eradicate tumors.
Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing
Authors: Verrier Eloi R. , Langevin Christelle
Published: February 2021

Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.
Genetic Conservation Management of Marine Resources and Ecosystems of Patagonian Fjords
Authors: Addamo Anna Maria , Zaccara Serena , Försterra Günter , Höfer Juan , García-Jiménez Ricardo , Crosa Giuseppe , Machordom Annie
Published: February 2021

The Chilean fjord region includes many remote and poorly known areas where management plans for the marine living resources and conservation strategies are urgently needed. Few data are available about the spatial distribution of its marine invertebrate fauna, prevalently influenced by complex interactions between biotic and abiotic factors, animal behavior and human activities. Patagonian fjords are a hotspot for finfish aquaculture, elevating Chile to the world’s second producer of farmed salmon, after Norway, a condition that emphasizes the necessity to develop strategies for a sustainable aquaculture management. The present study focuses on the emblematic cold-water coralDesmophyllum dianthus, dwelling the Comau Fjord from shallow to deep waters, with the aim to illustrate population structure, demography and adaptation of the species and its potential use for the development of a sustainable conservation and management plan for human activities. The analyses of microsatellite loci ofD. dianthusindividuals from four sampling localities along horizontal and vertical gradients of Comau Fjord, lead to identify them as a panmictic population. The results also contributed to consider a careful examination of the synchrony between the temporal and spatial variations of environmental factors and the biological cycle of the species as key role player in the inference of autecology of the species. The discussion stresses the importance of molecular analyses as extremely helpful tools for studies focusing on remote areas and non-model organisms, where logistic difficulties and limited scientific knowledge hamper a better management and conservation of marine resources, and in particular the relevance of multidisciplinary approaches to reduce the extensive knowledge gap on the remote fjord ecosystems of Patagonia. This study also highlights the importance of oceanographic information in the entire process of the analyses and interpretation of genetic results.
Marine Bacteria Community in a 150-m Depth Tachai Island, the Southeast Andaman Sea of Thailand
Authors: Sripan Donlaporn , Wilantho Alisa , Khitmoh Khunnalack , Wongsawaeng Doonyapong , Ouazzani Jamal , Chavanich Suchana , Tongsima Sissades , Somboonna Naraporn
Published: February 2021

The southeast Andaman Sea 52-m off the west coast of Phang Nga province, Thailand, is located in the Indian Ocean, representing a hotspot for marine biodiversity of the world. This study utilized metagenomics combined 16S rRNA gene (V3–V4) sequencing, and firstly revealed the microbiota and their metabolism potentials of this site at an epipelagic depth (150-m depth, TC150M), including comparison with its pelagic depth (30-m depth, TC30M) as well as other nearby Thailand and global ocean sites. Between TC150M and TC30M, the TC150M microbial metagenomics was an eight-fold higher, and the microbiota comprised, for examples more abundant Bacteroidetes while fewer Proteobacteria, than the TC30M. The microbial metabolic potentials of the TC150M were statistically higher in replication repair and metabolisms of amino acids, lipids, nucleotides, and xenobiotics biodegradation, etc. Following comparative microbiota analyses between three Andaman Sea sites and two Gulf of Thailand sites, the relatively great proportions of Bacteroidetes, Nitrospirae, Gemmatimonadetes, and Chlorobi characterized the southeast Andaman Sea. Nevertheless, the microbiota representing Thailand marine sites remained distinguished from the global ocean sites where beta diversities were close. Thai maritime sites showed proportionally higher Proteobacteria, Bacteroides, Nitrospirae, Gemmatimonadetes, and Chlorobi. Thus, the Thai marine microbiota database helps better understand our global ocean microbiota and microbial metabolic potentials. Here, the microbial metabolism potentials between Thailand and the global ocean sites of relatively close microbiota databases encompose the similar functions yet in statistically different frequencies. Our research provided the first preliminary marine microbiome comparison between the epipelagic and pelagic sea levels of the southeast Andaman Sea, Thailand.
Case Report: Refusal of an Veno-Arterial Extracorporeal Membrane Oxygenation Due to Malignant Disease? — An Extremely Rare Form of Cardiac Involvement in Acute Myeloid Leukemia
Authors: Zotzmann Viviane , Wengenmayer Tobias , Lang Corinna N. , Staudacher Dawid L. , Mueller-Peltzer Katharina , Bamberg Fabian , Marks Reinhard , Bode Christoph , Wäsch Ralph
Published: February 2021

We report here on a 61-year-old patient with acute right heart failure of unclear etiology. Echocardiography revealed a myocardial mass infiltrating the heart, though, we assumed a cardiac lymphoma. A VA-ECMO was implanted as bridging for diagnosis and therapy. Our patient received chemotherapy, under which the tumor (of unknown etiology at this point) reached a partial remission. Nine months after first admission the patient developed acute myeloid leukemia withDNMT3aandTET2mutations. Retrospective analysis of the cardiac biopsy revealed the identical mutations and matched with the diagnosis of an extremely rare primary extramedullary manifestation of an AML (myelosarcoma). The patient received induction-chemotherapy and was planned for consolidating allogeneic stem cell transplantation. From this case, we conclude that an extracorporeal therapy should be discussed in selected patients even in case of an initially fatal appearing prognosis. In selected cases, extracorporeal support can generate enough time for diagnosis and therapy. However, transparent planning, including discussion of best supportive care strategies involving the patient's family are indispensable requirements for starting ECMO in such patients.
Prospective Comparison of Saliva and Nasopharyngeal Swab Sampling for Mass Screening for COVID-19
Authors: Nacher Mathieu , Mergeay-Fabre Mayka , Blanchet Denis , Benoit Orelie , Pozl Tristan , Mesphoule Pauline , Sainte-Rose Vincent , Vialette Véronique , Toulet Bruno , Moua Aurélie , Saout Mona , Simon Stéphane , Guidarelli Manon , Galindo Muriel , Biche Barbara , Faurous William , Chaizemartin Laurie , Fahrasmane Aniza , Rochemont Devi , Vignier Nicolas , Vabret Astrid , Demar Magalie
Published: February 2021

Current testing for COVID-19 relies on reverse-transcriptase polymerase chain reaction from a nasopharyngeal swab specimen. Saliva samples have advantages regarding ease and painlessness of collection, which does not require trained staff and may allow self-sampling. We enrolled 776 persons at various field-testing sites and collected nasopharyngeal and pooled saliva samples. One hundred sixty two had a positive COVID-19 RT-PCR, 61% were mildly symptomatic and 39% asymptomatic. The sensitivity of RT-PCR on saliva samples vs. nasopharygeal swabs varied depending on the patient groups considered or on Ct thresholds. There were 10 (6.2%) patients with a positive saliva sample and a negative nasopharyngeal swab, all of whom had Ct values <25 for three genes. For symptomatic patients for whom the interval between symptoms onset and sampling was <10 days sensitivity was 77% but when excluding persons with isolated N gene positivity (54/162), sensitivity was 90%. In asymptomatic patients, the sensitivity was only 24%. When we looked at patients with Cts <30, sensitivity was 83 or 88.9% when considering two genes. The relatively good performance for patients with low Cts suggests that Saliva testing could be a useful and acceptable tool to identify infectious persons in mass screening contexts, a strategically important task for contact tracing and isolation in the community.
Advances in Genetic Engineering Technology and Its Application in the Industrial Fungus Aspergillus oryzae
Authors: Jin Feng-Jie , Hu Shuang , Wang Bao-Teng , Jin Long
Published: February 2021

The filamentous fungusAspergillus oryzaeis an important strain in the traditional fermentation and food processing industries and is often used in the production of soy sauce, soybean paste, and liquor-making. In addition,A. oryzaehas a strong capacity to secrete large amounts of hydrolytic enzymes; therefore, it has also been used in the enzyme industry as a cell factory for the production of numerous native and heterologous enzymes. However, the production and secretion of foreign proteins byA. oryzaeare often limited by numerous bottlenecks that occur during transcription, translation, protein folding, translocation, degradation, transport, secretion, etc. The existence of these problems makes it difficult to achieve the desired target in the production of foreign proteins byA. oryzae. In recent years, with the decipherment of the whole genome sequence, basic research and genetic engineering technologies related to the production and utilization ofA. oryzaehave been well developed, such as the improvement of homologous recombination efficiency, application of selectable marker genes, development of large chromosome deletion technology, utilization of hyphal fusion techniques, and application of CRISPR/Cas9 genome editing systems. The development and establishment of these genetic engineering technologies provided a great deal of technical support for the industrial production and application ofA. oryzae. This paper reviews the advances in basic research and genetic engineering technologies of the fermentation strainA. oryzaementioned above to open up more effective ways and research space for the breeding ofA. oryzaeproduction strains in the future.