bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Key Regulators of Hepatitis C Virus-Induced Hepatocellular Carcinoma by Integrating Whole-Genome and Transcriptome Sequencing Data
Authors: Chen Guolin , Zhang Wei , Ben Yiran
Published: September 2021

Background: Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in the understanding of the biological basis of HCC development, the molecular mechanisms underlying HCV-induced HCC (HCC-HCV) remain unclear. The carcinogenic potential of HCV varies according to the genotype and mutation in its viral sequence. Moreover, regulatory pathways play important roles in many pathogenic processes. Therefore, identifying the pathways by which HCV induces HCC may enable improved HCC diagnosis and treatment.

Methods: We employed a systematic approach to identify an important regulatory module in the process of HCV-HCC development to find the important regulators. First, an HCV-related HCC subnetwork was constructed based on the gene expression in HCC-HCV patients and HCC patients. A priority algorithm was then used to extract the module from the subnetworks, and all the regulatory relationships of the core genes of the network were extracted. Integrating the significantly highly mutated genes involved in the HCC-HCV patients, core regulatory modules and key regulators related to disease prognosis and progression were identified.

Result: The key regulatory genes including EXO1, VCAN, KIT, and hsa-miR-200c-5p were found to play vital roles in HCV-HCC development. Based on the statistics analysis, EXO1, VCAN, and KIT mutations are potential biomarkers for HCV–HCC prognosis at the genomic level, whereas has-miR-200c-5P is a potential biomarker for HCV–HCC prognosis at the expression level.

Conclusion: We identified three significantly mutated genes and one differentially expressed miRNA, all related to HCC prognosis. As potential pathogenic factors of HCC, these genes and the miRNA could be new biomarkers for HCV-HCC diagnosis.
ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele
Authors: González-Domínguez Carlos Alberto , Fiesco-Roa Moisés O. , Gómez-Carmona Samuel , Kleinert-Altamirano Anke Paula Ingrid , He Miao , Daniel Earnest James Paul , Raymond Kimiyo M. , Abreu-González Melania , Manrique-Hernández Sandra , González-Jaimes Ana , Salinas-Marín Roberta , Molina-Garay Carolina , Carrillo-Sánchez Karol , Flores-Lagunes Luis Leonardo , Jiménez-Olivares Marco , Muñoz-Rivas Anallely , Cruz-Muñoz Mario E. , Ruíz-García Matilde , Freeze Hudson H. , Mora-Montes Héctor M. , Alaez-Verson Carmen , Martínez-Duncker Iván
Published: September 2021

This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1, the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N-glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient’s serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.
Chromobox Homolog 8 (CBX8) in Human Tumor Carcinogenesis and Prognosis: A Pancancer Analysis Using Multiple Databases
Authors: Shi Dongjie , Ao Lei , Yu Hua , Xia Yongzhi , Li Juan , Zhong Wenjie , Xia Haijian
Published: September 2021

Some emerging studies have suggested that chromobox homolog 8 (CBX8) may play a critical role in carcinogenesis and prognosis in human cancer. Based on The Cancer Genome Atlas (TCGA)’s available data and the Gene Expression Omnibus (GEO) database, we conducted a systematic analysis of the carcinogenic effects of the CBX8 gene. We used TIMER2, GEPIA2, UALCAN, cBioPortal, Kaplan-Meier plotter, OncoLnc, STRING, HPA, and Oncomine data analysis websites and R data analysis software to analyze available data. The results show that the level of expression of CBX8 was significantly different among 27 different types of tumors and adjacent normal tissues. Moreover, we found that CBX8 expression had a close relationship with prognosis in some kinds of cancers. The phosphorylation level of some protein sites (such as S256) was significantly increased in tumors. CD8 + T-cell, B-cell and cancer-associated fibroblast infiltration levels were associated with CBX8 expression. The results of enrichment analysis indicated that the main biological activities of CBX8 are connected to gene transcription and repair of DNA damage. In conclusion, the level of expression of CBX8 was closely related to carcinogenesis and prognosis of some kinds of tumors, which needs further experimental verification.
Probing T Cell 3D Mechanosensing With Magnetically-Actuated Structures
Authors: Sachar Chirag , Kam Lance C.
Published: September 2021

The ability of cells to recognize and respond to the mechanical properties of their environment is of increasing importance in T cell physiology. However, initial studies in this direction focused on planar hydrogel and elastomer surfaces, presenting several challenges in interpretation including difficulties in separating mechanical stiffness from changes in chemistry needed to modulate this property. We introduce here the use of magnetic fields to change the structural rigidity of microscale elastomer pillars loaded with superparamagnetic nanoparticles, independent of substrate chemistry. This magnetic modulation of rigidity, embodied as the pillar spring constant, changed the interaction of mouse naïve CD4+ T cells from a contractile morphology to one involving deep embedding into the array. Furthermore, increasing spring constant was associated with higher IL-2 secretion, showing a functional impact on mechanosensing. The system introduced here thus separates local substrate stiffness and long-range structural rigidity, revealing new facets of T cell interaction with their environment.
Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway
Authors: Barratt Jonathan , Weitz Ilene
Published: September 2021

The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.
Human Mitochondrial Ribosomal RNA Modification-Based Classification Contributes to Discriminate the Prognosis and Immunotherapy Response of Glioma Patients
Authors: Wang Peng , Li Jingying , Wu Miaojing , Ye Minghua , Huang Kai , Zhu Xingen
Published: September 2021

Background

Epigenetic regulations of the tumor microenvironment (TME) and immunotherapy have been investigated in recent years. Nevertheless, the potential value of mitochondrial ribosomal RNA (mt-rRNA) modification in regulation of the TME and immunotherapy remains unknown.

Methods

We comprehensively investigated the mt-rRNA-modification patterns in glioma patients based on nine regulators of mt-rRNA. Subsequently, these modification patterns were correlated systematically with immunologic characteristics and immunotherapy. An “mt-rRNA predictor” was constructed and validated in multiple publicly available cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients.

Results

Two distinct patterns of mt-rRNA modification were determined based on the evidence that nine regulators of mt-rRNA correlated significantly with most clinicopathologic characteristics, immunomodulators, TME, immune-checkpoint blockers (ICBs), and prognosis. Patients with mt-rRNA subtype II presented significantly poorer overall survival/progression-free survival (OS/PFS), but higher tumor mutational burden (TMB), more somatic mutations, and copy number variation (CNV). These two mt-rRNA subtypes had distinct TME patterns and responses to ICB therapy. An mt-rRNA predictor was constructed and validated in four glioma cohorts. The subtype with high mt-rRNA score, characterized by increased TMB, infiltration of immune cells, and activation of immunity, suggested an immune-activated phenotype, and was also linked to greater sensitivity to immunotherapy using anti-programmed cell death protein 1 (PD-1) but resistance to temozolomide.

Conclusions

Regulators of mt-rRNA modification have indispensable roles in the complexity and diversity of the TME and prognosis. This novel classification based on patterns of mt-rRNA modification could provide an effective prognostic predictor and guide more appropriate immunotherapy/chemotherapy strategies for glioma patients.
A Peripheral Immune Signature of Labor Induction
Authors: Ando Kazuo , Hédou Julien J. , Feyaerts Dorien , Han Xiaoyuan , Ganio Edward A. , Tsai Eileen S. , Peterson Laura S. , Verdonk Franck , Tsai Amy S. , Marić Ivana , Wong Ronald J. , Angst Martin S. , Aghaeepour Nima , Stevenson David K. , Blumenfeld Yair J. , Sultan Pervez , Carvalho Brendan , Stelzer Ina A. , Gaudillière Brice
Published: September 2021

Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8+ T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being.
CD49a Identifies Polyfunctional Memory CD8 T Cell Subsets that Persist in the Lungs After Influenza Infection
Authors: Reilly Emma C. , Sportiello Mike , Emo Kris Lambert , Amitrano Andrea M. , Jha Rakshanda , Kumar Ashwin B. R. , Laniewski Nathan G. , Yang Hongmei , Kim Minsoo , Topham David J.
Published: September 2021

CD8 T cell memory offers critical antiviral protection, even in the absence of neutralizing antibodies. The paradigm is that CD8 T cell memory within the lung tissue consists of a mix of circulating TEMcells and non-circulating TRMcells. However, based on our analysis, the heterogeneity within the tissue is much higher, identifying TCM, TEM, TRM, and a multitude of populations which do not perfectly fit these classifications. Further interrogation of the populations shows that TRMcells that express CD49a, both with and without CD103, have increased and diverse effector potential compared with CD49a negative populations. These populations function as a one-man band, displaying antiviral activity, chemokine production, release of GM-CSF, and the ability to kill specific targetsin vitrowith delayed kinetics compared with effector CD8 T cells. Together, this study establishes that CD49a defines multiple polyfunctional CD8 memory subsets after clearance of influenza infection, which act to eliminate virus in the absence of direct killing, recruit and mature innate immune cells, and destroy infected cells if the virus persists.
Engineering an Antibody V Gene-Selective Vaccine
Authors: Ronsard Larance , Yousif Ashraf S. , Peabody Julianne , Okonkwo Vintus , Devant Pascal , Mogus Alemu Tekewe , Barnes Ralston M. , Rohrer Daniel , Lonberg Nils , Peabody David , Chackerian Bryce , Lingwood Daniel
Published: September 2021

The ligand-binding surface of the B cell receptor (BCR) is formed by encoded and non-encoded antigen complementarity determining regions (CDRs). Genetically reproducible or ‘public’ antibodies can arise when the encoded CDRs play deterministic roles in antigen recognition, notably within human broadly neutralizing antibodies against HIV and influenza virus. We sought to exploit this by engineering virus-like-particle (VLP) vaccines that harbor multivalent affinity against gene-encoded moieties of the BCR antigen binding site. As proof of concept, we deployed a library of RNA bacteriophage VLPs displaying random peptides to identify a multivalent antigen that selectively triggered germline BCRs using the human VH gene IGVH1-2*02. This VLP selectively primed IGHV1-2*02 BCRs that were present within a highly diversified germline antibody repertoire within humanized mice. Our approach thus provides methodology to generate antigens that engage specific BCR configurations of interest, in the absence of structure-based information.
Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors
Authors: Lu Jie , Sun Kun , Yang Huiping , Fan Dan , Huang He , Hong Yi , Wu Shuiyan , Zhou HuiTing , Fang Fang , Li YanHong , Meng Lijun , Huang Jie , Bai Zhenjiang
Published: September 2021

Background

Sepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown.

Methods

Peripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro.

Results

Our results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1β, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-β.

Conclusions

Collectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.
Environmental DNA Based Surveillance for the Highly Invasive Carpet Sea Squirt Didemnum vexillum: A Targeted Single-Species Approach
Authors: Matejusova Iveta , Graham Jennifer , Bland Fiona , Lacaze Jean-Pierre , Herman Guillaume , Brown Lyndsay , Dalgarno Eric , Bishop John D. , Kakkonen Jenni E. , Smith Kirsty F. , Douglas Alex
Published: September 2021

The presence and diversity of marine non-native species, the number of new invasions, and the impact on native communities and habitats are important metrics used to assess the health of marine ecosystems. Monitoring for marine non-native species, using traditional approaches such as rapid assessment surveys (RASs), requires taxonomic expertise and may still fail to detect rare or inconspicuous species. This study reports a validation process for a quantitative PCR (qPCR) assay based on the cytochrome oxidase 1 gene, designed to detect highly invasive tunicate Didemnum vexillum by targeting environmental DNA (eDNA) present in water samples. The D. vexillum qPCR assay showed high sensitivity, with the threshold limit of detection (LOD) and modeled LOD3 (based on triplicate qPCR reactions) estimated as 9.187 and 1.117 copies reaction–1, respectively and the limit of quantification (LOQ) was calculated as 18 copies reaction–1. Analyses of water samples collected from selected Pacific oyster farms and recreational marinas in Scotland showed 100% concordance between the historical data on presence of D. vexillum from RASs and detection of D. vexillum eDNA. Consistency of detection of D. vexillum eDNA among different sampling points within each infected sampling site varied, ranging between 100% positive throughout the site to some sampling points testing “negative” or only as “suspected” for D. vexillum. Sites with lower within-site detection consistency included sites with a low density of D. vexillum as reported by RASs or were sites undergoing D. vexillum management. The present pilot monitoring program demonstrates the potential to generate important data on presence of D. vexillum. This program will be scaled up across large geographic regions and used in the first instance to focus and target the traditional RASs to D. vexillum eDNA-positive sites in a cost-effective way, with an aim to verify the species presence by visual observation and direct Sanger sequencing of positive qPCR products.
Mitochondrial Genome of Eleutheronema rhadinum With an Additional Non-coding Region and Novel Insights Into the Phylogenetics
Authors: Zhong Liqiang , Wang Minghua , Li Daming , Tang Shengkai , Chen Xiaohui
Published: September 2021

The complete mitochondrial genome of Eleutheronema rhadinum was determined for the first time. The E. rhadinum mitogenome was 16,718 bp in length, comprising 13 protein coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), 1 control region (CR), and 1 L-strand replication origin (OL). The genome organization, and base composition were similar to other teleosts. An additional non-coding region detected in the HSL cluster, was with significant similarity to the nearby tRNA-Leu (CUN), which could be a useful marker for identifying E. rhadinum and Eleutheronema tetradactylum. Furthermore, phylogenetic analysis showed species in the family Polynemidae were well clustered together. But sister relationships between Polynemidae and Sciaenidae, Menidae plus Lactariidae were refused by present study.
Hyperuricemia Predicts Adverse Outcomes After Myocardial Infarction With Non-obstructive Coronary Arteries
Authors: Mohammed Abdul-Quddus , Abdu Fuad A. , Liu Lu , Zhang Wen , Yin Guoqing , Xu Yawei , Che Wenliang
Published: September 2021

Background: Serum uric acid (SUA) is a well-known predictor of adverse outcomes in patients with various clinical conditions. However, the impact of SUA on patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) remains unclear. Here, we aimed at investigating the potential association between hyperuricemia and the adverse outcomes in MINOCA patients.

Methods: Overall, 249 MINOCA patients were enrolled in the present study. Clinical characteristics and laboratory data, were measured in all patients. Based on SUA levels, patients were classified into two groups; the hyperuricemia group [SUA level > 6 mg/dL (360 μmol/L) in women and > 7 mg/dL (420 μmol/L) in men], and the normuricemia group. The primary endpoint of our study was major adverse cardiac events (MACE), defined as cardiovascular death, stroke, heart failure, non-fatal MI, and angina rehospitalization.

Results: Seventy-two patients were in hyperuricemia group and 177 in normuricemia group. Fifty-two MACE events were recorded after 30 months of follow-up period. The incidence of MACE was higher in hyperuricemia group compared with normuricemia group (31.9 vs. 16.3%, P = 0.006). Kaplan-Meier survival curves illustrated a significantly increased risk of MACE in hyperuricemia group (log-rank P = 0.006). The multivariable logistic analysis demonstrated that hyperuricemia was independently associated with a high risk of MACE after 30 months of follow-up (OR, 2.234; 95% CI, 1.054–4.737, P = 0.036).

Conclusion: Hyperuricemia is associated with adverse outcomes and appears to be an independent predictor of MACE in MINOCA patients. This finding suggests that the SUA levels may serve as a surrogate biomarker related to risk prediction and adverse outcomes of MINOCA patients.
Seasonal Dynamics of Epiphytic Microbial Communities on Marine Macrophyte Surfaces
Authors: Korlević Marino , Markovski Marsej , Zhao Zihao , Herndl Gerhard J. , Najdek Mirjana
Published: September 2021

Surfaces of marine macrophytes are inhabited by diverse microbial communities. Most studies focusing on epiphytic communities of macrophytes did not take into account temporal changes or applied low sampling frequency approaches. The seasonal dynamics of epiphytic microbial communities was determined in a meadow ofCymodocea nodosainvaded byCaulerpa cylindraceaand in a monospecific settlement ofC. cylindraceaat monthly intervals. For comparison the ambient prokaryotic picoplankton community was also characterized. At the OTU level, the microbial community composition differed between the ambient water and the epiphytic communities exhibiting host-specificity. Also, successional changes were observed connected to the macrophyte growth cycle. Taxonomic analysis, however, showed similar high rank taxa (phyla and classes) in the ambient water and the epiphytic communities, with the exception ofDesulfobacterota, which were only found onC. cylindracea.Cyanobacteriashowed seasonal changes while other high rank taxa were present throughout the year. In months of highCyanobacteriapresence the majority of cyanobacterial sequences were classified asPleurocapsa. Phylogenetic groups present throughout the year (e.g.,Saprospiraceae, Rhodobacteraceae, members without known relatives withinGammaproteobacteria, Desulfatitalea, and members without known relatives withinDesulfocapsaceae) constituted most of the sequences, while less abundant taxa showed seasonal patterns connected to the macrophyte growth cycle. Taken together, epiphytic microbial communities of the seagrassC. nodosaand the macroalgaC. cylindraceaappear to be host-specific and contain taxa that undergo successional changes.
Identification of the Natural Transformation Genes in Riemerella anatipestifer by Random Transposon Mutagenesis
Authors: Huang Li , Liu Mafeng , Ammanath Aparna Viswanathan , Zhu Dekang , Jia Renyong , Chen Shun , Zhao Xinxin , Yang Qiao , Wu Ying , Zhang Shaqiu , Huang Juan , Ou Xumin , Mao Sai , Gao Qun , Sun Di , Tian Bin , Götz Friedrich , Wang Mingshu , Cheng Anchun
Published: September 2021

In our previous study, it was shown that Riemerella anatipestifer, a Gram-negative bacterium, is naturally competent, but the genes involved in the process of natural transformation remain largely unknown. In this study, a random transposon mutant library was constructed using the R. anatipestifer ATCC11845 strain to screen for the genes involved in natural transformation. Among the 3000 insertion mutants, nine mutants had completely lost the ability of natural transformation, and 14 mutants showed a significant decrease in natural transformation frequency. We found that the genes RA0C_RS04920, RA0C_RS04915, RA0C_RS02645, RA0C_RS04895, RA0C_RS05130, RA0C_RS05105, RA0C_RS09020, and RA0C_RS04870 are essential for the occurrence of natural transformation in R. anatipestifer ATCC11845. In particular, RA0C_RS04895, RA0C_RS05130, RA0C_RS05105, and RA0C_RS04870 were putatively annotated as ComEC, DprA, ComF, and RecA proteins, respectively, in the NCBI database. However, RA0C_RS02645, RA0C_RS04920, RA0C_RS04915, and RA0C_RS09020 were annotated as proteins with unknown function, with no homology to any well-characterized natural transformation machinery proteins. The homologs of these proteins are mainly distributed in the members of Flavobacteriaceae. Taken together, our results suggest that R. anatipestifer encodes a unique natural transformation machinery.
Blood Meals With Active and Heat-Inactivated Serum Modifies the Gene Expression and Microbiome of Aedes albopictus
Authors: Calle-Tobón Arley , Holguin-Rocha Andres F. , Moore Celois , Rippee-Brooks Meagan , Rozo-Lopez Paula , Harrod Jania , Fatehi Soheila , Rua-Uribe Guillermo L. , Park Yoonseong , Londoño-Rentería Berlin
Published: September 2021

The Asian “tiger mosquito” Aedes albopictus is currently the most widely distributed disease-transmitting mosquito in the world. Its geographical expansion has also allowed the expansion of multiple arboviruses like dengue, Zika, and chikungunya, to higher latitudes. Due to the enormous risk to global public health caused by mosquitoes species vectors of human disease, and the challenges in slowing their expansion, it is necessary to develop new and environmentally friendly vector control strategies. Among these, host-associated microbiome-based strategies have emerged as promising options. In this study, we performed an RNA-seq analysis on dissected abdomens of Ae. albopictus females from Manhattan, KS, United States fed with sugar and human blood containing either normal or heat-inactivated serum, to evaluate the effect of heat inactivation on gene expression, the bacteriome transcripts and the RNA virome of this mosquito species. Our results showed at least 600 genes with modified expression profile when mosquitoes were fed with normal vs. heat-inactivated-containing blood. These genes were mainly involved in immunity, oxidative stress, lipid metabolism, and oogenesis. Also, we observed bacteriome changes with an increase in transcripts of Actinobacteria, Rhodospirillaceae, and Anaplasmataceae at 6 h post-feeding. We also found that feeding with normal blood seems to particularly influence Wolbachia metabolism, demonstrated by a significant increase in transcripts of this bacteria in mosquitoes fed with blood containing normal serum. However, no differences were observed in the virome core of this mosquito population. These results suggest that heat and further inactivation of complement proteins in human serum may have profound effect on mosquito and microbiome metabolism, which could influence interpretation of the pathogen-host interaction findings when using this type of reagents specially when measuring the effect of Wolbachia in vector competence.
MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis
Authors: Chen Yunqiang , Shi Yuheng , Wu Jing , Qi Nan
Published: September 2021

Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.
Synergy Between Beta-Lactams and Lipo-, Glyco-, and Lipoglycopeptides, Is Independent of the Seesaw Effect in Methicillin-Resistant Staphylococcus aureus
Authors: Zhang Rutan , Barreras Beltran Ismael A. , Ashford Nathaniel K. , Penewit Kelsi , Waalkes Adam , Holmes Elizabeth A. , Hines Kelly M. , Salipante Stephen J. , Xu Libin , Werth Brian J.
Published: September 2021

Methicillin-resistant S. aureus (MRSA) are resistant to beta-lactams, but synergistic activity between beta-lactams and glycopeptides/lipopeptides is common. Many have attributed this synergy to the beta-lactam-glycopeptide seesaw effect; however, this association has not been rigorously tested. The objective of this study was to determine whether the seesaw effect is necessary for synergy and to measure the impact of beta-lactam exposure on lipid metabolism. We selected for three isogenic strains with reduced susceptibility to vancomycin, daptomycin, and dalbavancin by serial passaging the MRSA strain N315. We used whole genome sequencing to identify genetic variants that emerged and tested for synergy between vancomycin, daptomycin, or dalbavancin in combination with 6 beta-lactams with variable affinity for staphylococcal penicillin binding proteins (PBPs), including nafcillin, meropenem, ceftriaxone, ceftaroline, cephalexin, and cefoxitin, using time-kills. We observed that the seesaw effect with each beta-lactam was variable and the emergence of the seesaw effect for a particular beta-lactam was not necessary for synergy between that beta-lactam and vancomycin, daptomycin, or dalbavancin. Synergy was more commonly observed with vancomycin and daptomycin based combinations than dalbavancin in time-kills. Among the beta-lactams, cefoxitin and nafcillin were the most likely to exhibit synergy using the concentrations tested, while cephalexin was the least likely to exhibit synergy. Synergy was more common among the resistant mutants than the parent strain. Interestingly N315-D1 and N315-DAL0.5 both had mutations in vraTSR and walKR despite their differences in the seesaw effect. Lipidomic analysis of all strains exposed to individual beta-lactams at subinhibitory concentrations suggested that in general, the abundance of cardiolipins (CLs) and most free fatty acids (FFAs) positively correlated with the presence of synergistic effects while abundance of phosphatidylglycerols (PGs) and lysylPGs mostly negatively correlated with synergistic effects. In conclusion, the beta-lactam-glycopeptide seesaw effect and beta-lactam-glycopeptide synergy are distinct phenomena. This suggests that the emergence of the seesaw effect may not have clinical importance in terms of predicting synergy. Further work is warranted to characterize strains that don’t exhibit beta-lactam synergy to identify which strains should be targeted with combination therapy and which ones cannot and to further investigate the potential role of CLs in mediating synergy.
Brain Network to Placebo and Nocebo Responses in Acute Experimental Lower Back Pain: A Multivariate Granger Causality Analysis of fMRI Data
Authors: Shi Yu , Cui Shaoye , Zeng Yanyan , Huang Shimin , Cai Guiyuan , Yang Jianming , Wu Wen
Published: September 2021

Background and Objective: Placebo and nocebo responses are widely observed. Herein, we investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas.

Method: After completing the ALBP model, 20 healthy subjects were given two interventions, once during a placebo intervention and once during a nocebo intervention, pseudo-randomly ordered. fMRI scans were performed synchronously during each intervention, and visual analog scale (VAS) scores were collected at the end of each intervention. The fMRI data were then analyzed using multivariate GCA.

Results: Our results found statistically significant differences in VAS scores from baseline (pain status) for both placebo and nocebo interventions, as well as between placebo and nocebo interventions. In placebo network, we found a negative lagged-temporal correlation between multiple brain areas, including the dorsolateral prefrontal cortex (DLPFC), secondary somatosensory cortex area, anterior cingulate cortex (ACC), and insular cortex (IC); and a positive lagged-temporal correlation between multiple brain areas, including IC, thalamus, ACC, as well as the supplementary motor area (SMA). In the nocebo network, we also found a positive lagged-temporal correlation between multiple brain areas, including the primary somatosensory cortex area, caudate, DLPFC and SMA.

Conclusion: The results of this study suggest that both pain-related network and reward system are involved in placebo and nocebo responses. The placebo response mainly works by activating the reward system and inhibiting pain-related network, while the nocebo response is the opposite. Placebo network also involves the activation of opioid-mediated analgesia system (OMAS) and emotion pathway, while nocebo network involves the deactivation of emotional control. At the same time, through the construction of the GC network, we verified our hypothesis that nocebo and placebo networks share part of the same brain regions, but the two networks also have their own unique structural features.
Client-Server Approach for Managing Visual Attention, Integrated in a Cognitive Architecture for a Social Robot
Authors: Martín Francisco , Ginés Jonatan , Rodríguez-Lera Francisco J. , Guerrero-Higueras Angel M. , Matellán Olivera Vicente
Published: September 2021

This paper proposes a novel system for managing visual attention in social robots. This system is based on a client/server approach that allows integration with a cognitive architecture controlling the robot. The core of this architecture is a distributed knowledge graph, in which the perceptual needs are expressed by the presence of arcs to stimuli that need to be perceived. The attention server sends motion commands to the actuators of the robot, while the attention clients send requests through the common knowledge representation. The common knowledge graph is shared by all levels of the architecture. This system has been implemented on ROS and tested on a social robot to verify the validity of the approach and was used to solve the tests proposed in RoboCup @ Home and SciROc robotic competitions. The tests have been used to quantitatively compare the proposal to traditional visual attention mechanisms.
Corticothalamic Pathways From Layer 5: Emerging Roles in Computation and Pathology
Authors: Mease Rebecca A. , Gonzalez Antonio J.
Published: September 2021

Large portions of the thalamus receive strong driving input from cortical layer 5 (L5) neurons but the role of this important pathway in cortical and thalamic computations is not well understood. L5-recipient “higher-order” thalamic regions participate in cortico-thalamo-cortical (CTC) circuits that are increasingly recognized to be (1) anatomically and functionally distinct from better-studied “first-order” CTC networks, and (2) integral to cortical activity related to learning and perception. Additionally, studies are beginning to elucidate the clinical relevance of these networks, as dysfunction across these pathways have been implicated in several pathological states. In this review, we highlight recent advances in understanding L5 CTC networks across sensory modalities and brain regions, particularly studies leveraging cell-type-specific tools that allow precise experimental access to L5 CTC circuits. We aim to provide a focused and accessible summary of the anatomical, physiological, and computational properties of L5-originating CTC networks, and outline their underappreciated contribution in pathology. We particularly seek to connect single-neuron and synaptic properties to network (dys)function and emerging theories of cortical computation, and highlight information processing in L5 CTC networks as a promising focus for computational studies.
Microstructural Abnormalities of White Matter Across Tourette Syndrome: A Voxel-Based Meta-Analysis of Fractional Anisotropy
Authors: Yang Chengmin , Yao Li , Liu Naici , Zhang Wenjing , Tao Bo , Cao Hengyi , Gong Qiyong , Lui Su
Published: September 2021

Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with multiple motor and vocal tics whose neural basis remains unclear. Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural alternations in TS, but the findings are inconclusive. In this study, we aimed to elucidate the most consistent white matter deficits in patients with TS.

Method: By systematically searching online databases up to December 2020 for all DTI studies comparing fractional anisotropy (FA) between patients with TS and healthy controls (HCs), we conducted anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis to investigate FA differences in TS, as well as performed meta-regression analysis to explore the effects of demographics and clinical characteristics on white matter abnormalities among TS.

Results: A total of eight datasets including 168 patients with TS and 163 HCs were identified. We found that TS patients showed robustly decreased FA in the corpus callosum (CC) and right inferior longitudinal fasciculus (ILF) compared with HCs. These two regions preserved significance in the sensitivity analysis. No regions of increased FA were reported. Meta-regression analysis revealed that age, sex, tic severity, or illness duration of patients with TS were not linearly correlated with decreased FA.

Conclusion: Patients with TS display deficits of white matter microstructure in the CC and right ILF known to be important for interhemispheric connections as well as long association fiber bundles within one hemisphere. Because the results reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in TS.
Efficacy of a Direct Aspiration First-Pass Technique (ADAPT) for Endovascular Treatment in Different Etiologies of Large Vessel Occlusion: Embolism vs. Intracranial Atherosclerotic Stenosis
Authors: Liao Geng , Zhang Zhenyu , Zhang Guangzhi , Du Weijie , Li Chaomao , Liang Hanxiang
Published: September 2021

Background and Aims: Aspiration thrombectomy is an effective method of recanalizing large vessel occlusion (LVO). However, the efficacy of a direct aspiration first-pass technique (ADAPT) for recanalization of LVO of different etiologies is not properly understood.

Methods: The prospectively collected database on ADAPT was reviewed retrospectively. We defined two groups of enrolled patients: the embolism-related occlusions (EMB-O) group and the intracranial atherosclerotic stenosis (ICAS)-related occlusion (ICAS-O) group. Baseline characteristics, procedural variables, and post-procedural variables were collected. Multivariate logistic regression analysis was used to identify first-pass recanalization predictors.

Results: Of 114 registered patients, 94 were eligible for this study (51 patients in the EMB-O group and 43 patients in the ICAS-O group). Achieving successful reperfusion immediately after direct aspiration was more frequent in the EMB-O group than in the ICAS-O group (64.71 vs. 27.91%, respectively, p = 0.006), with fewer additional rescue treatments needed (35.29 vs. 70.09%, respectively, p = 0.001). The EMB-O group also showed a higher final successful reperfusion rate (96.8 vs. 74.41%, p = 0.006). However, the 90-day good functional outcomes were not affected by the groups. Independent predictors of first-pass success of aspiration included the isolated middle cerebral artery site of occlusion, embolic etiology, and use of larger bore catheters.

Conclusions: The efficacy of ADAPT recanalization approach was better in EMB-O than in ICAS-O. In case of embolic etiology and the isolated MCA site of occlusion, using a larger aspiration catheter for direct aspiration thrombectomy may be reasonable.
Altered Gray Matter Volume, Functional Connectivity, and Degree Centrality in Early-Onset Type 2 Diabetes Mellitus
Authors: Feng Yue , Li Yifan , Tan Xin , Liang Yi , Ma Xiaomeng , Chen Yuna , Lv Wenjiao , Wu Jinjian , Kang Shangyu , Li Mingrui , Qiu Shijun
Published: September 2021

Background: Structural and functional brain alterations that underlie cognitive decline have been observed in elderly adults with type 2 diabetes mellitus (T2DM); however, whether these alterations can be observed in patients with early-onset T2DM remains unclear. Therefore, we aimed to describe the abnormalities in brain volume and functional patterns in patients with early-onset T2DM in the present study.

Methods: We enrolled 20 patients with early-onset T2DM and 20 healthy controls (HCs). Changes in brain volume were assessed using voxel-based morphology (VBM), while changes in brain function were assessed using degree centrality (DC) and functional connectivity (FC).

Results: Compared to HCs, patients with early-onset T2DM exhibited gray matter reductions in the left orbital superior, middle, and inferior frontal gyri as well as the right superior frontal gyrus. The gray matter reductions in the right superior frontal gyrus were negatively associated with the urine albumin to creatinine ratio. Furthermore, increased DC values were observed in the left superior temporal gyrus, left Heschl gyrus, and left hippocampus in patients with early-onset T2DM. An FC analysis of these regions revealed elevated connectivity in the right precuneus, left inferior parietal gyrus, left Heschl gyrus, bilateral post-central gyrus, bilateral insula, bilateral superior temporal gyrus, and bilateral medial and paracingulate gyrus. Furthermore, the FC of the hubs to the superior temporal gyrus, insula, and Heschl gyrus was increased and positively correlated with trail making test-B.

Conclusion: Decreased local gray matter volume and increased DC and FC may represent the neurobiological mechanism underlying cognitive dysfunction in patients with early-onset T2DM.
Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
Authors: Lauxmann Stephan , Sonnenberg Lukas , Koch Nils A. , Bosselmann Christian , Winter Natalie , Schwarz Niklas , Wuttke Thomas V. , Hedrich Ulrike B. S. , Liu Yuanyuan , Lerche Holger , Benda Jan , Kegele Josua
Published: September 2021

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.

Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.

Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.

Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.