bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Study of Ultrasonographic Risk Factors for Central Lymph Node Metastasis of Papillary Thyroid Carcinoma
Authors: Guang Yang , He Wen , Zhang Wei , Zhang Hongxia , Zhang Yukang , Wan Fang
Published: December 2021

Background

Thyroid cancer is the most common malignancy of the endocrine system worldwide. Papillary thyroid cancer (PTC) is the most common pathologic type. The preoperative diagnosis of PTC and central lymph node metastasis (CLNM) or metastatic tendency is of great clinical significance to the diagnosis, treatment and prognosis of these patients. This study was conducted to investigate the correlation between ultrasound features and central CLNM of PTC.

Methods

This study retrospectively analyzed patients who underwent PTC surgery and central lymph node dissection in the Department of Surgery, Beijing Tiantan Hospital, from January 2019 to February 2020. According to the inclusion and exclusion criteria, data from 136 patients were ultimately included, and the clinical and ultrasonic data of the patients were analyzed by multivariate regression to evaluate the correlation among grayscale ultrasound (US), superb microvascular imaging (SMI) and contrast-enhanced ultrasound (CEUS) features of thyroid nodules and CLNM of PTCs.

Results

The multivariate analysis showed that tumor size, multifocality, microcalcification characteristics, SMI vascularization, and CEUS evaluation of contact with the adjacent capsule were correlated with PTC metastasis (P=0.008, P=0.001, P=0.028, P=0.041, and P< 0.001, respectively). Comparisons of the area under the ROC curves revealed that the area under the ROC curve of the degree of nodular invasion into the thyroid capsule was the largest (AUC: 0.754). The sensitivity and specificity for evaluating CLNM of PTC were 67.7% and 83.1%, respectively.

Conclusions

Ultrasound characteristics of the following features are associated with a high risk of lymph node metastasis in PTCs: maximum diameter of nodules ≥1 cm, multifocality, ≥5 microcalcifications, abundant blood flow of SMI in nodules and nodule contact with the thyroid capsule ≥25% under CEUS. Ultrasound has clinical value in the preoperative evaluation of CLNM of PTCs.
Optimal Placement and Sizing of Distributed Generators Based on Multiobjective Particle Swarm Optimization
Authors: Yang Deyu , Jia Junqing , Wu Wenli , Cai Wenchao , An Dong , Luo Ke , Yang Bo
Published: December 2021

To solve the problems of environmental pollution and energy consumption, the development of renewable energy sources becomes the top priority of current energy transformation. Therefore, distributed power generation has received extensive attention from engineers and researchers. However, the output of distributed generation (DG) is generally random and intermittent, which will cause various degrees of impact on the safe and stable operation of power system when connected to different locations, different capacities, and different types of power grids. Thus, the impact of sizing, type, and location needs to be carefully considered when choosing the optimal DG connection scheme to ensure the overall operation safety, stability, reliability, and efficiency of power grid. This work proposes a distinctive objective function that comprehensively considers power loss, voltage profile, pollution emissions, and DG costs, which is then solved by the multiobjective particle swarm optimization (MOPSO). Finally, the effectiveness and feasibility of the proposed algorithm are verified based on the IEEE 33-bus and 69-bus distribution network.
Interactive Effects of Microplastics and Tetracycline on Bioaccumulation and Biochemical Status in Jian Carp (Cyprinus carpio var. Jian)
Authors: Zhang Chaonan , Wang Qiujie , Zuo Zhiheng , Ding Jianhua , Xu Guohuan , Zou Jixing
Published: December 2021

Microplastics (MPs) and tetracycline (TC) are severe emerging pollutants in the aquatic environment. But there is a lack of research to investigate the interactive effects of MPs and TC in vivo. This study used Jian carp (Cyprinus carpio var. Jian) as the model organism to explore the bioaccumulation and biochemical status when exposed to MPs and TC, alone and combined. The accumulation of TC and MPs in intestine, variation of enzyme activities in intestine, and expression of immune-related genes in muscle were evaluated. Our results found the bioaccumulation of MPs was not affected by TC, but the presence of MPs would change the content of TC within 48 h. The superoxide dismutase (SOD) and lactate dehydrogenase (LDH) activity showed that TC-MP combined exposure could reduce oxidative damage to Jian carps compared to MP exposure alone. The integrated biomarker response (IBR) index showed that SOD activity was sensitive to TC-MP exposure. In addition, co-exposure to MPs and TC could alleviate the overexpression of interleukin 1 beta (IL-1β), interleukin 10 (IL-10), transforming growth factor beta (TGF-β), and toll like receptor 2 (TLR-2) induced by TC in muscles. TLR-2 gene has the potential to be the candidate gene reflecting the injury of TC exposure. In conclusion, it is inferred that co-exposure may reduce the toxicity of individual exposure in the living organisms. This study provides essential information for the risk assessment of pollution with MPs and TC, individually and combined, as well as a foundation to investigate the interactive effects of MPs and antibiotics on aquatic ecosystems.
Socio-Ecological Outcomes of Single-Species Fisheries Management: The Case of Yellow Perch in Lake Erie
Authors: Lee Katherine , Apriesnig Jenny , Zhang Hongyan
Published: December 2021

This manuscript uses seminal models in fisheries economics to assess the ecosystem effects of policy focused on sustainable management of a single fish stock. Economic models representing fishing decisions under open access and two fisheries management schemes are parameterized using data from the four management units in the Lake Erie Yellow Perch (Persus flavenscens) fishery and linked with an end-to-end ecosystem model representative of the lake food web and spatial species interactions. We find that the sustainable harvest rules from single species economic models result in significant changes to biomass of species in planktivorous, omnivorous, and piscivorous groups in the ecosystem model. These impacts can be traced through the food web back to harvest rules implemented in the management units. Most notably, the biomass of several non-target but also commercially harvested fish species are reduced through Yellow Perch fishing. In some cases, the economic losses to coexisting fisheries exceeds benefits gained from implementing the Yellow Perch management scheme. Our results imply that while an ecosystem-based approach to fisheries management requires weighing trade-offs between multiple fisheries, an ex ante understanding of the whole-system consequences of harvest rules can be critical for developing policy that overall enhances ecological and social wellbeing.
Oliver Tambo International Airport, South Africa: Land-Use Conflicts Between Airports and Wildlife Habitats
Authors: Robinson Lance , Mearns Kevin , McKay Tracey
Published: December 2021

Airports stimulate tourism and trade and are a vital link in any country’s tourism infrastructure and economy. Large airports such as South Africa’s busiest airport, the OR Tambo International Airport, in Ekurhuleni, Gauteng, are usually located on the periphery of cities, usually on land that forms part of the peri-urban economy, reserved perhaps for farming or left undeveloped. As a result, such land often becomes a wildlife haven within the more “urbanized” or developed areas. Unfortunately, this places wildlife, especially birds on a collision course with aircraft. So much so that bird and other animal strikes cost the aviation industry millions of US dollars annually. Therefore, it is essential to reduce the number of wildlife strikes, not only lower the risk of damage to aircraft, increase passenger safety and reduce operational delays, but also prevent a decline in local wildlife populations. Thus, this paper argues that South Africa must improve its management of land-use close to airports to minimize the potential for wildlife strikes. In that regard, this study catalogs the different habitats and land-use types surrounding OR Tambo International Airport, identifying potential bird hazard zones using kernel density analysis. This identifies which areas pose the highest risk of bird strikes. Although land-use and land zoning by the International Civil Aviation Organization (ICAO) recommends a 13 km buffer zone around airports, this study shows that land-use in the buffer zone must also take potential bird strikes into account. Thus, airport operators need to work with land-use planning authorities and neighboring stakeholders to do so.
Digital Evolution for Ecology Research: A Review
Authors: Dolson Emily , Ofria Charles
Published: December 2021

In digital evolution, populations of computational organisms evolve via the same principles that govern natural selection in nature. These platforms have been used to great effect as a controlled system in which to conduct evolutionary experiments and develop novel evolutionary theory. In addition to their complex evolutionary dynamics, many digital evolution systems also produce rich ecological communities. As a result, digital evolution is also a powerful tool for research on eco-evolutionary dynamics. Here, we review the research to date in which digital evolution platforms have been used to address eco-evolutionary (and in some cases purely ecological) questions. This work has spanned a wide range of topics, including competition, facilitation, parasitism, predation, and macroecological scaling laws. We argue for the value of further ecological research in digital evolution systems and present some particularly promising directions for further research.
A Literature Review of Performance Metrics of Automated Driving Systems for On-Road Vehicles
Authors: Sharath Mysore Narasimhamurthy , Mehran Babak
Published: December 2021

The article presents a review of recent literature on the performance metrics of Automated Driving Systems (ADS). More specifically, performance indicators of environment perception and motion planning modules are reviewed as they are the most complicated ADS modules. The need for the incorporation of the level of threat an obstacle poses in the performance metrics is described. A methodology to quantify the level of threat of an obstacle is presented in this regard. The approach involves simultaneously considering multiple stimulus parameters (that elicit responses from drivers), thereby not ignoring multivariate interactions. Human-likeness of ADS is a desirable characteristic as ADS share road infrastructure with humans. The described method can be used to develop human-like perception and motion planning modules of ADS. In this regard, performance metrics capable of quantifying human-likeness of ADS are also presented. A comparison of different performance metrics is then summarized. ADS operators have an obligation to report any incident (crash/disengagement) to safety regulating authorities. However, precrash events/states are not being reported. The need for the collection of the precrash scenario is described. A desirable modification to the data reporting/collecting is suggested as a framework. The framework describes the precrash sequences to be reported along with the possible ways of utilizing such a valuable dataset (by the safety regulating authorities) to comprehensively assess (and consequently improve) the safety of ADS. The framework proposes to collect and maintain a repository of precrash sequences. Such a repository can be used to 1) comprehensively learn and model the precrash scenarios, 2) learn the characteristics of precrash scenarios and eventually anticipate them, 3) assess the appropriateness of the different performance metrics in precrash scenarios, 4) synthesize a diverse dataset of precrash scenarios, 5) identify the ideal configuration of sensors and algorithms to enhance safety, and 6) monitor the performance of perception and motion planning modules.
Mitochondrial Genetic Diversity, Population Structure and Detection of Antillean and Amazonian Manatees in Colombia: New Areas and New Techniques
Authors: Caballero Susana , Ortiz-Giral Maria Camila , Bohorquez Laura , Lozano Mojica Juan Diego , Caicedo-Herrera Dalila , Arévalo-González Katherine , Mignucci-Giannoni Antonio A.
Published: December 2021

The Antillean manatee (Trichechus manatus) and the Amazonian manatee (Trichechus inunguis) are distributed in rivers in the Caribbean and Amazonian region of Colombia respectively. For 30 years, genetic information has been obtained from these populations in order to inform conservation programs for these endangered species and decide on the location to release them back to the wild. However, in previous studies, samples from rivers in some areas of the country were not included, given the difficulties to access these regions due to either logistic or safety issues. In this study, we analyzed mitochondrial DNA (mtDNA) control region (CR) sequences of from samples of T. manatus (n = 37) and T. inunguis (n = 4) (410 and 361 bp, respectively), obtained in new and previously unexplored rivers and bays in the country, including Santa Marta, Urabá Gulf, Ayapel Marsh (San Jorge River Basin), Meta River and Magdalena Medio and the low Magdalena River (Cesar Province and Canal del Dique) as well as additional samples from Puerto Nariño in the Colombian Amazon. Our results included the discovery of two newly described mtDNA CR haplotypes for T. manatus. In addition, we confirmed significant population differentiation at the mitochondrial level between the Magdalena and Sinú rivers and differentiation among areas of the same river, including the middle and low Magdalena River. This differentiation may be related to anthropic changes in the river since construction of the Canal del Dique in the XVI century. We also tested environmental DNA sampling and analyses techniques to evaluate its potential use for manatee detection and monitoring in bodies of water in Colombia, in order to evaluate new areas for future manatee conservation initiatives. We emphasize the need to continue using genetic information to provide evidence on the potential best locations to undertake animal release to prevent outbreeding depression.
Genome-wide Association Study for Carcass Primal Cut Yields Using Single-step Bayesian Approach in Hanwoo Cattle
Authors: Naserkheil Masoumeh , Mehrban Hossein , Lee Deukmin , Park Mi Na
Published: December 2021

The importance of meat and carcass quality is growing in beef cattle production to meet both producer and consumer demands. Primal cut yields, which reflect the body compositions of carcass, could determine the carcass grade and, consequently, command premium prices. Despite its importance, there have been few genome-wide association studies on these traits. This study aimed to identify genomic regions and putative candidate genes related to 10 primal cut traits, including tenderloin, sirloin, striploin, chuck, brisket, top round, bottom round, shank, flank, and rib in Hanwoo cattle using a single-step Bayesian regression (ssBR) approach. After genomic data quality control, 43,987 SNPs from 3,745 genotyped animals were available, of which 3,467 had phenotypic records for the analyzed traits. A total of 16 significant genomic regions (1-Mb window) were identified, of which five large-effect quantitative trait loci (QTLs) located on chromosomes 6 at 38–39 Mb, 11 at 21–22 Mb, 14 at 6–7 Mb and 26–27 Mb, and 19 at 26–27 Mb were associated with more than one trait, while the remaining 11 QTLs were trait-specific. These significant regions were harbored by 154 genes, among which TOX, FAM184B, SPP1, IBSP, PKD2, SDCBP, PIGY, LCORL, NCAPG, and ABCG2 were noteworthy. Enrichment analysis revealed biological processes and functional terms involved in growth and lipid metabolism, such as growth (GO:0040007), muscle structure development (GO:0061061), skeletal system development (GO:0001501), animal organ development (GO:0048513), lipid metabolic process (GO:0006629), response to lipid (GO:0033993), metabolic pathways (bta01100), focal adhesion (bta04510), ECM–receptor interaction (bta04512), fat digestion and absorption (bta04975), and Rap1 signaling pathway (bta04015) being the most significant for the carcass primal cut traits. Thus, identification of quantitative trait loci regions and plausible candidate genes will aid in a better understanding of the genetic and biological mechanisms regulating carcass primal cut yields.
Hotspot Mutations in SARS-CoV-2
Authors: Saha Indrajit , Ghosh Nimisha , Sharma Nikhil , Nandi Suman
Published: December 2021

Since its emergence in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread very rapidly around the world, resulting in a global pandemic. Though the vaccination process has started, the number of COVID-affected patients is still quite large. Hence, an analysis of hotspot mutations of the different evolving virus strains needs to be carried out. In this regard, multiple sequence alignment of 71,038 SARS-CoV-2 genomes of 98 countries over the period from January 2020 to June 2021 is performed using MAFFT followed by phylogenetic analysis in order to visualize the virus evolution. These steps resulted in the identification of hotspot mutations as deletions and substitutions in the coding regions based on entropy greater than or equal to 0.3, leading to a total of 45 unique hotspot mutations. Moreover, 10,286 Indian sequences are considered from 71,038 global SARS-CoV-2 sequences as a demonstrative example that gives 52 unique hotspot mutations. Furthermore, the evolution of the hotspot mutations along with the mutations in variants of concern is visualized, and their characteristics are discussed as well. Also, for all the non-synonymous substitutions (missense mutations), the functional consequences of amino acid changes in the respective protein structures are calculated using PolyPhen-2 and I-Mutant 2.0. In addition to this, SSIPe is used to report the binding affinity between the receptor-binding domain of Spike protein and human ACE2 protein by considering L452R, T478K, E484Q, and N501Y hotspot mutations in that region.
CircARVCF Contributes to Cisplatin Resistance in Gastric Cancer by Altering miR-1205 and FGFR1
Authors: Zhang Ruirui , Zhao Huanyu , Yuan Hongmei , Wu Jian , Liu Haiyan , Sun Suan , Zhang Zhengwei , Wang Jiayang
Published: December 2021

Background: Chemoresistance is a major barrier to the treatment of human cancers. Circular RNAs (circRNAs) are implicated in drug resistance in cancers, including gastric cancer (GC). In this study, we aimed to explore the functions of circRNA Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (circARVCF) in cisplatin (DDP) resistance in GC.

Methods: The expression of circARVCF, microRNA-1205 (miR-1205) and fibroblast growth factor receptor 1 (FGFR1) was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot assay or immunohistochemistry (IHC) assay. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were performed to evaluate DDP resistance and cell colony formation ability. Transwell assay was conducted to assess cell migration and invasion. Flow cytometry analysis was done to analyze cell apoptosis. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were manipulated to analyze the relationships of circARVCF, miR-1205 and FGFR1. Murine xenograft model was constructed to explore DDP resistance in vivo.

Results: CircARVCF level was increased in DDP-resistant GC tissues and cells. CircARVCF silencing inhibited DDP resistance, colony formation and metastasis and induced apoptosis in DDP-resistant GC cells. CircARVCF directly interacted with miR-1205 and miR-1205 inhibition reversed circARVCF silencing-mediated effect on DDP resistance in DDP-resistant GC cells. FGFR1 served as the target gene of miR-1205. MiR-1205 overexpression restrained the resistance of DDP-resistant GC cells to DDP, but FGFR1 elevation abated the effect. In addition, circARVCF knockdown repressed DDP resistance in vivo.

Conclusion: CircARVCF enhanced DDP resistance in GC by elevating FGFR1 through sponging miR-1205.
GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy
Authors: Heliö Krista , Mäyränpää Mikko I. , Saarinen Inka , Ahonen Saija , Junnila Heidi , Tommiska Johanna , Weckström Sini , Holmström Miia , Toivonen Mia , Nikus Kjell , Hathaway Julie , Siivonen Pauli , Muona Mikko , Sistonen Johanna , Salmenperä Pertteli , Gentile Massimiliano , Paananen Jussi , Myllykangas Samuel , Alastalo Tero-Pekka , Heliö Tiina , Koskenvuo Juha
Published: December 2021

Background: Familial dilated cardiomyopathy (DCM) is a monogenic disorder typically inherited in an autosomal dominant pattern. We have identified two Finnish families with familial cardiomyopathy that is not explained by a variant in any previously known cardiomyopathy gene. We describe the cardiac phenotype related to homozygous truncating GCOM1 variants.

Methods and Results: This study included two probands and their relatives. All the participants are of Finnish ethnicity. Whole-exome sequencing was used to test the probands; bi-directional Sanger sequencing was used to identify the GCOM1 variants in probands’ family members. Clinical evaluation was performed, medical records and death certificates were obtained. Immunohistochemical analysis of myocardial samples was conducted. A homozygous GCOM1 variant was identified altogether in six individuals, all considered to be affected. None of the nine heterozygous family members fulfilled any cardiomyopathy criteria. Heart failure was the leading clinical feature, and the patients may have had a tendency for atrial arrhythmias.

Conclusions: This study demonstrates the significance of GCOM1 variants as a cause of human cardiomyopathy and highlights the importance of searching for new candidate genes when targeted gene panels do not yield a positive outcome.
Identification and Characterization of Dimorphic Expression of Sex-Related Genes in Rock Bream, a Fish With Multiple Sex Chromosomes
Authors: Li Huan , Zhu Qihui , Chen Ruiyi , Liu Mingtao , Xu Dongdong
Published: December 2021

The rock bream (Oplegnathus fasciatus) is a typical fish with a unique multiple sex chromosome system. In this study, we investigated the gene expression profiling in the gonads and brains of both males and females using RNA-Seq to identify sex-related genes and pathways. In accordance with the dimorphic expression profiles, combined with Gene ontology and KEGG enrichment analyses, a number of potential genes and pathways associated with sex determination were obtained from transcriptional analysis, especially some sex-biased genes and pathways. Next, we selected 18 candidate genes and analyzed their expression in different tissues and developmental stages. We found that the expression levels of Amh, Dmrt1, Sox9, Dmrtb1, and Nanos2 were significantly higher in the testis than those in the ovary or other tissues, whereas the expression levels of ZP4, Bouncer, RNF208, FoxH1, and TOB were significantly higher in the ovary than those in the testis. Furthermore, the expression levels of these genes in different developmental stages of gonads also showed sexually dimorphic patterns, suggesting that they might play important roles during gonadal development. These genes are useful markers for investigating sex determination and differentiation in rock bream. The findings of this study can provide insights into the molecular mechanisms of sex determination and differentiation in fish with multiple sex chromosome systems.
Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment
Authors: Zhou Bingbo , Zhang Chuan , Zheng Lei , Wang Zhiqiang , Chen Xue , Feng Xuan , Zhang Qinghua , Hao Shengju , Wei Liwan , Gu Weiyue , Hui Ling
Published: December 2021

Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered.

Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family.

Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before.

Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.
Mating Stimulates the Immune Response and Sperm Storage-Related Genes Expression in Spermathecae of Bumblebee (Bombus terrestris) Queen
Authors: Guo Yueqin , Zhang Qi , Hu Xiao , Pang Chunxiu , Li Jilian , Huang Jiaxing
Published: December 2021

Bumblebee queens have remarkable spermathecae that store sperm for year-round reproduction. The spermathecal gland is regarded as a secretory organ that could benefit sperm storage. Queen mating provokes substantial physiological, behavioral, and gene expression changes. Here, the transcriptomes of spermathecae were compared between virgins and mated queens of the bumblebee, Bombus terrestris L., at 24 h post mating. Differentially expressed genes were further validated by real time quantitative PCR and immunofluorescence assay. In total, the expression of 11, 069 and 10, 862 genes were identified in virgins and mated queens, respectively. We identified that 176 differentially expressed genes between virgin and mated queen spermathecae: 110 (62.5%) genes were upregulated, and 66 (37.5%) genes were downregulated in mated queens. Most of the differentially expressed genes validated by RT-qPCR were concentrated on immune response [i.e., leucine-rich repeat-containing protein 70 (35.8-fold), phenoloxidase 2 (41.9-fold), and defensin (4.9-fold)] and sperm storage [i.e., chymotrypsin inhibitor (6.2-fold), trehalose transporter Tret1 (1.7-, 1.9-, 2.4-, and 2.4-fold), and heterogeneous nuclear ribonucleoprotein A3 (1.2-, and 2.6-fold)] functions in the spermathecae of mated queens. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) was hypothesized to promote the mating behavior according to RT-qPCR and immunofluorescence assay. The expression levels of most upregulated immune genes were decreased significantly at 3 days post mating. In conclusion, the external sperm transfer into spermathecae led to the significantly upregulated immune response genes in bumblebees. These gene expression differences in queen spermathecae contribute to understanding the bumblebee post mating regulatory network.
miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
Authors: Yang Jing , Do-Umehara Hanh Chi , Zhang Qiao , Wang Huashan , Hou Changchun , Dong Huali , Perez Edith A. , Sala Marc A. , Anekalla Kishore R. , Walter James M. , Liu Shuwen , Wunderink Richard G. , Budinger G.R. Scott , Liu Jing
Published: December 2021

Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3’ untranslated region (3’UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3’UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.
Fecal Microbiota Transplantation Controls Progression of Experimental Autoimmune Hepatitis in Mice by Modulating the TFR/TFH Immune Imbalance and Intestinal Microbiota Composition
Authors: Liang Ma , Liwen Zhang , Jianguo Song , Juan Dai , Fei Ding , Yin Zhang , Changping Wu , Jianping Chen
Published: December 2021

Intestinal microbiota (IM) dysbiosis contributes to the development of autoimmune hepatitis (AIH). This study aimed to investigate the potential effect of fecal microbiota transplantation (FMT) in a murine model of experimental AIH (EAH), a condition more similar to that of AIH patients. Changes in the enteric microbiome were determined in AIH patients and EAH mice. Moreover, we established an experimental model of secondary EAH mice harboring dysbiosis (ABx) to analyze the effects of therapeutic FMT administration on follicular regulatory T (TFR) and helper T (TFH) cell imbalances and IM composition in vivo. Alterations of the IM composition and bacterial translocation occurred in AIH patients compared to nonalcoholic fatty liver disease patients and healthy controls (HCs). Therapeutic FMT significantly attenuated liver injury and bacterial translocation and improved the imbalance between splenic TFR cells and TFH cells in ABx EAH mice. Furthermore, therapeutic FMT also partially reversed the increasing trend in serum liver enzymes (ALT and AST) of CXCR5−/−EAH mice on the 28th day. Finally, therapeutic FMT could effectively restore antibiotic-induced IM dysbiosis in EAH mice. Taken together, our findings demonstrated that FMT was capable of controlling hepatitis progression in EAH mice, and the associated mechanism might be involved in the regulation of the TFR/TFH immune imbalance and the restoration of IM composition.
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires
Authors: Ceglia Valentina , Kelley Erin J. , Boyle Annalee S. , Zurawski Sandra , Mead Heather L. , Harms Caroline E. , Blanck Jean-Philippe , Flamar Anne-Laure , Kirschman Jung Hwa , Ogongo Paul , Ernst Joel D. , Levy Yves , Zurawski Gerard , Altin John A.
Published: December 2021

Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous ‘Clusters of Expanded TCRs (CETs)’ can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.
Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis
Authors: Hassani Asma , Reguraman Narendran , Shehab Safa , Khan Gulfaraz
Published: December 2021

Epstein-Barr virus (EBV) is a common herpesvirus associated with malignant and non-malignant conditions. An accumulating body of evidence supports a role for EBV in the pathogenesis of multiple sclerosis (MS), a demyelinating disease of the CNS. However, little is known about the details of the link between EBV and MS. One obstacle which has hindered research in this area has been the lack of a suitable animal model recapitulating natural infection in humans. We have recently shown that healthy rabbits are susceptible to EBV infection, and viral persistence in these animals mimics latent infection in humans. We used the rabbit model to investigate if peripheral EBV infection can lead to infection of the CNS and its potential consequences. We injected EBV intravenously in one group of animals, and phosphate-buffered saline (PBS) in another, with and without immunosuppression. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques. Our investigations uncovered important findings that could not be previously addressed. We showed that primary peripheral EBV infection can lead to the virus traversing the CNS. Cell associated, but not free virus in the plasma, correlated with CNS infection. The infected cells within the brain were found to be B-lymphocytes. Most notably, animals injected with EBV, but not PBS, developed inflammatory cellular aggregates in the CNS. The incidence of these aggregates increased in the immunosuppressed animals. The cellular aggregates contained compact clusters of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes, but not myelinated nerve fibers. Moreover, studying EBV infection over a span of 28 days, revealed that the peak point for viral load in the periphery and CNS coincides with increased occurrence of cellular aggregates in the brain. Finally, peripheral EBV infection triggered temporal changes in the expression of latent viral transcripts and cytokines in the brain. The present study provides the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and highlights a unique model to dissect viral mechanisms contributing to the development of MS.
Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth
Authors: Reijmen Eva , De Mey Sven , Van Damme Helena , De Ridder Kirsten , Gevaert Thierry , De Blay Emmy , Bouwens Luc , Collen Christine , Decoster Lore , De Couck Marijke , Laoui Damya , De Grève Jacques , De Ridder Mark , Gidron Yori , Goyvaerts Cleo
Published: December 2021

The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.
Early Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review
Authors: Cavalcanti Nara Vasconcelos , Palmeira Patrícia , Jatene Marcelo Biscegli , de Barros Dorna Mayra , Carneiro-Sampaio Magda
Published: December 2021

Background and Aims

Congenital heart diseases (CHDs) are diagnosed in approximately 9 in 1,000 newborns, and early cardiac corrective surgery often requires partial or complete thymectomy. As the long-term effect of early thymectomy on the subsequent development of the immune system in humans has not been completely elucidated, the present study aimed to evaluate the effects of thymus removal on the functional capacity of the immune system after different periods.

Methods

A systematic review of the literature was performed using MEDLINE, EMBASE, LILACS and Scopus. The inclusion criteria were original studies that analyzed any component of the immune system in patients with CHD who had undergone thymectomy during cardiac surgery in the first years of life. The results were evaluated for the quality of evidence.

Results

Twenty-three studies were selected and showed that patients who underwent a thymectomy in the first years of life tended to exhibit important alterations in the T cell compartment, such as fewer total T cells, CD4+, CD8+, naïve and CD31+ T cells, lower TRECs, decreased diversity of the TCR repertoire and higher peripheral proliferation (increased Ki-67 expression) than controls. However, the numbers of memory T cells and Treg cells differed across the selected studies.

Conclusions

Early thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland.

Systematic Review Registration

Prospero [157188].
Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
Authors: Pal Lalit , Nandani Raj , Kumar Pawan , Swami Bharati , Roy Gargi , Bhaskar Sangeeta
Published: December 2021

TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ−/− mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.
Corona Virus Disease 2019 (COVID-19) as a System-Level Infectious Disease With Distinct Sex Disparities
Authors: Emadi-Baygi Modjtaba , Ehsanifard Mahsa , Afrashtehpour Najmeh , Norouzi Mahnaz , Joz-Abbasalian Zahra
Published: December 2021

The current global pandemic of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) causing COVID-19, has infected millions of people and continues to pose a threat to many more. Angiotensin-Converting Enzyme 2 (ACE2) is an important player of the Renin-Angiotensin System (RAS) expressed on the surface of the lung, heart, kidney, neurons, and endothelial cells, which mediates SARS-CoV-2 entry into the host cells. The cytokine storms of COVID-19 arise from the large recruitment of immune cells because of the dis-synchronized hyperactive immune system, lead to many abnormalities including hyper-inflammation, endotheliopathy, and hypercoagulability that produce multi-organ dysfunction and increased the risk of arterial and venous thrombosis resulting in more severe illness and mortality. We discuss the aberrated interconnectedness and forthcoming crosstalks between immunity, the endothelium, and coagulation, as well as how sex disparities affect the severity and outcome of COVID-19 and harm men especially. Further, our conceptual framework may help to explain why persistent symptoms, such as reduced physical fitness and fatigue during long COVID, may be rooted in the clotting system.
SMAC Mimetics as Therapeutic Agents in HIV Infection
Authors: Molyer Bengisu , Kumar Ashok , Angel Jonathan B.
Published: December 2021

Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.
A20 Haploinsufficiency in East Asia
Authors: Kadowaki Tomonori , Kadowaki Saori , Ohnishi Hidenori
Published: December 2021

A20, encoded by the TNFAIP3 gene, is a negative regulator of tumor necrosis factor (TNF)-nuclear factor-κB signaling. It was recently demonstrated that A20 haploinsufficiency (HA20), caused by a heterozygous mutation in the TNFAIP3 gene, can present as an early onset autoinflammatory disease resembling Behçet’s disease (BD). In addition to autoinflammatory symptoms, HA20 was also reported to be associated with autoimmune diseases and immunodeficiency. Because the phenotypes associated with HA20 are broad, with different severities observed even among individuals in the same family with identical mutations, it has been assumed that the symptoms of HA20 may depend on genetic background and environmental factors. In this review, we summarize the characteristics of patients with HA20 in East Asia and compare these with patients in other regions, mainly the USA and Europe. Patients with HA20 in East Asia developed recurrent fever more frequently than patients in other regions, but were less likely to develop typical BD symptoms such as skin rashes and genital ulcers. In addition, patients with HA20 in East Asia had low rates of complication with autoimmune diseases and low autoantibody detection rates. While anti-TNF-α agents were the primary treatments for severe HA20 in East Asia, anti-interleukin-1 agents and Janus kinase inhibitors were also administered in other regions. Future studies will need to establish methods for analyzing the pathophysiology of HA20 and determining optimal treatment strategies for each patient.
COVID-19 Vaccine Hesitancy Among Chinese Population: A Large-Scale National Study
Authors: Wu Jian , Li Quanman , Silver Tarimo Clifford , Wang Meiyun , Gu Jianqin , Wei Wei , Ma Mingze , Zhao Lipei , Mu Zihan , Miao Yudong
Published: December 2021

Globally, vaccine hesitancy is a growing public health problem. It is detrimental to the consolidation of immunization program achievements and elimination of vaccine-targeted diseases. The objective of this study was to estimate the prevalence of COVID-19 vaccine hesitancy in China and explore its contributing factors. A national cross-sectional online survey among Chinese adults (≥18 years old) was conducted between August 6, 2021 and August 9 via a market research company. We collected sociodemographic information; lifestyle behavior; quality of life; the knowledge, awareness, and behavior of COVID-19; the knowledge, awareness, and behavior of COVID-19 vaccine; willingness of COVID-19 vaccination; accessibility of COVID-19 vaccination services; skepticism about COVID-19 and COVID-19 vaccine; doctor and vaccine developer scale; and so on. Odds ratios (OR) with 95% confidence intervals (CI) were used to estimate the associations by using logistic regression models. A total of 29,925 residents (48.64% men) were enrolled in our study with mean age of 30.99 years. We found an overall prevalence of COVID-19 vaccine hesitancy at 8.40% (95% CI, 8.09–8.72) in primary vaccination and 8.39% (95% CI, 8.07–8.70) in booster vaccination. In addition, after adjusting for potential confounders, we found that women, higher educational level, married residents, higher score of health condition, never smoked, increased washing hands, increased wearing mask, increased social distance, lower level of vaccine conspiracy beliefs, disease risks outweigh vaccine risk, higher level of convenient vaccination, and higher level of trust in doctor and developer were more willing to vaccinate than all others (all p < 0.05). Age, sex, educational level, marital status, chronic disease condition, smoking, healthy behaviors, the curability of COVID-19, the channel of accessing information of COVID-19 vaccine, endorsement of vaccine conspiracy beliefs, weigh risks of vaccination against risks of the disease, making a positive influence on the health of others around you, and lower trust in healthcare system may affect the variation of willingness to take a COVID-19 vaccine (all p < 0.05). The prevalence of COVID-19 vaccine hesitancy was modest in China, even with the slight resulting cascade of changing vaccination rates between the primary and booster vaccination. Urgent action to address vaccine hesitancy is needed in building trust in medical personnel and vaccine producers, promoting the convenience of vaccination services, and spreading reliable information of COVID-19 vaccination via the Internet and other media.