bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes
Authors: Lincez Pamela J. , Shanina Iryna , Horwitz Marc S.
Published: November 2021

Seemingly redundant in function, melanoma differentiation-associated protein 5 (MDA5) and toll-like receptor- 3 (TLR3) both sense RNA viruses and induce type I interferon (IFN-I). Herein, we demonstrate that changes in sensing of the same virus by MDA5 and TLR3 can lead to distinct signatures of IFN-α and IFN-ß resulting in different disease outcomes. Specifically, infection with a diabetogenic islet β cell-tropic strain of coxsackievirus (CB4) results in diabetes protection under reduced MDA5 signaling conditions while reduced TLR3 function retains diabetes susceptibility. Regulating the induction of IFN-I at the site of virus infection creates a local site of interferonopathy leading to loss of T cell regulation and induction of autoimmune diabetes. We have not demonstrated another way to prevent T1D in the NOD mouse, rather we believe this work has provided compounding evidence for a specific control of IFN-I to drive a myriad of responses ranging from virus clearance to onset of autoimmune diabetes.
Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells
Authors: Guolo Fabio , Minetto Paola , Pesce Silvia , Ballerini Filippo , Clavio Marino , Cea Michele , Frello Michela , Garibotto Matteo , Greppi Marco , Bozzo Matteo , Miglino Maurizio , Passannante Monica , Marcolin Riccardo , Tedone Elisabetta , Colombo Nicoletta , Mangerini Rosa , Bo Alessandra , Ruzzenenti Maria Rosaria , Carlier Paolo , Serio Alberto , Luchetti Silvia , Dominietto Alida , Varaldo Riccardo , Candiani Simona , Agostini Vanessa , Ravetti Jean Louis , Del Zotto Genny , Marcenaro Emanuela , Lemoli Roberto Massimo
Published: November 2021

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the “adaptive” NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.
Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma
Authors: Yan Min , Hu Jing , Ping Yanyan , Xu Liwen , Liao Gaoming , Jiang Zedong , Pang Bo , Sun Shangqin , Zhang Yunpeng , Xiao Yun , Li Xia
Published: November 2021

The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy.
Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease
Authors: Lu Yanjun , Li Ke , Hu Yu , Wang Xiong
Published: November 2021

Immune infiltration of peripheral natural killer (NK) cells in the brain has been observed in Alzheimer’s disease (AD). Immunity-related genes (IRGs) play an essential role in immune infiltration; however, the expression of IRGs and possible regulatory mechanisms involved in AD remain unclear. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD were analyzed and PBMCs obtained from the ImmPort database were screened for cluster marker genes. IRG activity was calculated using the AUCell package. A bulk sequencing dataset of AD brain tissues was analyzed to explore common IRGs between PBMCs and the brain. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. The protein-protein interaction network of key TFs were generated using the STRING database. Eight clusters were identified, including memory CD4 T, NKT, NK, B, DC, CD8 T cells, and platelets. NK cells were significantly decreased in patients with AD, while CD4 T cells were increased. NK and DC cells exhibited the highest IRG activity. GO and KEGG analyses of the scRNA and bulk sequencing data showed that the DEGs focused on the immune response. Seventy common IRGs were found in both peripheral NK cells and the brain. Seventeen TFs were associated with IRG expression, and the PPI network indicated that STAT3, IRF1, and REL were the hub TFs. In conclusion, we propose that peripheral NK cells may infiltrate the brain and contribute to neuroinflammatory changes in AD through bioinformatic analysis of scRNA and bulk sequencing data. Moreover, STAT3 may be involved in the transcriptional regulation of IRGs in NK cells.
Revising Host Phenotypes of Sepsis Using Microbiology
Authors: Zhao Huiying , Kennedy Jason N. , Wang Shu , Brant Emily B. , Bernard Gordon R. , DeMerle Kimberley , Chang Chung-Chou H. , Angus Derek C. , Seymour Christopher W.
Published: November 2021

Background: There is wide heterogeneity in sepsis in causative pathogens, host response, organ dysfunction, and outcomes. Clinical and biologic phenotypes of sepsis are proposed, but the role of pathogen data on sepsis classification is unknown.

Methods: We conducted a secondary analysis of the Recombinant Human Activated Protein C (rhAPC) Worldwide Evaluation in Severe Sepsis (PROWESS) Study. We used latent class analysis (LCA) to identify sepsis phenotypes using, (i) only clinical variables (“host model”) and, (ii) combining clinical with microbiology variables (e.g., site of infection, culture-derived pathogen type, and anti-microbial resistance characteristics, “host-pathogen model”). We describe clinical characteristics, serum biomarkers, and outcomes of host and host-pathogen models. We tested the treatment effects of rhAPC by phenotype using Kaplan-Meier curves.

Results: Among 1,690 subjects with severe sepsis, latent class modeling derived a 4-class host model and a 4-class host-pathogen model. In the host model, alpha type (N = 327, 19%) was younger and had less shock; beta type (N=518, 31%) was older with more comorbidities; gamma type (N = 532, 32%) had more pulmonary dysfunction; delta type (N = 313, 19%) had more liver, renal and hematologic dysfunction and shock. After the addition of microbiologic variables, 772 (46%) patients changed phenotype membership, and the median probability of phenotype membership increased from 0.95 to 0.97 (P < 0.01). When microbiology data were added, the contribution of individual variables to phenotypes showed greater change for beta and gamma types. In beta type, the proportion of abdominal infections (from 20 to 40%) increased, while gamma type patients had an increased rate of lung infections (from 50 to 78%) with worsening pulmonary function. Markers of coagulation such as d-dimer and plasminogen activator inhibitor (PAI)-1 were greater in the beta type and lower in the gamma type. The 28 day mortality was significantly different for individual phenotypes in host and host-pathogen models (both P < 0.01). The treatment effect of rhAPC obviously changed in gamma type when microbiology data were added (P-values of log rank test changed from 0.047 to 0.780).

Conclusions: Sepsis host phenotype assignment was significantly modified when microbiology data were added to clinical variables, increasing cluster cohesiveness and homogeneity.
Expression of Genes Located on the Incompatibility Group FIB Plasmids at Transcription and Protein Levels in Iron-Modified Growth Conditions
Authors: Abbott Carter N. , Felix Monique , Foley Steven L. , Khajanchi Bijay K.
Published: November 2021

Salmonella enterica strains often harbor plasmids representing several incompatibility groups (Inc) including IncFIB, which have been previously associated with carrying antimicrobial resistance and virulence associated genes. To better understand the distribution of virulence genes on IncFIB plasmids, we analyzed 37 complete whole genome and plasmid sequences of different S. enterica isolates from multiple serovars. Many of the sequences analyzed carried multiple virulence-associated genes, including those associated with iron acquisition systems; thus we aimed to determine how iron-rich (IR) and various iron-depleted (ID) conditions affected the transcription of iron acquisition and virulence genes including sitA, iutA, iucA, and enolase at different time intervals. sitA, iutA, and enolase from S. enterica that were grown in Luria-Bertani broth (LB) ID (LBID) conditions were substantially upregulated when compared to LBIR conditions. For both S. enterica strains that were grown at various LBID conditions, addition of 200 μM bipyridyl in the growth medium yielded the highest transcription for all four genes, followed by the 100 μM concentration. An antibody using a peptide targeting aerobactin receptor gene iutA encoded by IncFIB was generated and used to examine the protein expression in the wild-type, recipient, and transconjugant strain in LB, LBID, and LBIR growth conditions using Western blot analyses. A 70 KDa protein band was detected in the wild-type and transconjugant that carried the IncFIB plasmid, while this band was not detected in the recipient strain that lacked this plasmid.
Towards Real-Time and Affordable Strain-Level Metagenomics-Based Foodborne Outbreak Investigations Using Oxford Nanopore Sequencing Technologies
Authors: Buytaers Florence E. , Saltykova Assia , Denayer Sarah , Verhaegen Bavo , Vanneste Kevin , Roosens Nancy H. C. , Piérard Denis , Marchal Kathleen , De Keersmaecker Sigrid C. J.
Published: November 2021

The current routine laboratory practices to investigate food samples in case of foodborne outbreaks still rely on attempts to isolate the pathogen in order to characterize it. We present in this study a proof of concept using Shiga toxin-producing Escherichia coli spiked food samples for a strain-level metagenomics foodborne outbreak investigation method using the MinION and Flongle flow cells from Oxford Nanopore Technologies, and we compared this to Illumina short-read-based metagenomics. After 12 h of MinION sequencing, strain-level characterization could be achieved, linking the food containing a pathogen to the related human isolate of the affected patient, by means of a single-nucleotide polymorphism (SNP)-based phylogeny. The inferred strain harbored the same virulence genes as the spiked isolate and could be serotyped. This was achieved by applying a bioinformatics method on the long reads using reference-based classification. The same result could be obtained after 24-h sequencing on the more recent lower output Flongle flow cell, on an extract treated with eukaryotic host DNA removal. Moreover, an alternative approach based on in silico DNA walking allowed to obtain rapid confirmation of the presence of a putative pathogen in the food sample. The DNA fragment harboring characteristic virulence genes could be matched to the E. coli genus after sequencing only 1 h with the MinION, 1 h with the Flongle if using a host DNA removal extraction, or 5 h with the Flongle with a classical DNA extraction. This paves the way towards the use of metagenomics as a rapid, simple, one-step method for foodborne pathogen detection and for fast outbreak investigation that can be implemented in routine laboratories on samples prepared with the current standard practices.
Properties of Modestobacter deserti sp. nov., a Kind of Novel Phosphate-Solubilizing Actinobacteria Inhabited in the Desert Biological Soil Crusts
Authors: Jiang Zhu-Ming , Zhang Bing-Huo , Sun Hong-Min , Zhang Tao , Yu Li-Yan , Zhang Yu-Qin
Published: November 2021

Three Gram-stain-positive, aerobic, motile actinobacterial strains designated as CPCC 205119T, CPCC 205215, and CPCC 205251 were isolated from different biological soil crust samples collected from Tengger Desert, China. The 16S rRNA gene sequence comparison of these three strains showed they had almost identical 16S rRNA genes, which were closely related to members of the family Geodermatophilaceae, with the highest similarities of 96.3–97.3% to the species of Modestobacter. In the phylogenetic tree based on 16S rRNA gene sequences, these isolates clustered into a subclade next to the branch containing the species of Modestobacter lapidis and Modestobacter multiseptatus, within the lineage of the genus Modestobacter. The comparative genomic characteristics (values of ANI, dDDH, AAI, and POCP) and the phenotypic properties (morphological, physiological, and chemotaxonomic characteristics) of these isolates readily supported to affiliate them to the genus Modestobacter as a single separate species. For which, we proposed that the isolates CPCC 205119T, CPCC 205215, and CPCC 205251 represent a novel species of the genus Modestobacter as Modestobacter deserti sp. nov. CPCC 205119T (=I12A-02624=NBRC 113528T=KCTC 49201T) is the type strain. The genome of strain CPCC 205119T consisted of one chromosome (4,843,235bp) containing 4,424 coding genes, 48 tRNA genes, five rRNA genes, three other ncRNA genes, and 101 pseudogenes, with G+C content of 74.7%. The whole-genome sequences analysis indicated that this species contained alkaline phosphatase genes (phoA/phoD), phosphate transport-related genes (phoU, phnC, phnD, phnE, phoB, phoH, phoP, phoR, pitH, ppk, pstA, pstB, pstC, and pstS), trehalose-phosphate synthase gene (otsA), trehalose 6-phosphate phosphatase gene (otsB) and other encoding genes for the properties that help the microorganisms to adapt to harsh environmental conditions prevalent in deserts. Strains of this species could solubilize tricalcium phosphate [Ca3(PO4)2] and phytin, assimilate pyrophosphate, thiophosphate, dithiophosphate, phosphoenol pyruvate, 2-deoxy-d-glucose-6-phosphate, and cysteamine-S-phosphate.
Bacterial and Fungal Infections Promote the Bone Erosion Progression in Acquired Cholesteatoma Revealed by Metagenomic Next-Generation Sequencing
Authors: Jiang Hua , Wu Chengpeng , Xu Jingjie , Wang Qi , Shen Lei , Ou Xunyan , Liu Hongyan , Han Xu , Wang Jun , Ding Wenchao , Hu Lidan , Chen Xiangjun
Published: November 2021

An acquired cholesteatoma generally occurs as a consequence of otitis media and eustachian tube dysfunction. Patients with acquired cholesteatoma generally present with chronic otorrhea and progressive conductive hearing loss. There are many microbes reportedly associated with acquired cholesteatoma. However, conventional culture-based techniques show a typically low detection rate for various pathogenetic bacteria and fungi. Metagenomic next-generation sequencing (mNGS), an emerging powerful platform offering higher sensitivity and higher throughput for evaluating many samples at once, remains to be studied in acquired cholesteatoma. In this study, 16 consecutive patients from January 2020 to January 2021 at the Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU) were reviewed. We detected a total of 31 microbial species in patients, mNGS provided a higher detection rate compared to culture (100% vs. 31.25%, p = 0.000034). As the severity of the patient’s pathological condition worsens, the more complex types of microbes were identified. The most commonly detected microbial genus was Aspergillus (9/16, 56.25%), especially in patients suffering from severe bone erosion. In summary, mNGS improves the sensibility to identify pathogens of cholesteatoma patients, and Aspergillus infections increase bone destruction in acquired cholesteatoma.
Detection of Mosaic Variants in Mothers of MPS II Patients by Next Generation Sequencing
Authors: Oliveira Netto Alice Brinckmann , Brusius-Facchin Ana Carolina , Leistner-Segal Sandra , Kubaski Francyne , Josahkian Juliana , Giugliani Roberto
Published: November 2021

Mucopolysaccharidosis type II is an X-linked lysosomal storage disorder caused by mutations in the IDS gene that encodes the iduronate-2-sulfatase enzyme. The IDS gene is located on the long arm of the X-chromosome, comprising 9 exons, spanning approximately 24 kb. The analysis of carriers, in addition to detecting mutations in patients, is essential for genetic counseling, since the risk of recurrence for male children is 50%. Mosaicism is a well-known phenomenon described in many genetic disorders caused by a variety of mechanisms that occur when a mutation arises in the early development of an embryo. Sanger sequencing is limited in detecting somatic mosaicism and sequence change levels of less than 20% may be missed. The Next Generation Sequencing (NGS) has been increasingly used in diagnosis. It is a sensitive and fast method for the detection of somatic mosaicism. Compared to Sanger sequencing, which represents a cumulative signal, NGS technology analyzes the sequence of each DNA read in a sample. NGS might therefore facilitate the detection of mosaicism in mothers of MPS II patients. The aim of this study was to reanalyze, by NGS, all MPS II mothers that showed to be non-carriers by Sanger analysis. Twelve non-carriers were selected for the reanalysis on the Ion PGM and Ion Torrent S5 platform, using a custom panel that includes the IDS gene. Results were visualized in the Integrative Genomics Viewer (IGV). We were able to detected the presence of the variant previously found in the index case in three of the mothers, with frequencies ranging between 13 and 49% of the reads. These results suggest the possibility of mosaicism in the mothers. The use of a more sensitive technology for detecting low-level mosaic mutations is essential for accurate recurrence-risk estimates. In our study, the NGS analysis showed to be an effective methodology to detect the mosaic event.
Structural Analysis of the Caenorhabditis elegans Dauer Larval Anterior Sensilla by Focused Ion Beam-Scanning Electron Microscopy
Authors: Britz Sebastian , Markert Sebastian Matthias , Witvliet Daniel , Steyer Anna Maria , Tröger Sarah , Mulcahy Ben , Kollmannsberger Philip , Schwab Yannick , Zhen Mei , Stigloher Christian
Published: November 2021

At the end of the first larval stage, the nematode Caenorhabditis elegans developing in harsh environmental conditions is able to choose an alternative developmental path called the dauer diapause. Dauer larvae exhibit different physiology and behaviors from non-dauer larvae. Using focused ion beam-scanning electron microscopy (FIB-SEM), we volumetrically reconstructed the anterior sensory apparatus of C. elegans dauer larvae with unprecedented precision. We provide a detailed description of some neurons, focusing on structural details that were unknown or unresolved by previously published studies. They include the following: (1) dauer-specific branches of the IL2 sensory neurons project into the periphery of anterior sensilla and motor or putative sensory neurons at the sub-lateral cords; (2) ciliated endings of URX sensory neurons are supported by both ILso and AMso socket cells near the amphid openings; (3) variability in amphid sensory dendrites among dauers; and (4) somatic RIP interneurons maintain their projection into the pharyngeal nervous system. Our results support the notion that dauer larvae structurally expand their sensory system to facilitate searching for more favorable environments.
Effect of Vitamin D Supplementation on the Prognosis of Post-stroke Fatigue: A Retrospective Cohort Study
Authors: Wang Long , Zhao Xue-min , Wang Fu-yu , Wu Jun-Cang , Wang Yu
Published: November 2021

Objective: We aimed to evaluate the effect of vitamin D supplementation in post-stroke fatigue (PSF) patients with vitamin D deficiency on fatigue symptoms and outcomes.

Methods: Patients with primary acute ischemic stroke (AIS) were recruited consecutively from July 2016 to June 2018. Post-stroke fatigue patients were screened out with the Fatigue Severity Scale (FSS) questionnaire, serum concentrations of 25-hydroxyvitamin D [25-(OH)-D] were assessed with enzyme-linked immunosorbent assay (ELISA), and neurological function was evaluated with FSS and modified Rankin Scale (mRS) scoring criteria. Post-stroke fatigue patients with vitamin D deficiency were divided into two groups: a study group in which patients received vitamin D supplementation (cholecalciferol, 600 IU/day) along with usual care, and a control group in which patients received usual care alone. At the end of 1 and 3 months after treatment, all PSE patients accepted re-measurement of serum vitamin D and re-evaluation of fatigue and neurological function.

Results: A total of 532 AIS patients were consecutively recruited to participate in this study. Patients without PSF, non-vitamin D deficiency, pre-stroke fatigue, or vitamin D supplementation were excluded from the study. In addition, patients who were lost to follow-up were also excluded. Finally, 139 out of 532 (26.1%) patients with PSF and vitamin D deficiency received vitamin D supplementation treatment. Fatigue Severity Scale score was significantly lower in the study group than in the control group at 1 month (t = −4.731, p < 0.01) and 3 months (t = −7.937, p < 0.01) after treatment. One month after treatment, mRS score in the study group was lower than that in the control group without statistical difference (t = −0.660, p > 0.05), whereas mRS was significantly higher in the study group than in the control group at 3 months after treatment (t = −4.715, p < 0.01).

Conclusions: Our results indicated that vitamin D supplementation could improve fatigue symptoms and neurological outcomes in PSF patients with vitamin D deficiency. Subject to replication in other settings, a randomized controlled trial (RCT) might be undertaken to validate the potential beneficial impact of vitamin D supplementation in post-stroke patients found to be vitamin D deficient.
The Added Benefit of Opicapone When Used Early in Parkinson's Disease Patients With Levodopa-Induced Motor Fluctuations: A Post-hoc Analysis of BIPARK-I and -II
Authors: Rocha José-Francisco , Ebersbach Georg , Lees Andrew , Tolosa Eduardo , Ferreira Joaquim J. , Poewe Werner , Rascol Olivier , Stocchi Fabrizio , Antonini Angelo , Magalhães Diogo , Gama Helena , Soares-da-Silva Patrício
Published: November 2021

Introduction: Opicapone (OPC) was efficacious in reducing OFF-time in two pivotal trials in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (BIPARK-I and -II). Post-hoc analyses of these trials evaluated the efficacy of OPC following pre-defined segmentation of the wide spectrum of motor fluctuations in PD.

Methods: Data from matching treatment arms in BIPARK-I and -II were combined for the placebo (PLC) and OPC 50-mg groups, and exploratory post-hoc analyses were performed to investigate the efficacy of OPC 50 mg vs. PLC in subgroups of patients who were in “earlier” vs. “later” stages of both their disease course (e.g., duration of PD <6 years vs. ≥6 years) and levodopa treatment pathway (e.g., number of daily levodopa intakes <4 vs. ≥4). Efficacy variables included changes from baseline in absolute OFF-time and total ON-time.

Results: The Full Analysis Set included 517 patients (PLC, n = 255; OPC 50 mg, n = 262). OPC 50 mg was significantly more effective than PLC in reducing OFF-time and increasing ON-time in the majority of subgroup analyses (p < 0.05). Moreover, patients in “earlier” stages of both their disease course and levodopa treatment pathway experienced numerically greater efficacy when using OPC 50 mg, in comparison with those in “later” stages.

Conclusion: OPC 50 mg was efficacious over the whole trajectory of motor fluctuation evolution in PD patients. There was also a signal for enhanced efficacy in patients who were earlier vs. later in their disease course and levodopa treatment pathway.
Improving Deep Brain Stimulation Electrode Performance in vivo Through Use of Conductive Hydrogel Coatings
Authors: Hyakumura Tomoko , Aregueta-Robles Ulises , Duan Wenlu , Villalobos Joel , Adams Wendy K. , Poole-Warren Laura , Fallon James B.
Published: November 2021

Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson’s disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo, and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical advantage and stability of CH coating in the brain supports the suitability of this coating technology for future development of smaller, higher fidelity electrode arrays with higher charge density requirement.
Cornelia de Lange Syndrome as Paradigm of Chromatinopathies
Authors: Parenti Ilaria , Kaiser Frank J.
Published: November 2021

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.
Longitudinal Analysis of the Effect of Repeated Transarterial Chemoembolization for Liver Cancer on Portal Venous Pressure
Authors: Frangakis Constantine , Sohn Jae Ho , Bas Ahmet , Chapiro Julius , Schernthaner Ruediger E. , Lin MingDe , Hamilton James P. , Pawlik Timothy M. , Hong Kelvin , Duran Rafael
Published: November 2021

Objectives

Investigate long-term effects of repeated transarterial chemoembolization (TACE) on portal venous pressure (PVP) using non-invasive surrogate markers of portal hypertension.

Methods

Retrospective, Institutional Review Board-approved study. 99 patients [hepatocellular carcinoma (HCC) group (n=57); liver metastasis group (n=42)] who underwent 279TACEs and had longitudinal pre-/post-therapy contrast-enhanced-MRI (n=388) and complete blood work were included. Outcomes of interest were platelet count (PC), spleen volume, ascites and portosystemic collaterals. Variables included TACE type/number, tumor type, microcatheter location, Child-Pugh, baseline tumor burden (tumor number/total/largest size), vessel invasion, alpha-fetoprotein, Eastern Cooperative Oncology Group (ECOG) performance status, and Model for End-Stage Liver Disease (MELD) score. Generalized Estimating Equations assessed the associations between TACE and outcomes. Power analysis determined the sample size was sufficient.

Results

No significant change in PC over time was observed in either groups, regardless of liver function (P>0.05). Baseline spleen volume was 226 cm3 for metastatic group, and was larger by 204 cm3 for HCC group (P<0.001). Spleen volume increased by 20 cm3 (95%CI: 8-32; P=0.001) for both groups after 1stTACE and by 16cm3/TACE (P=0.099) over the full follow-up (up to 9TACEs). Spleen volume also tended to increase by 23cm3 (95%CI: -1–48; P=0.064) with higher tumor burden. Odds of developing moderate/severe ascites for metastatic patients was decreased by 0.5 (95%CI: 0.3–0.9; P=0.014), regardless of the Child-Pugh, and increased by 1.5 (95%CI: 1.2–1.9; P<0.001) among HCC patients with unstable Child-Pugh, whereas no change was noted with stable Child-Pugh. HCC patients with unstable Child-Pugh demonstrated a significant increase in portosystemic collaterals number over time (P=0.008). PVP-related complications such as variceal bleeding post-TACE were low (0.4%).

Conclusion

Repeated TACEs did seem to have an impact on PVP. However, the increase in PVP had marginal effects with low portal hypertension-related complications.
Mass Cytometry in Hematologic Malignancies: Research Highlights and Potential Clinical Applications
Authors: Astle John M. , Huang Huiya
Published: November 2021

Recent advances in global gene sequencing technologies and the effect they have had on disease diagnosis, therapy, and research have fueled interest in technologies capable of more broadly profiling not only genes but proteins, metabolites, cells, and almost any other component of biological systems. Mass cytometry is one such technology, which enables simultaneous characterization of over 40 parameters per cell, significantly more than can be achieved by even the most state-of-the-art flow cytometers. This mini-review will focus on how mass cytometry has been utilized to help advance the field of neoplastic hematology. Common themes among published studies include better defining lineage sub-populations, improved characterization of tumor microenvironments, and profiling intracellular signaling across multiple pathways simultaneously in various cell types. Reviewed studies highlight potential applications for disease diagnosis, prognostication, response to therapy, measurable residual disease analysis, and identifying new therapies.
Screening to Identify an Immune Landscape-Based Prognostic Predictor and Therapeutic Target for Prostate Cancer
Authors: Shen Yanting , Xu Huan , Long Manmei , Guo Miaomiao , Li Peizhang , Zhan Ming , Wang Zhong
Published: November 2021

Objectives

Existing prognostic risk assessment strategies for prostate cancer (PCa) remain unsatisfactory. Similar treatments for patients at the same disease stage can lead to different survival outcomes. Thus, we aimed to explore a novel immune landscape-based prognostic predictor and therapeutic target for PCa patients.

Methods

A total of 490 PCa patients from The Cancer Genome Atlas Project (TCGA) cohort were analyzed to obtain immune landscape-based prognostic features. Then, analyses at different levels were performed to explore the relevant survival mechanisms, prognostic predictors, and therapeutic targets. Finally, experimental verification was performed using a tissue microarray (TMA) from 310 PCa patients. Furthermore, a nomogram was constructed to provide a quantitative approach for predicting the prognosis of patients with PCa.

Results

The immune landscape-based risk score (ILBRS) was obtained. Then, VAV1, which presented a significant positive correlation with Treg infiltration and ILBRS, was screened and identified to be significantly related to the prognosis of PCa. Finally, experimental verification confirmed the prognostic value of VAV1 for PCa prognosis at the protein level.

Conclusions

VAV1 has the potential to be developed as an immune landscape-based PCa prognostic predictor and therapeutic target and will help improve prognosis by enabling the selection of individualized, targeted therapy.
Case Report: Retroaortic Innominate Vein With Supracardiac Total Anomalous Pulmonary Venous Connection
Authors: Ifuku Toshinobu , Kuraoka Ayako , Ohhira Tomoko , Sagawa Koichi , Nakano Toshihide , Kado Hideaki
Published: November 2021

A retroaortic innominate vein (RAIV) is a rare anomaly that passes posterior to the ascending aorta to join the superior vena cava and is associated with congenital heart disease (CHD). The RAIV and normal left innominate vein (LIV) rarely duplicate. The etiology of the RAIV and its relationship with CHD remains unknown. We report a case involving a 1-month-old baby girl with RAIV and supracardiac total anomalous pulmonary venous connection (TAPVC). Transthoracic echocardiogram demonstrated a pulmonary venous confluence (CPV) posterior to the left atrium, an abnormal vertical vein (VV) that originated from the CPV, and a normally positioned LIV. Three-dimensional cardiac computed tomography revealed the VV and RAIV to which it merged. This is the first reported case of a combination of RAIV and isolated TAPVC. We speculate that the VV is connected to the CPV during fetal life, thus leaving the RAIV behind. The RAIV may be detected in various forms with the development of new diagnostic imaging methods. Although a RAIV itself does not require treatment, establishing a correct diagnosis before invasive tests and procedures are performed can help prevent unexpected complications.
Hydroxy-Safflower Yellow A Alleviates Osteoporosis in Ovariectomized Rat Model by Inhibiting Carbonic Anhydrase 2 Activity
Authors: Wang Yang , Li Xiaoyan , Deng Feifei , Yin Ruofeng
Published: November 2021

Background: To investigate the therapeutic effect of Hydroxy-safflower yellow A (HSYA) on rat’s osteoporosis and explore its potential mechanism of action.

Methods: Bilateral ovariectomized female rats (OVX) were used to establish a postmenopausal rat model of osteoporosis. HSYA was given as an intervention, and estradiol was used as a positive control. The levels of serum alkaline phosphatase (ALP), calcium ion (Ca2+), and inorganic phosphorus (IP) were used to detect bone loss. Three months after modeling, the rats were sacrificed and the rat’s ovaries, kidneys, tibia, and femur were used to calculate the organ index. The bone marrow of the femur of the rats was stained with Giemsa staining. The femur strength of rats was measured by INSTRON. The degree of osteoporosis was detected by pathological staining after decalcification of bone tissue. Predicted the main targets of HSYA in combination with bioinformatics, and the proteins related to osteoclast differentiation were detected in combination with western blotting. The effect of HSYA on the differentiation of RAW264.7 cells into osteoclasts was observed.

Results: The Giemsa staining and serum test results showed that the operation was successful and affected bone metabolism. In the bone strength test, HSYA significantly increased the maximum threshold of femoral load in rats. Pathological examination showed that tibial cartilage, trabecular bone, and cortex significantly increased after treatment with HYSA. The number of osteoblasts increased while the number of osteoclasts decreased—elevated levels of type I and III collagen. Autodock was used for molecular docking of potential targets of HSYA. qPCR and western blot were used to show that the expression levels of CA2 and osteoclast differentiation-related proteins were significantly decreased after HSYA treatment. Cell level results showed that HSYA could inhibit the activity of osteoclasts and the ability of RAW264.7 cells to differentiate into osteoclasts.

Conclusion: HSYA can inhibit the differentiation and formation of osteoclasts by inhibiting the expression of CA2 and relieving osteoporosis symptoms in OVX rats.
Anti-Inflammatory Effects of BoNT/A Against Complete Freund’s Adjuvant-Induced Arthritis Pain in Rats: Transcriptome Analysis
Authors: Li Xinhe , Ye Yinshuang , Zhou Wenwen , Shi Qilin , Wang Lin , Li Tieshan
Published: November 2021

Arthritis is the most common cause to lead to chronic pain. Botulinum toxin type A (BoNT/A) has been widely used to treat chronic pain. In our previous study, we confirmed the anti-inflammatory and antinociceptive effects of BoNT/A in the Complete Freund’s Adjuvant (CFA)-induced arthritis model, but the underlying anti-inflammatory mechanism was not fully elucidated. The purpose of this study was to investigate the anti-inflammatory effects and mechanisms of BoNT/A on arthritis using transcriptomic analysis. The BoNT/A was injected into the rat ankle joint on day 21 after CFA injection. The von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. Five days after BoNT/A treatment, gene expression profiling in dorsal root ganglion (DRG) was performed using RNA sequencing (RNA-seq). The differentially expressed genes (DEGs) were analyzed by various tools. The mechanical allodynia and thermal hyperalgesia were significantly reversed after BoNT/A injection. RNA-seq revealed 97 DEGs between the CFA group and Sham group; these DEGs were enriched inflammatory response, IL-17 signaling pathway, etc. There are 71 DEGs between the CFA+BoNT/A group and the CFA group; these DEGs related to response to peptide, PI3K-Akt signaling pathway, ECM–receptor interactions, etc. Three key genes were significantly decreased after CFA-induced arthritis pain, while BoNT/A increased the expression of these genes. The identification of S100A9, S100A8, and MMP8 genes can provide new therapeutic targets for arthritis pain and affect the signaling pathway to play an anti-inflammatory role after the treatment of BoNT/A.
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets
Authors: Jing Muhan , Wang Shanshan , Li Ding , Wang Zeyu , Li Ziwen , Lu Yichen , Sun Tong , Qiu Chen , Chen Fang , Yu Haijuan , Zhang Wei
Published: November 2021

Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin.
The Differentiate Effects of Resistance Training With or Without External Load on Young Soccer Players’ Performance and Body Composition
Authors: Falces-Prieto Moisés , Sáez de Villarreal-Sáez Eduardo , Raya-González Javier , González-Fernández Francisco Tomás , Clemente Filipe Manuel , Badicu Georgian , Murawska-Ciałowicz Eugenia
Published: November 2021

Purpose: The purpose of this study was to examine the effects of 15 weeks (2/week) of two different resistance training (RT) programs [the self-load group (SG) vs. the overload group (OG)] on selected measures of physical performance in young male soccer players.

Methods: The countermovement jump (CMJ), aerobic endurance (VO2 max), and body composition [body mass (BM), height (H), body fat percentage (% BF), and lean mass (LM)] were measured before and after the 15-week RT interventions. Subjects were randomized to treatments: 1. SG [age = 15.34 ± 1.34 years]; 2. OG [age = 16.28 ± 1.21 years].

Results: The level of significance set for the study (p ≤ 0.05). Within-group analysis did report significant differences in all variables for the SG (p = 0.008 to 0.001; ES = −0.33 to 1.41, small to large) as in the OG (p = 0.001; ES = 0.82 to 1.30, large). Between-groups analysis reported differences in CMJ (F = 4.32; p = 0.004) for the OG.

Conclusion: The main findings of this study indicated that RT with and without external load was effective in improving the measures of physical performance in young soccer players, with special attention to jumping ability, where the OG group was more effective. Furthermore, there is no interference to aerobic endurance. It is recommended that soccer coaches implement RT without external load in the early stages of training or in players with late maturation development and in those soccer clubs with limited material resources.
A Comprehensive Study on the Dynamic Change of Thermal Behavior During Lignocellulose Pyrolysis Catalyzed by Plant-Rich Metallic Elements
Authors: Huang Jiawei , Zheng Biao , Hong Zhou , Ouyang Peiyao , Li Yuanhua , Wu Aimin , Li Huiling
Published: November 2021

Evaluating the pyrolysis of lignocellulose via theoretical and computational approaches is of great importance for the efficient utilization of biomass. In this work, the dynamic changes in physicochemical properties of eucalyptus and bamboo during plant-rich metallic element-catalyzed pyrolysis process were investigated, and their thermal decomposition behaviors were explored by kinetic analysis. Results showed that the metal absorption capacity and thermal stability of eucalyptus were better than those of bamboo. The temperatures corresponding to the initial devolatilization and the highest weight loss value of eucalyptus/bamboo decreased in the catalysis order of Mg > Fe > Ca > Cu > K > Na. Fourier-transform infrared (FT-IR) results showed that the thermal stability of ester bond of glucuronoarabinoxylan was higher than that of acetyl groups. The maximum weight loss rate could be observed for samples with the lowest metal-loaded concentration (5%). Moreover, Mg and Fe presented the better catalytic performance for facilitating the lignocellulose pyrolysis in comparison with other investigated metallic elements.
The Moderating Role of Grit in the Relationship Between Perfectionism and Depression Among Chinese College Students
Authors: Zhang Jing , Liu Luming , Wang Wenchao
Published: November 2021

Background: As a personality trait, perfectionism has shown a close association with psychological disorders, such as depression. The protective effect of grit on depression has been confirmed by a series of recent studies. Therefore, it is necessary to investigate the buffering role of grit in the above relationship and the possible underlying mechanism.

Objective: Based on the multidimensional theory of perfectionism, we differentiated two dimensions of perfectionism as positive and negative and further examined the relationships between these two dimensions of perfectionism and depression. We also aimed to examine the possible moderating effect of grit on the above two relationships.

Methods: Us a questionnaire survey approach, a total of 2,602 college students (1,608 females and 994 males) were assessed using the Frost Multidimensional Perfectionism Scale the Short Grit Scale, and the Center for Epidemiological Studies-Depression Scale. Hierarchical regression analysis was used to investigate the direct effect of two dimensions of perfectionism on depression as well as the moderating role of grit in these associations.

Results: After controlling for gender, age, family income, and academic performance, both positive and negative perfectionism had positive predictive effects on depression, and grit negatively moderated these two relationships. Specifically, grit completely counteracted the effect of positive perfectionism on depression yet partly counteracted the effect of negative perfectionism on depression.

Conclusion: Grit prevents the depressive symptoms raised by positive and negative perfectionism.