bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Tocilizumab Therapy on Circulating B Cells and T Helper Cells in Patients With Neuromyelitis Optica Spectrum Disorder
Authors: Liu Ye , Zhang Huiming , Zhang Tian-Xiang , Yuan Meng , Du Chen , Zeng Pei , Huang Zhenning , Jia Dongmei , Yang Guili , Shi Fu-Dong , Zhang Chao
Published: July 2021

Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed its therapeutic efficacy on neuromyelitis optica spectrum disorder (NMOSD). To assess the immunological effects of this drug on B cells, follicular T helper (Tfh) cells, and peripheral T helper (Tph) cells in patients with NMOSD, peripheral B cell and Tfh cell phenotypes were evaluated in 26 patients with NMOSD before and after tocilizumab treatment by nine-color flow cytometry, as well as the expression of costimulatory and co-inhibitory molecules on B cells. Results showed that the frequency of CD27+IgD− switched memory B cells, CD27-IgD- double-negative B cells, and CD27highCD38high antibody-secreting cells was increased in patients with NMOSD. Tocilizumab treatment led to a significant shift of B cells to naïve B cells from memory B cells after 3 months. Three markers on B cells associated with T-cell activation (i.e., CD86 CD69, and HLA-DR) were downregulated after tocilizumab treatment. The frequencies of total Tfh and Tph cells were decreased, whereas that of follicular regulatory T cells tended to increase. Intrinsic increased PD-L1 and PD-L2 expression was characteristic of B cells in patients with NMOSD. Tocilizumab selectively restored PD-L1 on B-cell subsets. These results provided evidence that tocilizumab enhanced B- and T-cell homoeostasis by regulating B-cell differentiation and inhibiting lymphocyte activation in patients with NMOSD.
Prognostic Value of an Immunohistochemical Signature in Patients With Head and Neck Mucosal Melanoma
Authors: Xu Qing-Qing , Li Qing-Jie , Huang Cheng-Long , Cai Mu-Yan , Zhang Mei-Fang , Yin Shao-Han , Lu Li-Xia , Chen Lei
Published: July 2021

Purpose

We aimed to develop a prognostic immunohistochemistry (IHC) signature for patients with head and neck mucosal melanoma (MMHN).

Methods

In total, 190 patients with nonmetastatic MMHN with complete clinical and pathological data before treatment were included in our retrospective study.

Results

We extracted five IHC markers associated with overall survival (OS) and then constructed a signature in the training set (n=116) with the least absolute shrinkage and selection operator (LASSO) regression model. The validation set (n=74) was further built to confirm the prognostic significance of this classifier. We then divided patients into high- and low-risk groups according to the IHC score. In the training set, the 5-year OS rate was 22.0% (95% confidence interval [CI]: 11.2%- 43.2%) for the high-risk group and 54.1% (95% CI: 41.8%-69.9%) for the low-risk group (P<0.001), and in the validation set, the 5-year OS rate was 38.1% (95% CI: 17.9%-81.1%) for the high-risk group and 43.1% (95% CI: 30.0%-61.9%) for the low-risk group (P=0.26). Multivariable analysis revealed that IHC score, T stage, and primary tumor site were independent variables for predicting OS (all P<0.05). We developed a nomogram incorporating clinicopathological risk factors (primary site and T stage) and the IHC score to predict 3-, 5-, and 10-year OS.

Conclusions

A nomogram was generated and confirmed to be of clinical value. Our IHC classifier integrating five IHC markers could help clinicians make decisions and determine optimal treatments for patients with MMHN.
CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection
Authors: Veenhuis Rebecca T. , Garliss Caroline C. , Bailey Justin R. , Blankson Joel N.
Published: July 2021

HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies.
Transcriptome Analysis of Peripheral Blood Mononuclear Cells Reveals Distinct Immune Response in Asymptomatic and Re-Detectable Positive COVID-19 Patients
Authors: Zhang Jiaqi , Lin Dongzi , Li Kui , Ding Xiangming , Li Lin , Liu Yuntao , Liu Dongdong , Lin Jing , Teng Xiangyun , Li Yizhe , Liu Ming , Shen Jian , Wang Xiaodan , He Dan , Shi Yaling , Wang Dawei , Xu Jianhua
Published: July 2021

The existence of asymptomatic and re-detectable positive coronavirus disease 2019 (COVID-19) patients presents the disease control challenges of COVID-19. Most studies on immune responses in COVID-19 have focused on moderately or severely symptomatic patients; however, little is known about the immune response in asymptomatic and re-detectable positive (RP) patients. Here we performed a comprehensive analysis of the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from 48 COVID-19 patients which included 8 asymptomatic, 13 symptomatic, 15 recovered and 12 RP patients. The weighted gene co-expression network analysis (WGCNA) identified six co-expression modules, of which the turquoise module was positively correlated with the asymptomatic, symptomatic, and recovered COVID-19 patients. The red module positively correlated with symptomatic patients only and the blue and brown modules positively correlated with the RP patients. The analysis by single sample gene set enrichment analysis (ssGSEA) revealed a lower level of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, gene set enrichment analysis (GSEA) analysis showed the enrichment of TNFα/NF-κB and influenza infection in the RP patients compared with the recovered patients, indicating a hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression of COVID-19 disease and assist clinical management and the immunotherapy development for COVID-19.
Combination of a Sindbis-SARS-CoV-2 Spike Vaccine and αOX40 Antibody Elicits Protective Immunity Against SARS-CoV-2 Induced Disease and Potentiates Long-Term SARS-CoV-2-Specific Humoral and T-Cell Immunity
Authors: Scaglione Antonella , Opp Silvana , Hurtado Alicia , Lin Ziyan , Pampeno Christine , Noval Maria G. , Thannickal Sara A. , Stapleford Kenneth A. , Meruelo Daniel
Published: July 2021

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world’s population at record speeds. However, there is still a demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (αOX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T-cell response in mice. Protein binding, immunohistochemical, and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles, and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response, which can be used as a new candidate to combat SARS-CoV-2. Given the T-cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.
Optimisation of Parameters in a German Bight Circulation Model by 4DVAR Assimilation of Current and Water Level Observations
Authors: Schulz-Stellenfleth Johannes , Foerderreuther Silvia , Horstmann Jochen , Staneva Joanna
Published: July 2021

Uncertain parameters in a 3D barotropic circulation model of the German Bight are estimated with a variational optimisation approach. Surface current measurements from a high frequency (HF) radar are used in combination with acoustic Doppler current profiler (ADCP) and tide gauge observations as input for a 4DVAR assimilation scheme. The required cost function gradients are estimated using an adjoint model code. The focus of the study is on systematic errors of the model with the control vector including parameters of the bathymetry, bottom roughness, open boundary forcing, meteorological forcing as well as the turbulence model. The model uses the same bathymetry, open boundary forcing, and metereological forcing as the operational model run at the Federal Maritime and Hydrographic Agency (BSH). The baroclinic BSH model is used as a reference to put the performance of the optimised model into perspective. It is shown that the optimised model has better agreement with HF radar data and tide gauge observations both within the fortnight training period and the test period 1 month later. Current profile measurements taken at two platforms indicate that both models have comparable error magnitudes at those locations. The optimised model was also compared with independent drifter data. In this case, drifter simulations based on the BSH model and the respective operational drift model including some surface wave effects were used as a reference. Again, these comparison showed very similar results overall, with some larger errors of the tuned model in very shallow areas, where no observations were used for the tuning and surface wave effects, which are only explicitly considered in the BSH model, play a more important role. The tuned model seems to be slightly more dissipative than the BSH model with more energy entering through the western boundary and less energy leaving toward the north. It also became evident that the 4DVAR cost function minimisation process is complicated by momentum advection, which leads to non-differentiable dependencies of the model with respect to the control vector. It turned out that the omission of momentum advection in the adjoint code still leads to robust estimates of descent directions.
A Nonlinear Macro-Model for the Analysis of Monotonic and Cyclic Behaviour of Exterior RC Beam-Column Joints
Authors: Grande Ernesto , Imbimbo Maura , Napoli Annalisa , Nitiffi Riccardo , Realfonzo Roberto
Published: July 2021

The study presents a numerical investigation on exterior reinforced concrete (RC) beam-column joints under seismic actions based on a macro-modelling approach proposed by the authors in a recent paper. The followed approach makes use of the well-known “scissors model” where two nonlinear rotational springs arranged in series were introduced to schematize the shear behavior of the joint panel and, moreover, the possible occurrence of the debonding of longitudinal steel rebars at the beam-joint interface. In this paper, the scissor model is employed in the context of a novel predictive approach with the twofold objective to: 1) develop a new model for the estimate of the maximum shear strength of RC joints by performing a multivariate linear regression analysis on a set of experimental tests and, 2) define a new multilinear backbone joint shear stress-strain law to be assigned to one of the mentioned springs. In particular, the identification of the shear strain parameters is obtained by performing a sensitivity analysis in which a number of monotonic load-drift numerical curves are derived by varying the strain values in ranges opportunely a-priori defined and compared with the experimental ones to investigate their accuracy. Finally, cyclic analyses on RC joints collected in the experimental database are carried out by considering the backbone joint shear stress-strain law identified in the calibration process. The analyses are performed by using the nonlinear open-source finite element platform, OpenSees, in which the “pinching4” uniaxial material model, available in the software library, is implemented to set the parameters governing the hysteresis rules and pinching effect. To this purpose, five literature proposals suggesting the values to use for such parameters are taken into account and their assessment is presented in the paper. The obtained outcomes have allowed, on the one hand, to identify the proposal providing the best numerical simulations of the experimental results and, on the other end, to draw useful indications on how to further improve the cyclic modelling by opportunely modifying the setting of the “pinching4” material model parameters.
Is Face and Mask Touching a Real Struggle During the COVID-19 Pandemic? A Prospective Study Among Medical Students
Authors: Stefaniak Aleksandra A. , Krajewski Piotr K. , Białynicki-Birula Rafał , Nowicka Danuta , Szepietowski Jacek C.
Published: July 2021

There are limited data in the literature on the frequency of face- and mask-touching behavior as a potential vector for the self-inoculation and transmission of the novel coronavirus. In this prospective study, we assessed the facial touching behavior of 204 medical students. One hundred thirty-four subjects (65.68%) during the 15-min observation at least once touched the area of the mask (38.23%), eyes (38.23%), or other parts of the facial zone (49.02%). The mean number of touches was 11.98 ± 16.33 per hour. The results of our study reveal that there is no significant association between mask wearing and gender; however, there might be a tendency for people with eyeglasses to touch the area near the eyes more often.
Electrical Stimulation and Conductive Polymers as a Powerful Toolbox for Tailoring Cell Behaviour in vitro
Authors: Rocha Igor , Cerqueira Gabrielle , Varella Penteado Felipe , Córdoba de Torresi Susana I.
Published: July 2021

Electrical stimulation (ES) is a well-known method for guiding the behaviour of nerve cells in in vitro systems based on the response of these cells to an electric field. From this perspective, understanding how the electrochemical stimulus can be tuned for the design of a desired cell response is of great importance. Most biomedical studies propose the application of an electrical potential to cell culture arrays while examining the cell response regarding viability, morphology, and gene expression. Conversely, various studies failed to evaluate how the fine physicochemical properties of the materials used for cell culture influence the observed behaviours. Among the various materials used for culturing cells under ES, conductive polymers (CPs) are widely used either in pristine form or in addition to other polymers. CPs themselves do not possess the optimal surface for cell compatibility because of their hydrophobic nature, which leads to poor protein adhesion and, hence, poor bioactivity. Therefore, understanding how to tailor the chemical properties on the material surface will determine the obtention of improved ES platforms. Moreover, the structure of the material, either in a thin film or in porous electrospun scaffolds, also affects the biochemical response and needs to be considered. In this review, we examine how materials based on CPs influence cell behaviour under ES, and we compile the various ES setups and physicochemical properties that affect cell behaviour. This review concerns the culture of various cell types, such as neurons, fibroblasts, osteoblasts, and Schwann cells, and it also covers studies on stem cells prone to ES. To understand the mechanistic behaviour of these devices, we also examine studies presenting a more detailed biomolecular level of interaction. This review aims to guide the design of future ES setups regarding the influence of material properties and electrochemical conditions on the behaviour of in vitro cell studies.
Development of a Viral RdRp-Assisted Gene Silencing System and Its Application in the Identification of Host Factors of Plant (+)RNA Virus
Authors: Zhang Wang , Qiu Yanglin , Zhou Lingyun , Yin Jinlong , Wang Liqun , Zhi Haijian , Xu Kai
Published: July 2021

Gene silencing induced by hairpin RNA or virus infection expression is one of the major tools in genetics studies in plants. However, when dealing with essential genes, virus-induced gene silencing (VIGS) and transgenic expression of hairpin RNA could lead to plant death, while transient expression of hairpin RNA in leaves is often less competent in downregulating target gene mRNA levels. Here, we developed a transient double-stranded RNA (dsRNA) expression system assisted by a modified viral RNA-dependent RNA polymerase (RdRp) in plant leaves. We show that this system is more effective in inducing gene silencing than the intron-spliced hairpin RNA expression. Furthermore, by using this system, we tested the role of the early secretory pathway during infection of Soybean mosaic potyvirus (SMV). We found that key components of the coat protein complex II vesicles are required for the multiplication of SMV. Overall, this dsRNA-based gene silencing system is effective in downregulating plant gene expression and can be used to identify host genes involved in plant-virus interactions.
Safety Evaluation of Bifidobacterium lactis BL-99 and Lacticaseibacillus paracasei K56 and ET-22 in vitro and in vivo
Authors: Lu Hongyun , Zhao Wen , Liu Wei-Hsien , Sun Ting , Lou Hanghang , Wei Tianyu , Hung Wei-Lian , Chen Qihe
Published: July 2021

Probiotics have been reported to play a major role in maintaining the balance of microbiota in host. Consumption of food with probiotics has increased with consumer concerns regarding healthy diets and wellness. Correspondingly, safety evaluation of probiotics for human consumption has become increasingly important in food industry. Herein, we aimed to test the safety of Bifidobacterium lactis BL-99 and Lacticaseibacillus paracasei K56 and ET-22 strains in vitro and in vivo. In results, these strains were found to be negative for mucin degradation and platelet aggregation test. Additionally, the three strains were susceptible to eight antibiotics. In accordance with bacterial reversion mutation (Ames) assay, the tested strains had no genetic mutagenicity. Finally, it was confirmed that there were no dose-dependent mortality and toxicity throughout multidose oral toxicity tests in rats. Our findings demonstrated that B. lactis BL-99 and L. paracasei K56 and ET-22 can achieve the generally recognized as safe (GRAS) status as probiotics in the future.
Identification of Three Clf-Sdr Subfamily Proteins in Staphylococcus warneri, and Comparative Genomics Analysis of a Locus Encoding CWA Proteins in Staphylococcus Species
Authors: Sun Zhewei , Zhang Xueya , Zhou Danying , Zhou Kexin , Li Qiaoling , Lin Hailong , Lu Wei , Liu Hongmao , Lu Junwan , Lin Xi , Li Kewei , Xu Teng , Zhu Mei , Bao Qiyu , Zhang Hailin
Published: July 2021

Coagulase-negative Staphylococcus warneri is an opportunistic pathogen that is capable of causing several infections, especially in patients with indwelling medical devices. Here, we determined the complete genome sequence of a clinical S. warneri strain isolated from the blood culture of a 1-year-old nursling patient with acute upper respiratory infection. Genome-wide phylogenetic analysis confirmed the phylogenetic relationships between S. warneri and other Staphylococcus species. Using comparative genomics, we identified three cell wall-anchored (CWA) proteins at the same locus (sdr), named SdrJ, SdrK, and SdrL, on the chromosome sequences of different S. warneri strains. Structural predictions showed that SdrJ/K/L have structural features characteristic of Sdr proteins but exceptionally contained an unusual N-terminal repeat region. However, the C-terminal repetitive (R) region of SdrJ contains a significantly larger proportion of alanine (142/338, 42.01%) than the previously reported SdrI (37.00%). Investigation of the genetic organization revealed that the sdrJ/K/L genes were always followed by one or two glycosyltransferase genes, gtfA and gtfB and were present in an ∼56 kb region bordered by a pair of 8 bp identical direct repeats, named Sw-Sdr. This region was further found to be located on a 160-kb region subtended by a pair of 160-bp direct repeats along with other virulence genes and resistance genes. Sw-Sdr contained a putative integrase that was probably a remnant of a functional integrase. Evidence suggests that Sw-Sdr is improbably an efficient pathogenicity island. A large-scale investigation of Staphylococcus genomes showed that sdr loci were a potential hotspot of insertion sequences (ISs), which could lead to intraspecific diversity at these loci. Our work expanded the repository of Staphylococcus Sdr proteins, and for the first time, we established the connection between sdr loci and phylogenetic relationships and compared the sdr loci in different Staphylococcus species, which provided large insights into the genetic environment of CWA genes in Staphylococcus.
Selective Adsorption of Amino Acids in Crystals of Monohydrocalcite Induced by the Facultative Anaerobic Enterobacter ludwigii SYB1
Authors: Zhao Yanyang , Han Zuozhen , Yan Huaxiao , Zhao Hui , Tucker Maurice E. , Gao Xiao , Guo Na , Meng Ruirui , Owusu Daniel Cosmos
Published: July 2021

The morphology, crystal structure, and elemental composition of biominerals are commonly different from chemically synthesized minerals, but the reasons for these are not fully understood. A facultative anaerobic bacterium, Enterobacter ludwigii SYB1, is used in experiments to document the hydrochemistry, mineral crystallization, and cell surface characteristics of biomineralization. It was found that carbonate anhydrase and ammonia production were major factors influencing the alkalinity and saturation of the closed biosystem. X-ray diffraction (XRD) spectra showed that calcite, monohydrocalcite (MHC), and dypingite formed in samples with bacterial cells. It was also found that the (222) plane of MHC was the preferred orientation compared to standard data. Scanning transmission electron microscopy (STEM) analysis of cell slices provides direct evidence of concentrated calcium and magnesium ions on the surface of extracellular polymeric substances (EPS). In addition, high-resolution transmission electron microscopy (HRTEM) showed that crystallized nanoparticles were formed within the EPS. Thus, the mechanism of the biomineralization induced by E. ludwigii SYB1 can be divided into three stages: (i) the production of carbonate anhydrase and ammonia increases the alkalinity and saturation state of the milieu, (ii) free calcium and magnesium ions are adsorbed and chelated onto EPS, and (iii) nanominerals crystallize and grow within the EPS. Seventeen kinds of amino acids were identified within both biotic MHC and the EPS of SYB1, while the percentages of glutamic and aspartic acid in MHC increased significantly (p < 0.05). Furthermore, the adsorption energy was calculated for various amino acids on seven diffracted crystal faces, with preferential adsorption demonstrated on (111) and (222) faces. At the same time, the lowest adsorption energy was always that of glutamic and aspartic acid for the same crystal plane. These results suggest that aspartic and glutamic acid always mix preferentially in the crystal lattice of MHC and that differential adsorption of amino acids on crystal planes can lead to their preferred orientation. Moreover, the mixing of amino acids in the mineral structure may also have a certain influence on the mineral lattice dislocations, thus enhancing the thermodynamic characteristics.
A Review on the General Cheese Processing Technology, Flavor Biochemical Pathways and the Influence of Yeasts in Cheese
Authors: Zheng Xiaochun , Shi Xuewei , Wang Bin
Published: July 2021

Cheese has a long history and this naturally fermented dairy product contains a range of distinctive flavors. Microorganisms in variety cheeses are an essential component and play important roles during both cheese production and ripening. However, cheeses from different countries are still handmade, the processing technology is diverse, the microbial community structure is complex and the cheese flavor fluctuates greatly. Therefore, studying the general processing technology and relationship between microbial structure and flavor formation in cheese is the key to solving the unstable quality and standardized production of cheese flavor on basis of maintaining the flavor of cheese. This paper reviews the research progress on the general processing technology and key control points of natural cheese, the biochemical pathways for production of flavor compounds in cheeses, the diversity and the role of yeasts in cheese. Combined with the development of modern detection technology, the evolution of microbial structure, population evolution and flavor correlation in cheese from different countries was analyzed, which is of great significance for the search for core functional yeast microorganisms and the industrialization prospect of traditional fermented cheese.
Global Genomic Characterization of Salmonella enterica Serovar Telelkebir
Authors: Qiu Yu-feng , Nambiar Reshma B. , Xu Xue-bin , Weng Shun-tai , Pan Hang , Zheng Kui-cheng , Yue Min
Published: July 2021

Non-typhoidal Salmonella (NTS) is a common cause for self-limiting gastroenteritis, representing a public health concern globally. NTS is one of the leading causes of foodborne illnesses in China; however, the invasive infection caused by NTS is largely underappreciated. Here, we reported an NTS invasive infection caused by an infrequently reported serovar Telelkebir (13,23:d:e,n,z15) strain FJ001 in China, which carries antimicrobial-resistant genes [fosA7 and aac(6′)-Iaa] and typhoid-toxin genes (cdtB, pltA, and pltB). By conducting the whole genomic sequencing, we also investigated the relatedness of this strain with an additional 120 global contextual Salmonella enterica serovar Telelkebir (S. Telelkebir) isolates, and assessed the antimicrobial-resistant determinants and key virulence factors using the available genomic dataset. Notably, all 121 (100%) of the S. Telelkebir strains possessed the typhoid toxin genes cdtB, pltA, and pltB, and 58.67% (71/121) of S. Telelkebir harbored antimicrobial-resistant gene fosaA7. The study by core genome multilocus sequence typing (cgMLST) and core single-nucleotide polymorphism (SNP)-based phylogenomic analysis demonstrated that the S. Telelkebir isolates from different sources and locations clustered together. This suggests that regular international travels might increase the likelihood of rapid and extensive transmissions of potentially pathogenic bacteria. For the first time, our study revealed the antimicrobial resistance, virulence patterns, and genetic diversity of the serovar S. Telelkebir isolate in humans and similar isolates over the world. The present study also suggests that genomic investigation can facilitate surveillance and could offer added knowledge of a previously unknown threat with the unique combination of virulent and antimicrobial-resistant determinants.
A Chromosome-Scale Assembly of the Wheat Leaf Rust Pathogen Puccinia triticina Provides Insights Into Structural Variations and Genetic Relationships With Haplotype Resolution
Authors: Wu Jing Qin , Song Long , Ding Yi , Dong Chongmei , Hasan Mafruha , Park Robert F.
Published: July 2021

Despite the global economic importance of the wheat leaf rust pathogen Puccinia triticina (Pt), genomic resources for Pt are limited and chromosome-level assemblies of Pt are lacking. Here, we present a complete haplotype-resolved genome assembly at a chromosome-scale for Pt using the Australian pathotype 64-(6),(7),(10),11 (Pt64; North American race LBBQB) built upon the newly developed technologies of PacBio and Hi-C sequencing. PacBio reads with ∼200-fold coverage (29.8 Gb data) were assembled by Falcon and Falcon-unzip and subsequently scaffolded with Hi-C data using Falcon-phase and Proximo. This approach allowed us to construct 18 chromosome pseudomolecules ranging from 3.5 to 12.3 Mb in size for each haplotype of the dikaryotic genome of Pt64. Each haplotype had a total length of ∼147 Mb, scaffold N50 of ∼9.4 Mb, and was ∼93% complete for BUSCOs. Each haplotype had ∼29,800 predicted genes, of which ∼2,000 were predicted as secreted proteins (SPs). The investigation of structural variants (SVs) between haplotypes A and B revealed that 10% of the total genome was spanned by SVs, highlighting variations previously undetected by short-read based assemblies. For the first time, the mating type (MAT) genes on each haplotype of Pt64 were identified, which showed that MAT loci a and b are located on two chromosomes (chromosomes 7 and 14), representing a tetrapolar type. Furthermore, the Pt64 assembly enabled haplotype-based evolutionary analyses for 21 Australian Pt isolates, which highlighted the importance of a haplotype resolved reference when inferring genetic relationships using whole genome SNPs. This Pt64 assembly at chromosome-scale with full phase information provides an invaluable resource for genomic and evolutionary research, which will accelerate the understanding of molecular mechanisms underlying Pt-wheat interactions and facilitate the development of durable resistance to leaf rust in wheat and sustainable control of rust disease.
Dynamic Observation of Autophagy and Transcriptome Profiles in a Mouse Model of Bleomycin-Induced Pulmonary Fibrosis
Authors: Wang Yani , Hu Siqi , Shen Lisha , Liu Song , Wan Linyan , Yang Shuhui , Hou Mengjie , Tian Xinlun , Zhang Hongbing , Xu Kai-Feng
Published: July 2021

Pulmonary fibrosis is a group of progressive, fibrotic, and fatal lung diseases, and the role of autophagy in pulmonary fibrosis is controversial. In the current research, we dynamically observed a bleomycin-induced pulmonary fibrosis mouse model after 3, 7, 14, 21, and 28 days and investigated the expression of autophagy markers. We found that autophagy markers were not significantly changed on the indicated days in the mouse lung tissue. Then, RNA-Seq was used to analyze the gene expression and associated functions and pathways in fibrotic lung tissue on different days post-bleomycin. In addition, short time series expression miner (STEM) analysis was performed to explore the temporal post-bleomycin gene expression. Through STEM, continually up- or downregulated profiles did not demonstrate the critical role of autophagy in the development of fibrosis. Furthermore, gene ontology (GO) annotations showed that continually upregulated profiles were mainly related to fibrosis synthesis, extracellular space, and inflammation, while enriched pathways were mainly related to the PI3K-Akt signaling pathway, ECM–receptor interactions, and focal adhesion signaling pathway. For continually downregulated profiles, GO annotations mainly involved sarcomere organization, muscle contraction, and muscle fiber development. The enriched KEGG signaling pathways were the cAMP signaling pathway, cGMP-PKG signaling pathway, calcium signaling pathway, and cardiac muscle contraction. Moreover, we analyzed autophagy-related genes’ expression in specific cells from a publicly available database of three human and one animal study of pulmonary fibrosis using single-cell sequencing technology. All results consistently demonstrated no critical role of autophagy in the pathogenesis of pulmonary fibrosis. In summary, autophagy may not critically and consistently change during the development of pulmonary fibrosis at different stages post-bleomycin in a mouse model. These continually up- or downregulated profiles, including gene profiles, and the corresponding functions and pathways may provide mechanistic insights into IPF therapy.
Cold-Induced RNA-Binding Protein Promotes Glucose Metabolism and Reduces Apoptosis by Increasing AKT Phosphorylation in Mouse Skeletal Muscle Under Acute Cold Exposure
Authors: Liu Yang , Liu Peng , Hu Yajie , Cao Yu , Lu Jingjing , Yang Yuying , Lv Hongming , Lian Shuai , Xu Bin , Li Shize
Published: July 2021

The main danger of cold stress to animals in cold regions is systemic metabolic changes and protein synthesis inhibition. Cold-induced RNA-binding protein is a cold shock protein that is rapidly up-regulated under cold stimulation in contrast to the inhibition of most proteins and participates in multiple cellular physiological activities by regulating targets. Therefore, this study was carried out to investigate the possible mechanism of CIRP-mediated glucose metabolism regulation and survival promotion in skeletal muscle after acute cold exposure. Skeletal muscle and serum from mice were obtained after 0, 2, 4 and 8 h of acute hypothermia exposure. Subsequently, the changes of CIRP, metabolism and apoptosis were examined. Acute cold exposure increased energy consumption, enhanced glycolysis, increased apoptosis, and up-regulated CIRP and phosphorylation of AKT. In addition, CIRP overexpression in C2C12 mouse myoblasts at each time point under 37°C and 32°C mild hypothermia increased AKT phosphorylation, enhanced glucose metabolism, and reduced apoptosis. CIRP knockdown by siRNA interference significantly reduced the AKT phosphorylation of C2C12 cells. Wortmannin inhibited the AKT phosphorylation of skeletal muscle after acute cold exposure, thereby inhibiting glucose metabolism and aggravating apoptosis. Taken together, acute cold exposure up-regulates CIRP in mouse skeletal muscle, which regulates glucose metabolism and maintains energy balance in skeletal muscle cells through the AKT signaling pathway, thus slowing down the apoptosis of skeletal muscle cells.
DNA Methylation Signature of Epileptic Encephalopathy-Related Pathogenic Genes Encoding Ion Channels in Temporal Lobe Epilepsy
Authors: Tao Hua , Chen Zengqiang , Wu Jianhao , Chen Jun , Chen Yusen , Fu Jiawu , Sun Chaowen , Zhou Haihong , Zhong Wangtao , Zhou Xu , Li Keshen
Published: July 2021

Epilepsy is characterized by highly abnormal synchronous discharge of brain neurons, and ion channels are fundamental in the generation and modulation of neural excitability. Considering that abnormal methylation can either activate or repress genes, this study was designed to explore the DNA methylation signature of pathogenic genes encoding ion channels in temporal lobe epilepsy (TLE). In total, 38 TLE patients and 38 healthy controls were enrolled in the study, and genomic DNA and total protein of the lymphocytes were extracted from peripheral blood samples to assess methylation and protein levels. The DNA methylation levels of all 12 genes examined were significantly lower in the TLE group than in the control group. After false-positive correction, 83.3% (10/12) of these genes, namely, gamma-aminobutyric acid type A receptor subunit beta1 (GABRB1), gamma-aminobutyric acid type A receptor subunit beta2 (GABRB2), gamma-aminobutyric acid type A receptor subunit beta1 (GABRB3), glutamate ionotropic receptor NMDA type subunit 1 (GRIN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), potassium voltage-gated channel subfamily A member 2 (KCNA2), potassium voltage-gated channel subfamily B member 1 (KCNB1), and potassium sodium-activated channel subfamily T member 1 (KCNT1), were still differentially expressed. Among these ion channels, HCN1 and KCNA2 were selected to evaluate the effects of DNA methylation, and the levels of these proteins were inversely upregulated in the TLE group compared to the control group. As the genes identified as having differential methylation levels are involved in both excitatory and inhibitory ion channels, this study observed by binary logistic regression that hypermethylated GARAB1 was an independent risk factor for TLE, indicating that the overwhelming effect of ion channels on TLE is probably inhibitory from the perspective of DNA methylation. All these findings support the involvement of DNA methylation in TLE pathologies, but the mechanisms need to be further investigated.
Between Limb Muscle Co-activation Patterns in the Paretic Arm During Non-paretic Arm Tasks in Hemiparetic Cerebral Palsy
Authors: Hill Nayo M. , Sukal-Moulton Theresa , Dewald Julius P. A.
Published: July 2021

Tasks of daily life require the independent use of the arms and hands. Individuals with hemiparetic cerebral palsy (HCP) often experience difficulty with fine motor tasks demonstrating mirrored movements between the arms. In this study, bilateral muscle activations were quantified during single arm isometric maximum efforts and submaximal reaching tasks. The magnitude and direction of mirrored activation was examined in 14 individuals with HCP and 9 age-matched controls. Participants generated maximum voluntary torques (MVTs) in five different directions and completed ballistic reaches while producing up to 80% of shoulder abduction MVT. Electromyography (EMG) signals were recorded from six upper extremity muscles bilaterally. Participants with HCP demonstrated more mirrored activation when volitionally contracting the non-paretic (NP) arm than the paretic arm (F= 83.543,p< 0.001) in isometric efforts. Increased EMG activation during reach acceleration resulted in a larger increase in rest arm co-activation when reaching with the NP arm compared to the paretic arm in the HCP group (t= 8.425,p< 0.001). Mirrored activation is more pronounced when driving the NP arm and scales with effort level. This directionality of mirroring is indicative of the use of ipsilaterally terminating projections of the corticospinal tract (CST) originating in the non-lesioned hemisphere. Peripheral measures of muscle activation provide insight into the descending pathways available for control of the upper extremity after early unilateral brain injury.
Adapting Footfall Rhythmicity to Auditory Perturbations Affects Resilience of Locomotor Behavior: A Proof-of-Concept Study
Authors: Ravi Deepak K. , Heimhofer Caroline C. , Taylor William R. , Singh Navrag B.
Published: July 2021

For humans, the ability to effectively adapt footfall rhythm to perturbations is critical for stable locomotion. However, only limited information exists regarding how dynamic stability changes when individuals modify their footfall rhythm. In this study, we recorded 3D kinematic activity from 20 participants (13 males, 18–30 years old) during walking on a treadmill while synchronizing with an auditory metronome sequence individualized to their baseline walking characteristics. The sequence then included unexpected temporal perturbations in the beat intervals with the subjects required to adapt their footfall rhythm accordingly. Building on a novel approach to quantify resilience of locomotor behavior, this study found that, in response to auditory perturbation, the mean center of mass (COM) recovery time across all participants who showed deviation from steady state (N = 15) was 7.4 (8.9) s. Importantly, recovery of footfall synchronization with the metronome beats after perturbation was achieved prior (+3.4 [95.0% CI +0.1, +9.5] s) to the recovery of COM kinematics. These results highlight the scale of temporal adaptation to perturbations and provide implications for understanding regulation of rhythm and balance. Thus, our study extends the sensorimotor synchronization paradigm to include analysis of COM recovery time toward improving our understanding of an individual’s resilience to perturbations and potentially also their fall risk.
Cortical Synchrony as a Mechanism of Collinear Facilitation and Suppression in Early Visual Cortex
Authors: Evers Kris , Peters Judith , Senden Mario
Published: July 2021

Stimulus-induced oscillations and synchrony among neuronal populations in visual cortex are well-established phenomena. Their functional role in cognition are, however, not well-understood. Recent studies have suggested that neural synchrony may underlie perceptual grouping as stimulus-frequency relationships and stimulus-dependent lateral connectivity profiles can determine the success or failure of synchronization among neuronal groups encoding different stimulus elements. We suggest that the same mechanism accounts for collinear facilitation and suppression effects where the detectability of a target Gabor stimulus is improved or diminished by the presence of collinear flanking Gabor stimuli. We propose a model of oscillators which represent three neuronal populations in visual cortex with distinct receptive fields reflecting the target and two flankers, respectively, and whose connectivity is determined by the collinearity of the presented Gabor stimuli. Our model simulations confirm that neuronal synchrony can indeed explain known collinear facilitation and suppression effects for attended and unattended stimuli.
Colonization Ability and Impact on Human Gut Microbiota of Foodborne Microbes From Traditional or Probiotic-Added Fermented Foods: A Systematic Review
Authors: Roselli Marianna , Natella Fausta , Zinno Paola , Guantario Barbara , Canali Raffaella , Schifano Emily , De Angelis Maria , Nikoloudaki Olga , Gobbetti Marco , Perozzi Giuditta , Devirgiliis Chiara
Published: July 2021

A large subset of fermented foods act as vehicles of live environmental microbes, which often contribute food quality assets to the overall diet, such as health-associated microbial metabolites. Foodborne microorganisms also carry the potential to interact with the human gut microbiome via the food chain. However, scientific results describing the microbial flow connecting such different microbiomes as well as their impact on human health, are still fragmented. The aim of this systematic review is to provide a knowledge-base about the scientific literature addressing the connection between foodborne and gut microbiomes, as well as to identify gaps where more research is needed to clarify and map gut microorganisms originating from fermented foods, either traditional or added with probiotics, their possible impact on human gut microbiota composition and to which extent foodborne microbes might be able to colonize the gut environment. An additional aim was also to highlight experimental approaches and study designs which could be better standardized to improve comparative analysis of published datasets. Overall, the results presented in this systematic review suggest that a complex interplay between food and gut microbiota is indeed occurring, although the possible mechanisms for this interaction, as well as how it can impact human health, still remain a puzzling picture. Further research employing standardized and trans-disciplinary approaches aimed at understanding how fermented foods can be tailored to positively influence human gut microbiota and, in turn, host health, are therefore of pivotal importance.
Bioinformatics Analysis and Functional Verification of ADAMTS9-AS1/AS2 in Lung Adenocarcinoma
Authors: Liu Wei , Luo Wenguang , Zhou Peijie , Cheng Yong , Qian Liting
Published: July 2021

Long non-coding RNAs (lncRNAs), as competitive endogenous RNAs (ceRNAs), play a critical role in biological processes of cancer. However, the roles of specific lncRNAs in ceRNA network of lung adenocarcinoma (LUAD) remains largely unclear. Herein, we identified the roles of lncRNA ADAMTS9-AS1/AS2 (ADAMTS-AS1/AS2) in lung adenocarcinoma by bioinformatics analyses and functional verification. First, differentially expressed genes ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were screened out from GSE130779. Then the expression correlation of these three genes was analyzed. The results showed that ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were down-regulated in LUAD, and were positively correlated with each other. After that, miRcode was used to find miR-150 which binds to ADAMTS9-AS1/ADAMTS9-AS2/ADAMTS9. Next, co-expression analysis and functional enrichment analyses were performed to further analyze differentially expressed genes. The results showed that the differentially expressed genes were mainly enriched in Beta3 integrin cell surface interactions and epithelial-to-mesenchymal transition. Finally, the cell functions of ADAMTS9-AS1 and ADAMTS9-AS2 in A549 and NCI-H1299 cell lines were verified. In vitro cell studies confirmed that ADAMTS9-AS1 and ADAMTS9-AS2 play an inhibitory role in LUAD cells.
Digital Health for Supporting Precision Medicine in Pediatric Endocrine Disorders: Opportunities for Improved Patient Care
Authors: Fernandez-Luque Luis , Al Herbish Abdullah , Al Shammari Riyad , Argente Jesús , Bin-Abbas Bassam , Deeb Asma , Dixon David , Zary Nabil , Koledova Ekaterina , Savage Martin O.
Published: July 2021

Digitalization of healthcare delivery is rapidly fostering development of precision medicine. Multiple digital technologies, known as telehealth or eHealth tools, are guiding individualized diagnosis and treatment for patients, and can contribute significantly to the objectives of precision medicine. From a basis of “one-size-fits-all” healthcare, precision medicine provides a paradigm shift to deliver a more nuanced and personalized approach. Genomic medicine utilizing new technologies can provide precision analysis of causative mutations, with personalized understanding of mechanisms and effective therapy. Education is fundamental to the telehealth process, with artificial intelligence (AI) enhancing learning for healthcare professionals and empowering patients to contribute to their care. The Gulf Cooperation Council (GCC) region is rapidly implementing telehealth strategies at all levels and a workshop was convened to discuss aspirations of precision medicine in the context of pediatric endocrinology, including diabetes and growth disorders, with this paper based on those discussions. GCC regional investment in AI, bioinformatics and genomic medicine, is rapidly providing healthcare benefits. However, embracing precision medicine is presenting some major new design, installation and skills challenges. Genomic medicine is enabling precision and personalization of diagnosis and therapy of endocrine conditions. Digital education and communication tools in the field of endocrinology include chatbots, interactive robots and augmented reality. Obesity and diabetes are a major challenge in the GCC region and eHealth tools are increasingly being used for management of care. With regard to growth failure, digital technologies for growth hormone (GH) administration are being shown to enhance adherence and response outcomes. While technical innovations become more affordable with increasing adoption, we should be aware of sustainability, design and implementation costs, training of HCPs and prediction of overall healthcare benefits, which are essential for precision medicine to develop and for its objectives to be achieved.