bluuebunny/crossref_metadata_2025 huggingface dataset:
Stem Cell Mechanobiology and the Role of Biomaterials in Governing Mechanotransduction and Matrix Production for Tissue Regeneration
Authors: Naqvi S. M. , McNamara L. M.
Published: December 2020

Mechanobiology has underpinned many scientific advances in understanding how biophysical and biomechanical cues regulate cell behavior by identifying mechanosensitive proteins and specific signaling pathways within the cell that govern the production of proteins necessary for cell-based tissue regeneration. It is now evident that biophysical and biomechanical stimuli are as crucial for regulating stem cell behavior as biochemical stimuli. Despite this, the influence of the biophysical and biomechanical environment presented by biomaterials is less widely accounted for in stem cell-based tissue regeneration studies. This Review focuses on key studies in the field of stem cell mechanobiology, which have uncovered how matrix properties of biomaterial substrates and 3D scaffolds regulate stem cell migration, self-renewal, proliferation and differentiation, and activation of specific biological responses. First, we provide a primer of stem cell biology and mechanobiology in isolation. This is followed by a critical review of key experimental and computational studies, which have unveiled critical information regarding the importance of the biophysical and biomechanical cues for stem cell biology. This review aims to provide an informed understanding of the intrinsic role that physical and mechanical stimulation play in regulating stem cell behavior so that researchers may design strategies that recapitulate the critical cues and develop effective regenerative medicine approaches.
Chemical-Induced Cleft Palate Is Caused and Rescued by Pharmacological Modulation of the Canonical Wnt Signaling Pathway in a Zebrafish Model
Authors: Narumi Rika , Liu Shujie , Ikeda Naohiro , Morita Osamu , Tasaki Junichi
Published: December 2020

Cleft palate is one of the most frequent birth defects worldwide. It causes severe problems regarding eating and speaking and requires long-term treatment. Effective prenatal treatment would contribute to reducing the risk of cleft palate. The canonical Wnt signaling pathway is critically involved in palatogenesis, and genetic or chemical disturbance of this signaling pathway leads to cleft palate. Presently, preventative treatment for cleft palate during prenatal development has limited efficacy, but we expect that zebrafish will provide a useful high-throughput chemical screening model for effective prevention. To achieve this, the zebrafish model should recapitulate cleft palate development and its rescue by chemical modulation of the Wnt pathway. Here, we provide proof of concept for a zebrafish chemical screening model. Zebrafish embryos were treated with 12 chemical reagents known to induce cleft palate in mammals, and all 12 chemicals induced cleft palate characterized by decreased proliferation and increased apoptosis of palatal cells. The cleft phenotype was enhanced by combinatorial treatment with Wnt inhibitor and teratogens. Furthermore, the expression oftcf7andlef1as a readout of the pathway was decreased. Conversely, cleft palate was prevented by Wnt agonist and the cellular defects were also prevented. In conclusion, we provide evidence that chemical-induced cleft palate is caused by inhibition of the canonical Wnt pathway. Our results indicate that this zebrafish model is promising for chemical screening for prevention of cleft palate as well as modulation of the Wnt pathway as a therapeutic target.
Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion
Authors: Yuan MengYa , Yang YanRong , Li Yue , Yan ZhanJun , Lin ChangDong , Chen JianFeng
Published: December 2020

The homing of lymphocytes from blood to gut-associated lymphoid tissue is regulated by interaction between integrin α4β7 with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the endothelium of high endothelial venules (HEVs). However, the molecular basis of mucin-like domain, a specific structure of MAdCAM-1 regulating integrin α4β7-mediated cell adhesion remains obscure. In this study, we used heparan sulfate (HS), which is a highly acidic linear polysaccharide with a highly variable structure, to mimic the negative charges of the extracellular microenvironment and detected the adhesive behaviors of integrin α4β7 expressing 293T cells to immobilized MAdCAM-1 in vitro. The results showed that HS on the surface significantly promoted integrin α4β7-mediated cell adhesion, decreased the percentage of cells firmly bound and increased the rolling velocities at high wall shear stresses, which was dependent on the mucin-like domain of MAdCAM-1. Moreover, breaking the negative charges of the extracellular microenvironment of CHO-K1 cells expressing MAdCAM-1 with sialidase inhibited cell adhesion and rolling velocity of 293T cells. Mechanistically, electrostatic repulsion between mucin-like domain and negative charges of the extracellular microenvironment led to a more upright conformation of MAdCAM-1, which facilitates integrin α4β7-mediated cell adhesion. Our findings elucidated the important role of the mucin-like domain in regulating integrin α4β7-mediated cell adhesion, which could be applied to modulate lymphocyte homing to lymphoid tissues or inflammatory sites.
A Multi-Pronged Computational Pipeline for Prioritizing Drug Target Strategies for Latent Tuberculosis
Authors: Banerjee Ushashi , Sankar Santhosh , Singh Amit , Chandra Nagasuma
Published: December 2020

Tuberculosis is one of the deadliest infectious diseases worldwide and the prevalence of latent tuberculosis acts as a huge roadblock in the global effort to eradicate tuberculosis. Most of the currently available anti-tubercular drugs act against the actively replicating form of Mycobacterium tuberculosis (Mtb), and are not effective against the non-replicating dormant form present in latent tuberculosis. With about 30% of the global population harboring latent tuberculosis and the requirement for prolonged treatment duration with the available drugs in such cases, the rate of adherence and successful completion of therapy is low. This necessitates the discovery of new drugs effective against latent tuberculosis. In this work, we have employed a combination of bioinformatics and chemoinformatics approaches to identify potential targets and lead candidates against latent tuberculosis. Our pipeline adopts transcriptome-integrated metabolic flux analysis combined with an analysis of a transcriptome-integrated protein-protein interaction network to identify perturbations in dormant Mtb which leads to a shortlist of 6 potential drug targets. We perform a further selection of the candidate targets and identify potential leads for 3 targets using a range of bioinformatics methods including structural modeling, binding site association and ligand fingerprint similarities. Put together, we identify potential new strategies for targeting latent tuberculosis, new candidate drug targets as well as important lead clues for drug design.
Synthesis and Biomedical Applications of Lanthanides-Doped Persistent Luminescence Phosphors With NIR Emissions
Authors: Qin Xinyuan , Wang Jie , Yuan Quan
Published: December 2020

Persistent luminescence phosphors (PLPs) are largely used in biomedical areas owing to their unique advantages in reducing the autofluorescence and light-scattering interference from tissues. Moreover, PLPs with long-lived luminescence in the near-infrared (NIR) region are able to be applied in deep-tissue bioimaging or therapy due to the reduced light absorption of tissues in NIR region. Because of their abundant election levels and energy transfer channels, lanthanides are widely doped in PLPs for the generation of NIR persistent emissions. In addition, the crystal defects introduced by lanthanides-doping can serves as charge traps in PLPs, which contributes to the enhancement of persistent luminescence intensity and the increase of persistent time. In this paper, the research progress in the synthesis and biomedical applications of lanthanides-doped PLPs with NIR emissions are systematically summarized, which can provide instructions for the design and applications of PLPs in the future.
Nitric Oxide Production in Professional Skiers During Physical Activity at Maximum Load
Authors: Parshukova Olga I. , Varlamova Nina G. , Bojko Evgeny R.
Published: December 2020

The purpose of this study is to assess the production of nitric oxide in professional cross-country skiers with normotensive and hypertensive responses to physical activity at maximum load. The observation group included professional cross-country skiers (22.2 ± 7.1 years, = 107) who were current members of the national team of the Komi Republic. All the examined athletes performed the exercise test on a cycle ergometer “until exhaustion.” The following parameters were determined for each participant while they were sitting at rest, while at their anaerobic threshold level, during peak load, and during the recovery period (5th min): systolic blood pressure, diastolic blood pressure, heart rate, and the level of stable nitric oxide metabolites (nitrites, nitrates) in capillary blood samples. According to the blood pressure results, the cross-country skiers were divided into two groups. Group I included athletes with a normotensive response to stress. Group II was composed of individuals with a hypertensive response to stress. During the performance of the test “until exhaustion,” a significant (p < 0.05) increase in the amount of stable metabolites of nitric oxide was observed in the group of athletes with a normotensive response to the load compared with the group with a hypertensive response to the load. In athletes with a normotensive reaction to the load during exercise at maximum load and in the early recovery period, nitrate was prioritized in the regulation of vascular tone. The exercise test on a cycle ergometer “until exhaustion,” combined with the assessment of the levels of stable nitric oxide metabolites in plasma, can be considered a test for the early diagnosis of endothelial dysfunction in professional athletes.
Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies
Authors: Luci Carmelo , Bourinet Manon , Leclère Pierre S. , Anty Rodolphe , Gual Philippe
Published: December 2020

Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.
Are All Conservation Measures for Endangered Species Legitimate? Lines of Thinking With the European Hamster
Authors: Kletty Florian , Pelé Marie , Capber Fabrice , Habold Caroline
Published: December 2020

When dealing with the protection of an endangered species, it appears more and more important to address the ethical limits and the societal perception of the implemented conservation measures. This will be illustrated here through the example of conservation programs of the European hamster (Cricetus cricetus) in France. The main threats for this critically endangered rodent are the impoverishment and fragmentation of its habitat due to recent changes in agricultural practices and urbanization. Thus, the status of this species changed from harmful to endangered in only a few decades. This must lead to acceptance of the species by citizens and especially farmers paid to destroy this species until the 1990s while nowadays to protect it. To stem the decline, several measures have been taken through the last 20 years including population reinforcement, wild animal tracking, and implementation of suitable habitats. One can, therefore, discuss the efficiency of these measures and their integration in the entire socio-ecosystem. Population reinforcement and the questions that can arise from it will first be addressed. Secondly, in situ animal monitoring and implications of the methods used will be discussed. Third, we will deal with agricultural practices favorable to the species. Finally, we will highlight the links between European hamster conservation measures and wider problematics.
Biophysical and Socioeconomic Factors Associated to Deforestation and Forest Recovery in Brazilian Tropical Dry Forests
Authors: Espírito-Santo Mário Marcos do , Rocha André Medeiros , Leite Marcos Esdras , Silva Jhonathan Oliveira , Silva Lucas Augusto Pereira , Sanchez-Azofeifa Gerardo Arturo
Published: December 2020

The determination of land cover changes (LCCs) and their association to biophysical and socioeconomic factors is vital to support government policies toward the sustainable use of natural resources. The present study aimed to quantify deforestation, forest recovery and net cover change in tropical dry forests (TDFs) in Brazil from 2007 to 2016, and investigate how they are associated to biophysical and socioeconomic factors. We also assessed the effects of LCC variables in human welfare indicators. For this purpose, we used MODIS imagery to calculate TDF gross loss (deforestation), gross gain (forest recovery) and net cover change (the balance between deforestation and forest recovery) for 294 counties in three Brazilian states (Minas Gerais, Bahia, and Piauí). We obtained seven factors potentially associated to LCC at the county level: total county area, road density, humidity index, slope, elevation, and % change in human population and in cattle density. From 2007 to 2016, TDF cover increased from 76,693 to 80,964 km2 (+5.6%). This positive net change resulted from a remarkable forest recovery of 19,018 km2 (24.8%), offsetting a large deforested area (14,748 km2; 19.2%). Practically all these cover changes were a consequence of transitions from TDF to pastures and vice-versa, highlighting the importance of developing sustainable policies for cattle raising in TDF regions. Each LCC variable was associated to different set of factors, but two biophysical variables were significantly associated both to TDF area gained and lost per county: county area (positively) and slope (negatively), indicating that large and flat counties have very dynamic LCCs. The TDF net area change was only associated (negatively) to the humidity index, reflecting an increase in TDF cover in more arid counties. The net increase in Brazilian TDF area is likely a result from an interplay of biophysical and socioeconomic factors that reduced deforestation and caused pasture abandonment. Although the ecological integrity and permanence of secondary TDFs need further investigation, the recovery of this semi-arid ecosystem must be valued and accounted for in the national forest restoration programs, as it would significantly help achieving the goals established in the Bonn agreement and the Atlantic Rain Forest pact.
ChIAMM: A Mixture Model for Statistical Analysis of Long-Range Chromatin Interactions From ChIA-PET Experiments
Authors: Arega Yibeltal , Jiang Hao , Wang Shuangqi , Zhang Jingwen , Niu Xiaohui , Li Guoliang
Published: December 2020

Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is an important experimental method for detecting specific protein-mediated chromatin loops genome-wide at high resolution. Here, we proposed a new statistical approach with a mixture model, chromatin interaction analysis using mixture model (ChIAMM), to detect significant chromatin interactions from ChIA-PET data. The statistical model is cast into a Bayesian framework to consider more systematic biases: the genomic distance, local enrichment, mappability, and GC content. Using different ChIA-PET datasets, we evaluated the performance of ChIAMM and compared it with the existing methods, including ChIA-PET Tool, ChiaSig, Mango, ChIA-PET2, and ChIAPoP. The result showed that the new approach performed better than most top existing methods in detecting significant chromatin interactions in ChIA-PET experiments.
Revealing the Interactions Between Diabetes, Diabetes-Related Diseases, and Cancers Based on the Network Connectivity of Their Related Genes
Authors: Zhu Lijuan , Xiang Ju , Wang Qiuling , Wang Ailan , Li Chao , Tian Geng , Zhang Huajun , Chen Size
Published: December 2020

Diabetes-related diseases (DRDs), especially cancers pose a big threat to public health. Although people have explored pathological pathways of a few common DRDs, there is a lack of systematic studies on important biological processes (BPs) connecting diabetes and its related diseases/cancers. We have proposed and compared 10 protein–protein interaction (PPI)-based computational methods to study the connections between diabetes and 254 diseases, among which a method called DIconnectivity_eDMN performs the best in the sense that it infers a disease rank (according to its relation with diabetes) most consistent with that by literature mining. DIconnectivity_eDMN takes diabetes-related genes, other disease-related genes, a PPI network, and genes in BPs as input. It first maps genes in a BP into the PPI network to construct a BP-related subnetwork, which is expanded (in the whole PPI network) by a random walk with restart (RWR) process to generate a so-called expanded modularized network (eMN). Since the numbers of known disease genes are not high, an RWR process is also performed to generate an expanded disease-related gene list. For each eMN and disease, the expanded diabetes-related genes and disease-related genes are mapped onto the eMN. The association between diabetes and the disease is measured by the reachability of their genes on all eMNs, in which the reachability is estimated by a method similar to the Kolmogorov–Smirnov (KS) test. DIconnectivity_eDMN achieves an area under receiver operating characteristic curve (AUC) of 0.71 for predicting both Type 1 DRDs and Type 2 DRDs. In addition, DIconnectivity_eDMN reveals important BPs connecting diabetes and DRDs. For example, “respiratory system development” and “regulation of mRNA metabolic process” are critical in associating Type 1 diabetes (T1D) and many Type 1 DRDs. It is also found that the average proportion of diabetes-related genes interacting with DRDs is higher than that of non-DRDs.
Inhibiting Protein Kinase D Promotes Airway Epithelial Barrier Integrity in Mouse Models of Influenza A Virus Infection
Authors: Veazey Janelle M. , Eliseeva Sophia I , Hillman Sara E. , Stiles Kristie , Smyth Timothy R. , Morrissey Charlotte E. , Tillotson Erika J. , Topham Dave J. , Chapman Timothy J. , Georas Steve N.
Published: December 2020

Rationale

Protein kinase D (PKD) is a serine/threonine kinase family that is involved in a wide array of signaling pathways. Although PKD has been implicated in immune responses, relatively little is known about the function of PKD in the lung or during viral infections.

Objectives

We investigated the hypothesis that PKD is involved in multiple aspects of host response to viral infection.

Methods

The selective PKD inhibitor CRT0010166 was administered to C57BL/6 mice prior to and during challenge with either inhaled double-stranded RNA or Influenza A Virus. PKD signaling pathways were investigated in human bronchial epithelial cells treated with CRT0010166, double-stranded RNA, and/or infected with Influenza A Virus.

Measurements

Total protein and albumin accumulation in the bronchoalveolar fluid was used to asses inside/out leak. Clearance of inhaled FITC-dextran out of the airspace was used to assess outside/in leak. Cytokines and neutrophils in bronchoalveolar lavage were assayed with ELISAs and cytospins respectively. Viral RNA level was assessed with RT-PCR and protein level assessed by ELISA.

Main Results

PKD inhibition prevented airway barrier dysfunction and pro-inflammatory cytokine release. Epithelial cells express PKD3, and PKD3 siRNA knock-down inhibited polyI:C induced cytokine production. Lung epithelial-specific deletion of PKD3 (CC10-Cre x PKD3-floxed mice) partially attenuated polyI:C-induced barrier disruption in vivo. Mechanistically, we found that PKD promoted cytokine mRNA transcription, not secretion, likely through activating the transcription factor Sp1. Finally, prophylactic CRT treatment of mice promoted barrier integrity during influenza virus infection and reduced viral burden.

Conclusions

Inhibiting PKD promotes barrier integrity, limit pathogenic cytokine levels, and restrict Influenza A Virus infection. Therefore, PKD is an attractive target for novel antiviral therapeutics.
Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome
Authors: Augé Hélène , Notarantonio Anne-Béatrice , Morizot Romain , Quinquenel Anne , Fornecker Luc-Matthieu , Hergalant Sébastien , Feugier Pierre , Broséus Julien
Published: December 2020

Introduction

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS.

Methods

We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options.

Results

Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results.

Conclusion

RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
Absence of Anti-Glomerular Basement Membrane Antibodies in 200 Patients With Systemic Lupus Erythematosus With or Without Lupus Nephritis: Results of the GOODLUPUS Study
Authors: Bourse Chalvon Nellie , Orquevaux Pauline , Giusti Delphine , Gatouillat Gregory , Tabary Thierry , Tonye Libyh Marcelle , Chrusciel Jan , Drame Moustapha , Stockton-Bliard Grace , Amoura Zahir , Arnaud Laurent , Lorenz Hanns-Martin , Blaison Gilles , Bonnotte Bernard , Magy-Bertrand Nadine , Revuz Sabine , Voll Reinhard Edmund , Hinschberger Oliver , Schwarting Andreas , Pham Bach Nga , Martin Thierry , Pennaforte Jean-Loup , Servettaz Amelie
Published: December 2020

Introduction

Anti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.

Objective

The main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or withoutproliferativerenal damage and compared to a healthy control group.

Methodology

This retrospective study was performed on SLE patients’ sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).

Results

The cohort was composed of 100 SLE patients withproliferativeLN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found “ambivalent” (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.

Conclusion

Anti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.
Oral Immunotherapy and Basophil and Mast Cell Reactivity in Food Allergy
Authors: Paranjape Anuya , Tsai Mindy , Mukai Kaori , Hoh Ramona A. , Joshi Shilpa A. , Chinthrajah R. Sharon , Nadeau Kari C. , Boyd Scott D. , Galli Stephen J.
Published: December 2020

Basophil activation tests (BATs) can closely monitor,in vitro, a patient’s propensity to develop type I hypersensitivity reactions. Because of their high specificity and sensitivity, BATs have become promising diagnostic tools, especially in cases with equivocal clinical histories, skin prick test results, and/or levels of specific IgE to allergen extracts. BATs also are useful as tools for monitoring the effects of treatment, since oral immunotherapy (OIT) studies report a diminution in patients’ basophil responsiveness over the course of OIT. This review will discuss the BAT findings obtained before, during, and after OIT for food allergy. We will mainly focus on the association of basophil responsiveness, and alterations in basophil surface markers, with clinical outcomes and other clinical features, such as blood levels of specific IgG and IgE antibodies. The detailed analysis of these correlations will ultimately facilitate the use of BATs, along with other blood biomarkers, to differentiate short-term desensitization versus sustained unresponsiveness and to improve treatment protocols. Given the critical anatomic location of mast cells adjacent to the many IgE+plasma cells found in the gastrointestinal tissues of allergic individuals, we will also discuss the role of gastrointestinal mast cells in manifestations of food allergies.
Platelets and Regulatory T Cells May Induce a Type 2 Immunity That Is Conducive to the Progression and Fibrogenesis of Endometriosis
Authors: Xiao Fengyi , Liu Xishi , Guo Sun-Wei
Published: December 2020

Endometriosis is a hormonal disease, as well as a chronic inflammatory disease. While various immune cells are documented to be involved in endometriosis, there is a wanton lack of a bigger picture on how these cells are coordinated to work concertedly. Since endometriotic lesions experience cyclical bleeding, they are fundamentally wounds that undergo repeated tissue injury and repair (ReTIAR). In this study, we attempted to characterize the role of platelets and regulatory T cells (Tregs) in modulating the lesional immune microenvironment and its subsequent effects on lesional progression and fibrogenesis. Through two mouse experiments, we show that, by disrupting predominantly a type 2 immune response in lesional microenvironment, both platelets and Tregs depletion decelerated lesional progression and fibrogenesis, likely through the suppression of the TGF-β1/Smad3 and PDGFR-β/PI3K/Akt signaling pathways. In particular, platelet depletion resulted in significantly reduced lesional expression of thymic stromal lymphopoietin (TSLP), leading to reduced aggregation of macrophages and alternatively activated (M2) macrophages, and of Tregs, T helper 2 (Th2) and Th17 cells but increased aggregation of Th1 cells, in lesions, which, in turn, yields retarded fibrogenesis. Similarly, Tregs depletion resulted in suppression of platelet aggregation, and reduced aggregation of M2 macrophages, Th2 and Th17 cells but increased aggregation of Th1 cells, in lesions. Thus, both platelet and Tregs depletion decelerated lesional progression and fibrogenesis by disrupting predominantly a type 2 immunity in lesional microenvironment. Taken together, this suggests that both platelets and Tregs may induce a type 2 immunity in lesional microenvironment that is conducive to lesional progression and fibrogenesis.
The Role of NLRP3 Inflammasome in Pneumococcal Infections
Authors: Surabhi Surabhi , Cuypers Fabian , Hammerschmidt Sven , Siemens Nikolai
Published: December 2020

Inflammasomes are innate immune sensors that regulate caspase-1 mediated inflammation in response to environmental, host- and pathogen-derived factors. The NLRP3 inflammasome is highly versatile as it is activated by a diverse range of stimuli. However, excessive or chronic inflammasome activation and subsequent interleukin-1β (IL-1β) release are implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and diabetes. Accordingly, inflammasome inhibitor therapy has a therapeutic benefit in these diseases. In contrast, NLRP3 inflammasome is an important defense mechanism against microbial infections. IL-1β antagonizes bacterial invasion and dissemination. Unfortunately, patients receiving IL-1β or inflammasome inhibitors are reported to be at a disproportionate risk to experience invasive bacterial infections including pneumococcal infections. Pneumococci are typical colonizers of immunocompromised individuals and a leading cause of community-acquired pneumonia worldwide. Here, we summarize the current limited knowledge of inflammasome activation in pneumococcal infections of the respiratory tract and how inflammasome inhibition may benefit these infections in immunocompromised patients.
FDG-PET Profiles of Extratemporal Metabolism as a Predictor of Surgical Failure in Temporal Lobe Epilepsy
Authors: Tang Yongxiang , Liao Guang , Li Jian , Long Tingting , Li Yulai , Feng Li , Chen Dengming , Tang Beisha , Hu Shuo
Published: December 2020

Objective: Metabolic abnormality in the extratemporal area on fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is not an uncommon finding in drug-resistant temporal lobe epilepsy (TLE), however the correlation between extratemporal metabolic abnormalities and surgical long-term prognosis has not been fully elucidated. We aim to investigate FDG-PET extratemporal metabolic profiles predictive of failure in surgery for TLE patients.

Methods: Eighty-two patients with unilateral TLE (48 female, 34 male; 25.6 ± 10.6 years old; 37 left TLE, 45 right TLE) and 30 healthy age-matched controls were enrolled. Patients were classified either as experiencing seizure-recurrence (SZR, Engel class II through IV) or seizure-free (SZF, Engel class I) at least 1 year after surgery. Regional cerebral metabolism was evaluated by FDG-PET with statistical parametric mapping (SPM12). Abnormal metabolic profiles and patterns on FDG-PET in SZR group were evaluated and compared with those of healthy control and SZF subjects on SPM12. Volume and intensity as well as special brain areas of abnormal metabolism in temporal and extratemporal regions were quantified and visualized.

Results: With a median follow-up of 1.5 years, 60% of patients achieved Engel class I (SZF). SZR was associated with left TLE and widespread hypometabolism in FDG-PET visual assessment (both p < 0.05). All patients had hypometabolism in the ipsilateral temporal lobe but SZR was not correlated with volume or intensity of temporal hypometabolism (median, 1,456 vs. 1,040 mm3; p > 0.05). SZR was correlated with extratemporal metabolic abnormalities that differed according to lateralization: in right TLE, SZR exhibited larger volume in extratemporal areas compared to SZF (median, 11,060 vs. 2,112 mm3; p < 0.05). Surgical failure was characterized by Cingulum_Ant_R/L, Frontal_Inf_Orb_R abnormal metabolism in extratemporal regions. In left TLE, SZR presented a larger involvement of extratemporal areas similar to right TLE but with no significant (median, 5,873 vs. 3,464 mm3; p > 0.05), Cingulum_Ant_ R/L, Parietal_Inf_L, Postcentral_L, and Precuneus_R involved metabolic abnormalities were correlated with SZR.

Conclusions: Extratemporal metabolic profiles detected by FDG-PET may indicate a prominent cause of TLE surgery failure and should be considered in predictive models for epilepsy surgery. Seizure control after surgery might be improved by investigating extratemporal areas as candidates for resection or neuromodulation.
Antimycobacterial Potential of Mycobacteriophage Under Disease-Mimicking Conditions
Authors: Kalapala Yeswanth Chakravarthy , Sharma Pallavi Raj , Agarwal Rachit
Published: December 2020

Antibiotic resistance continues to be a major global health risk with an increase in multi-drug resistant infections seen across nearly all bacterial diseases. Mycobacterial infections such as Tuberculosis (TB) and Non-Tuberculosis infections have seen a significant increase in the incidence of multi-drug resistant and extensively drug-resistant infections. With this increase in drug-resistant Mycobacteria, mycobacteriophage therapy offers a promising alternative. However, a comprehensive study on the infection dynamics of mycobacteriophage against their host bacteria and the evolution of bacteriophage (phage) resistance in the bacteria remains elusive. We aim to study the infection dynamics of a phage cocktail against Mycobacteria under various pathophysiological conditions such as low pH, low growth rate and hypoxia. We show that mycobacteriophages are effective against M. smegmatis under various conditions and the phage cocktail prevents emergence of resistance for long durations. Although the phages are able to amplify after infection, the initial multiplicity of infection plays an important role in reducing the bacterial growth and prolonging efficacy. Mycobacteriophages are effective against antibiotic-resistant strains of Mycobacterium and show synergy with antibiotics such as rifampicin and isoniazid. Finally, we also show that mycobacteriophages are efficient against M. tuberculosis both under lag and log phase for several weeks. These findings have important implications for developing phage therapy for Mycobacterium.
Control of Methicillin-Resistant Staphylococcus aureus Strains Associated With a Hospital Outbreak Involving Contamination From Anesthesia Equipment Using UV-C
Authors: Ochoa Sara A. , Cruz-Córdova Ariadnna , Mancilla-Rojano Jetsi , Escalona-Venegas Gerardo , Esteban-Kenel Veronica , Franco-Hernández Isabel , Parra-Ortega Israel , Arellano-Galindo José , Hernández-Castro Rigoberto , Perez-López Citlalli F. , De la Rosa-Zamboni Daniela , Xicohtencatl-Cortes Juan
Published: December 2020

Methicillin-resistant Staphylococcus aureus (MRSA) is considered an opportunistic pathogen in humans and is mainly associated with healthcare-associated infections (HCAIs). This bacterium colonizes the skin and mucous membranes of healthy people and causes frequent hospital outbreaks. The aim of this study was to perform molecular typing of the staphylococcal cassette chromosome mec (SCCmec) and agr loci as wells as to establish the pulsotypes and clonal complexes (CCs) for MRSA and methicillin-sensitive S. aureus (MSSA) outbreaks associated with the operating room (OR) at a pediatric hospital. Twenty-five clinical strains of S. aureus (19 MRSA and 6 MSSA strains) were recovered from the outbreak (patients, anesthesia equipment, and nasopharyngeal exudates from external service anesthesia technicians). These clinical S. aureus strains were mainly resistant to benzylpenicillin (100%) and erythromycin (84%) and were susceptible to vancomycin and nitrofurantoin. The SCCmec type II was amplified in 84% of the S. aureus strains, and the most frequent type of the agr locus was agrII, which was amplified in 72% of the strains; however, the agrI and agrIII genes were mainly detected in MSSA strains. A pulsed-field gel electrophoresis (PFGE) analysis grouped the 25 strains into 16 pulsotypes (P), the most frequent of which was P1, including 10 MRSA strains related to the anesthesia equipment, external service anesthesia technicians, and hospitalized patients. Multilocus sequence typing (MLST) identified 15 sequence types (STs) distributed in nine CCs. The most prevalent ST was ST1011, belonging to CC5, which was associated with the SCCmec type II and agrII type. We postulate that the external service anesthesia technicians were MRSA carriers and that these strains were indirectly transmitted from the contaminated anesthesia equipment that was inappropriately disinfected. Finally, the MRSA outbreak was controlled when the anesthesia equipment disinfection was improved and hand hygiene was reinforced.
The Weathering Microbiome of an Outcropping Granodiorite
Authors: Napieralski Stephanie A. , Roden Eric E.
Published: December 2020

Microorganisms have long been recognized for their capacity to catalyze the weathering of silicate minerals. While the vast majority of studies on microbially mediated silicate weathering focus on organotrophic metabolism linked to nutrient acquisition, it has been recently demonstrated that chemolithotrophic ferrous iron [Fe(II)] oxidizing bacteria (FeOB) are capable of coupling the oxidation of silicate mineral Fe(II) to metabolic energy generation and cellular growth. In natural systems, complex microbial consortia with diverse metabolic capabilities can exist and interact to influence the biogeochemical cycling of essential elements, including iron. Here we combine microbiological and metagenomic analyses to investigate the potential interactions among metabolically diverse microorganisms in the near surface weathering of an outcrop of the Rio Blanco Quartz Diorite (DIO) in the Luquillo Mountains of Puerto Rico. Laboratory based incubations utilizing ground DIO as metabolic energy source for chemolithotrophic FeOB confirmed the ability of FeOB to grow via the oxidation of silicate-bound Fe(II). Dramatically accelerated rates of Fe(II)-oxidation were associated with an enrichment in microorganisms with the genetic capacity for iron oxidizing extracellular electron transfer (EET) pathways. Microbially oxidized DIO displayed an enhanced susceptibility to the weathering activity of organotrophic microorganisms compared to unoxidized mineral suspensions. Our results suggest that chemolithotrophic and organotrophic microorganisms are likely to coexist and contribute synergistically to the overall weathering of the in situ bedrock outcrop.
Antimicrobial Resistance and in silico Virulence Profiling of Aliarcobacter butzleri Strains From German Water Poultry
Authors: Müller Eva , Hotzel Helmut , Linde Jörg , Hänel Ingrid , Tomaso Herbert
Published: December 2020

Aliarcobacter butzleri is an emerging foodborne and zoonotic pathogen that is usually transmitted via contaminated food or water. A. butzleri is not only the most prevalent Aliarcobacter species, it is also closely related to thermophilic Campylobacter, which have shown increasing resistance in recent years. Therefore, it is important to assess its resistance and virulence profiles. In this study, 45 Aliarcobacter butzleri strains from water poultry farms in Thuringia, Germany, were subjected to an antimicrobial susceptibility test using the gradient strip diffusion method and whole-genome sequencing. In the phylogenetic analysis, the genomes of the German strains showed high genetic diversity. Thirty-three isolates formed 11 subgroups containing two to six strains. The antimicrobial susceptibility testing showed that 32 strains were resistant to erythromycin, 26 to doxycycline, and 20 to tetracycline, respectively. Only two strains were resistant to ciprofloxacin, while 39 strains were resistant to streptomycin. The in silico prediction of the antimicrobial resistance profiles identified a large repertoire of potential resistance mechanisms. A strong correlation between a gyrA point mutation (Thr-85-Ile) and ciprofloxacin resistance was found in 11 strains. A partial correlation was observed between the presence of the bla3 gene and ampicillin resistance. In silico virulence profiling revealed a broad spectrum of putative virulence factors, including a complete lipid A cluster in all studied genomes.
Potential Mechanisms for Traditional Chinese Medicine in Treating Airway Mucus Hypersecretion Associated With Coronavirus Disease 2019
Authors: Zhang Yuanfeng , Wang Zheyi , Zhang Yue , Tong Hongxuan , Zhang Yiling , Lu Tao
Published: December 2020

Background

The rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19.

Objective

To get core herbs with high used frequency applications in the actions of expectoration by using association rule algorithm and to investigate the multitarget mechanisms of core herbs in expectorant formulae for COVID-19 therapies.

Methods

Forty prescriptions for expectorant were retrieved from TCM Formulae. The ingredient compounds and targets of core herbs were collected from the TCMSP database, Gene-Cards, and NCBI. The protein interaction network (PPI) was constructed by SRING, and the network analysis was done by Cytoscape software. Bioconductor was applied for functional enrichment analysis of targets.

Results

The core herbs of expectorant could regulate core pathways (MAP kinase activity, cytokine receptor binding, G-protein-coupled receptor binding, etc.) via interactions of ingredients (glycyrol, citromitin, etc.) on mucin family to eliminate phlegm.

Conclusion

TCM herbal expectorant could regulate MAPK and cytokine-related pathways, thereby modulating Mucin-family to affect mucus generation and clearance and eventually retarding the deterioration of COVID-19 disease.
Lack of a Clear Behavioral Phenotype in an Inducible FXTAS Mouse Model Despite the Presence of Neuronal FMRpolyG-Positive Aggregates
Authors: Haify Saif N. , Mankoe Ruchira S. D. , Boumeester Valerie , van der Toorn Esmay C. , Verhagen Rob F. M. , Willemsen Rob , Hukema Renate K. , Bosman Laurens W. J.
Published: December 2020

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder caused by a 55–200 CGG repeat expansion in the 5′ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene. FXTAS is characterized by progressive cerebellar ataxia, Parkinsonism, intention tremors and cognitive decline. The main neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the brain. The molecular pathology of FXTAS involves the presence of 2 to 8-fold elevated levels of FMR1 mRNA, and of a repeat-associated non-AUG (RAN) translated polyglycine peptide (FMRpolyG). Increased levels of FMR1 mRNA containing an expanded CGG repeat can result in cellular toxicity by an RNA gain-of-function mechanism. The increased levels of CGG repeat-expanded FMR1 transcripts may create RNA foci that sequester important cellular proteins, including RNA-binding proteins and FMRpolyG, in intranuclear inclusions. To date, it is unclear whether the FMRpolyG-positive intranuclear inclusions are a cause or a consequence of FXTAS disease pathology. In this report we studied the relation between the presence of neuronal intranuclear inclusions and behavioral deficits using an inducible mouse model for FXTAS. Neuronal intranuclear inclusions were observed 4 weeks after dox-induction. After 12 weeks, high numbers of FMRpolyG-positive intranuclear inclusions could be detected in the hippocampus and striatum, but no clear signs of behavioral deficits related to these specific brain regions were found. In conclusion, the observations in our inducible mouse model for FXTAS suggest a lack of correlation between the presence of intranuclear FMRpolyG-positive aggregates in brain regions and specific behavioral phenotypes.
Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families
Authors: Xie Yongzhi , Lin Zhiqiang , Pakhrin Pukar Singh , Li Xiaobo , Wang Binghao , Liu Lei , Huang Shunxiang , Zhao Huadong , Cao Wanqian , Hu Zhengmao , Guo Jifeng , Shen Lu , Tang Beisha , Zhang Ruxu
Published: December 2020

Background and Objectives: Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort.

Aims and Methods: We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation.

Results: Two novel heterozygous mutations in GARS, c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with WARS, SORD, SIGMAR1, and HSPB1 mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in LRSAM1, was identified in a patient with mild dHMN phenotype.

Conclusion: Our study expanded the mutation spectrum of GARS mutations and added evidence that GARS mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and SORD mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.