bluuebunny/crossref_metadata_2025 huggingface dataset:
Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection
Authors: Hammers Daniel E. , Donahue Deborah L. , Tucker Zachary D. , Ashfeld Brandon L. , Ploplis Victoria A. , Castellino Francis J. , Lee Shaun W.
Published: November 2022

Group A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive human pathogen that employs several secreted and surface-bound virulence factors to manipulate its environment, allowing it to cause a variety of disease outcomes. One such virulence factor is Streptolysin S (SLS), a ribosomally-produced peptide toxin that undergoes extensive post-translational modifications. The activity of SLS has been studied for over 100 years owing to its rapid and potent ability to lyse red blood cells, and the toxin has been shown to play a major role in GAS virulence in vivo. We have previously demonstrated that SLS induces hemolysis by targeting the chloride-bicarbonate exchanger Band 3 in erythrocytes, indicating that SLS is capable of targeting host proteins to promote cell lysis. However, the possibility that SLS has additional protein targets in other cell types, such as keratinocytes, has not been explored. Here, we use bioinformatics analysis and chemical inhibition studies to demonstrate that SLS targets the electroneutral sodium-bicarbonate cotransporter NBCn1 in keratinocytes during GAS infection. SLS induces NF-κB activation and host cytotoxicity in human keratinocytes, and these processes can be mitigated by treating keratinocytes with the sodium-bicarbonate cotransport inhibitor S0859. Furthermore, treating keratinocytes with SLS disrupts the ability of host cells to regulate their intracellular pH, and this can be monitored in real time using the pH-sensitive dye pHrodo Red AM in live imaging studies. These results demonstrate that SLS is a multifunctional bacterial toxin that GAS uses in numerous context-dependent ways to promote host cell cytotoxicity and increase disease severity. Studies to elucidate additional host targets of SLS have the potential to impact the development of therapeutics for severe GAS infections.
Comparative analysis of the lung microbiota in patients with respiratory infections, tuberculosis, and lung cancer: A preliminary study
Authors: Xia Xiaoxue , Chen Jiang , Cheng Yiwen , Chen Feng , Lu Huoquan , Liu Jianfeng , Wang Ling , Pu Fengxia , Wang Ying , Liu Hua , Cao Daxing , Zhang Zhengye , Xia Zeping , Fan Meili , Ling Zongxin , Zhao Longyou
Published: November 2022

Recent evidence suggests that lung microbiota can be recognized as one of the ecological determinants of various respiratory diseases. However, alterations in the lung microbiota and associated lung immunity in these respiratory diseases remain unclear. To compare the lung microbiota and lung immune profiles in common respiratory diseases, a total of 78 patients were enrolled in the present study, including 21 patients with primary pulmonary tuberculosis (PTB), eight patients with newly diagnosed lung cancer (LC), and 49 patients with community-acquired pneumonia (CAP). Bronchoalveolar lavage fluid (BALF) was collected for microbiota and cytokine analyses. With MiSeq sequencing system, increased bacterial alpha-diversity and richness were observed in patients with LC than in those with PTB and CAP. Linear discriminant analysis effect size revealed that CAP-associated pulmonary microbiota were significantly different between the PTB and LC groups. More key functionally different genera were found in the PTB and LC groups than in the CAP group. The interaction network revealed stronger positive and negative correlations among these genera in the LC group than in the other two groups. However, increased BALF cytokine profiles were observed in the PTB group than in the other two groups, while BALF cytokines were correlated with key functional bacteria. This comparative study provides evidence for the associations among altered lung microbiota, BALF inflammation, and different respiratory disorders, which provides insight into the possible roles and mechanisms of pulmonary microbiota in the progression of respiratory disorders.
Sex related differences in the characteristics and outcomes of heart failure: A sub analysis of heart failure disease management study
Authors: Grupper Avishay , Freimark Dov , Murad Havi , Olmer Liraz , Benderly Michal , Ziv Arnona , Friedman Nurit , Kaufman Galit , Silber Haim , Kalter-Leibovici Ofra
Published: November 2022

Aims

This is a sub-analysis of a randomized controlled trial on heart failure (HF) disease management (DM) in which patients with HF (N = 1,360; 27.5% women) were assigned randomly to DM (N = 682) or usual care (UC) (N = 678). Study intervention did not significantly affect the rate of hospital admissions or mortality. This study evaluates sex-related differences in baseline characteristics, clinical manifestations, adherence to treatment and outcomes among the study cohort.

Methods

Association between sex and hospital admissions and mortality was tested in multivariable models adjusted for the patients’ baseline characteristics. The primary composite outcome of the study included time to first HF hospitalization or all-cause mortality. Secondary composite outcome included number of hospital admissions and days of hospitalization, for HF and all other causes.

Results

Compared to males, females recruited in the study were on average 3 years older [median age 72 (62, 78) vs. 75 (65, 82), p = 0.001], with higher prevalence of preserved left ventricular function (LVEF ≥50%) and lower frequency of ischemic heart disease (IHD) (p ≤ 0.001). Females had shorter 6-min walking distance and worse quality of life and depression scores at baseline (p < 0.001). The proportion of patients receiving HF recommended medical treatment was similar among females and males. During a median follow-up of 2.7 years (range: 0–5), there were no significant differences between females and males with respect to the time elapsed until the study primary endpoint and its components in univariate analysis [557 (56.5%) males and 218 (58.3%) females were hospitalized for HF or died for any cause; p > 0.05]. Multivariable analysis showed that females were significantly less likely than males to experience the primary outcome [adjusted hazard ratio (HR) = 0.835, 95% CI: 0.699, 0.998] or to die from any cause [adjusted HR = 0.712; 95%CI: 0.560, 0.901]. The sex-related mortality differences were especially significant among patients with non-preserved EF, with IHD or with recent HF hospitalization. Females also had lower rates of all-cause hospital admissions [adjusted rate ratio = 0.798; 95%CI: 0.705, 0.904] and were more likely to adhere to HF medical therapy compared to males.

Conclusion

Females with HF fare better than men. Sex related differences were not explained by baseline and morbidity-related characteristics or adherence to medical treatment.
Epicardial adipose tissue is associated with left atrial volume and fibrosis in patients with atrial fibrillation
Authors: Chahine Yaacoub , Askari-Atapour Bahareh , Kwan Kirsten T. , Anderson Carter A. , Macheret Fima , Afroze Tanzina , Bifulco Savannah F. , Cham Matthew D. , Ordovas Karen , Boyle Patrick M. , Akoum Nazem
Published: November 2022

Background

Obesity is a risk factor for atrial fibrillation (AF) and strongly influences the response to treatment. Atrial fibrosis shows similar associations. Epicardial adipose tissue (EAT) may be a link between these associations. We sought to assess whether EAT is associated with body mass index (BMI), left atrial (LA) fibrosis and volume.

Methods

LA fibrosis and EAT were assessed using late gadolinium enhancement, and Dixon MRI sequences, respectively. We derived 3D models incorporating fibrosis and EAT, then measured the distance of fibrotic and non-fibrotic areas to the nearest EAT to assess spatial colocalization.

Results

One hundred and three AF patients (64% paroxysmal, 27% female) were analyzed. LA volume index was 54.9 (41.2, 69.7) mL/m2, LA EAT index was 17.4 (12.7, 22.9) mL/m2, and LA fibrosis was 17.1 (12.4, 23.1)%. LA EAT was significantly correlated with BMI (R = 0.557, p < 0.001); as well as with LA volume and LA fibrosis after BSA adjustment (R = 0.579 and R = 0.432, respectively, p < 0.001 for both). Multivariable analysis showed LA EAT to be independently associated with LA volume and fibrosis. 3D registration of fat and fibrosis around the LA showed no clear spatial overlap between EAT and fibrotic LA regions.

Conclusion

LA EAT is associated with obesity (BMI) as well as LA volume and fibrosis. Regions of LA EAT did not colocalize with fibrotic areas, suggesting a systemic or paracrine mechanism rather than EAT infiltration of fibrotic areas.
Impulsive time series modeling with application to luteinizing hormone data
Authors: Runvik Håkan , Medvedev Alexander
Published: November 2022

This work considers the estimation of impulsive time series pertaining to biomedical systems and, in particular, to endocrine ones. We assume a signal model in the form of the output of a continuous linear time-invariant system driven by a sequence of instantaneous impulses, which concept is utilized here, in particular, for modeling of the male reproductive hormone axis. An estimation method to identify the impulsive sequence and the continuous system dynamics from sampled measurements of the output is proposed. Hinging on thorough mathematical analysis, the method improves upon a previously developed least-squares algorithm by resolving the trade-off between model fit and input sparsity, thus removing the need for manual tuning of user-defined estimation algorithm parameters. Experiments with synthetic data and Markov chain Monte-Carlo estimation demonstrate the viability of the proposed method, but also indicate that measurement noise renders the estimation problem ill-posed, as multiple estimates along a curve in the parameter space yield similar fits to data. The method is furthermore applied to clinical luteinizing hormone data collected from healthy males and, for comparability, one female, with similar results. Comparison between the estimated and theoretical elimination rates, as well as simulation of the estimated models, demonstrate the efficacy of the method. The sensitivity of the impulse distribution to the estimated elimination rates is investigated on a subject-specific data subset, revealing that the input sequence and elimination rate estimates can be interdependent. The dose-dependent effect of a selective gonadotropin releasing hormone receptor antagonist on the frequency and weights of the estimated impulses is also analyzed; a significant impact of the medication on the impulse weights is confirmed. To demonstrate the feasibility of the estimation approach for other hormones with pulsatile secretion, the modeling of cortisol data sets collected from three female adolescents was performed.
Osteoclast activity sculpts craniofacial form to permit sensorineural patterning in the zebrafish skull
Authors: Miao Kelly Z. , Cozzone Austin , Caetano-Lopes Joana , Harris Matthew P. , Fisher Shannon
Published: November 2022

Efforts to understand the morphogenesis of complex craniofacial structures have largely focused on the role of chondrocytes and osteoblasts. Along with these bone–creating cells, bone–resorbing osteoclasts are critical in homeostasis of adult skeletal structures, but there is currently limited information on their role in the complex morphogenetic events of craniofacial development. Fundamental aspects of skull formation and general skeletal development are conserved from zebrafish to mammals. Using a cathepsinK reporter, we documented osteoclast location in the developing zebrafish skull over several weeks, from 5.18 mm to 9.6 mm standard length (approximately 15 to 34 days post fertilization). While broad distribution of osteoclasts is consistent across individuals, they are sparse and the exact locations vary among fish and across developmental time points. Interestingly, we observed osteoclasts concentrating at areas associated with neuromasts and their associated nerves, in particular the hyomandibular foramina and around the supraorbital lateral line. These are areas of active remodeling. In contrast, other areas of rapid bone growth, such as the osteogenic fronts of the frontal and parietal bones, show no particular concentration of osteoclasts, suggesting that they play a special role in shaping bone near neuromasts and nerves. In csf1ra mutants lacking functional osteoclasts, the morphology of the cranial bone was disrupted in both areas. The hyomandibular foramen is present in the initial cartilage template, but after the initiation of ossification, the diameter of the canal is significantly smaller in the absence of osteoclasts. The diameter of the supraorbital lateral line canals was also reduced in the mutants, as was the number of pores associated with neuromasts, which allow for the passage of associated nerves through the bone. Our findings define important and previously unappreciated roles for osteoclast activity in shaping craniofacial skeletal structures with a particular role in bone modeling around peripheral cranial nerves, providing a scaffold for wiring the sensioneural system during craniofacial development. This has important implications for the formation of the evolutionarily diverse lateral line system, as well understanding the mechanism of neurologic sequelae of congenital osteoclast dysfunction in human craniofacial development.
Environmental footprinting of agri-food products traded in the European market
Authors: Popova Olha , Koval Viktor , Vdovenko Nataliia , Sedikova Iryna , Nesenenko Pavlo , Mikhno Inesa
Published: November 2022

Sustainable food principles and requirements established by the European Union are becoming a standard for all foodstuffs available on the EU market, and it should be taken into account by countries exporting agri-food products, such as Ukraine. The aim of this article is to generalize European milestones for defining sustainable foodstuffs, revealing their key differences from ecological/organic products, differentiating products in the carbon footprint level, and substantiating challenges for exports of agri-food products to the EU in terms of positioning their sustainability. The European market features an increasing differentiation of agri-food products in terms of sustainability and ecology, particularly carbon footprint indicators, which are examined in this article. More stringent monitoring of chemical pesticide and antimicrobial residues in products exported to the EU could be a challenge as the use of these products is expected to be reduced by 50% by 2030. This study substantiates the risks for agricultural production and exports in Ukraine caused by the differentiation of agri-food products in their sustainability indicators, enhancement of monitoring the level of residues of pesticides and active ingredients of veterinary drugs in agri-food products, and limitation of agri-food and agricultural raw material exports to the EU because of heavy greenhouse gas emissions during crop cultivation to produce biofuel. This study analyzes the economic growth of agri-food products that will take place only in the case of avoiding the impoverishment of natural resources, which is formalized based on the Robert Higgins’ model. The results of the research can be used for further strategic planning in the field of agricultural production with environmental regulation.
Green finance development and environmental sustainability: A panel data analysis
Authors: Khan Soha , Akbar Ahsan , Nasim Ismat , Hedvičáková Martina , Bashir Furrukh
Published: November 2022

This study considers five regions, i.e., South Asia, South-East Asia, China, Middle Eastern countries, and European countries, and took their data for 15 years. This study makes a significant contribution to the literature by examining the impact of green finance on environmental sustainability. Green finance development is represented by GDP, investment in renewable energy sources, investment in research and development (R&D) for eco-friendly projects, and public–private partnership investment in renewable energy projects. Green financing development in the chosen panel exhibits a distinct geographical cluster effect, with significant regional variances. The most important influencing elements are regional GDP, regional innovation level, and air quality, whereas the degree of financial development and industrial structure optimization are insignificant. The degree of financial development and industrial structure optimization are related to the amount of green finance development mostly via spillover effects. The degree of financial development has a positive spillover impact, but industrial structure optimization has a negative spillover effect. This study reveals that an increase in the production of energy from renewable sources, an increase in R&D, and the evolution of public–private partnership investment in renewable energy reduce CO2 emissions. It is evidenced that green finance in renewable energy sources is necessary to achieve environmental sustainability. There is a strong need to increase green finance in renewable sources to target the minimization of global CO2 emissions. There should be cross-border trade of renewable energy between regions/countries to mitigate CO2 emissions globally. Moreover, this study ranks the regions based on environmental sustainability, which may help researchers and decision-makers to entice foreign direct and private investment in these regions. The implications of the findings of the study suggest that environmental sustainability benefits greatly from green financing and investing in renewable energy sources through public–private partnerships, which represents one of the best ways to ensure environmental sustainability.
Discovering favorable genes, QTLs, and genotypes as a genetic resource for sesame (Sesamum indicum L.) improvement
Authors: Kefale Habtamu , Wang Linhai
Published: November 2022

Sesame (Sesamum indicum L.) is an ancient diploid oilseed crop with high oil content, quality protein, and antioxidant characteristics that is produced in many countries worldwide. The genes, QTLs, and genetic resources of sesame are utilized by sesame researchers and growers. Researchers have identified the many useful traits of this crop, which are available on different platforms. The genes, genotypes, QTLs, and other genetic diversity data of sesame have been collected and stored in more than nine genomic resources, and five sesame crop marker databases are available online. However, data on phenotypic and genotypic variability, which would contribute to sesame improvements, are limited and not yet accessible. The present study comprehensively reviewed more than 110 original published research papers and scientifically incorporated the results. The candidate genes, genotypes, and QTLs of significantly important traits of sesame were identified. Genetic resources related to grain yield and yield component traits, oil content and quality, drought tolerance, salt tolerance, waterlogging resistance, disease resistance, mineral nutrient, capsule shattering resistance, and other agronomic important traits of sesame were studied. Numerous candidate genotypes, genes, QTLs, and alleles associated with those traits were summarized and discovered. The chromosome regions and linkage groups, maps associated with the best traits, and candidate genes were also included. The variability presented in this paper combined with sesame genetic information will help inform further sesame improvement.
Integrated analyses of the methylome and transcriptome to unravel sex differences in the perirenal fat from suckling lambs
Authors: Fonseca Pablo A. S. , Alonso-García María , Pelayo Rocio , Marina Hector , Esteban-Blanco Cristina , Mateo Javier , Gutiérrez-Gil Beatriz , Arranz Juan-José , Suárez-Vega Aroa
Published: November 2022

In sheep, differences were observed regarding fat accumulation and fatty acid (FA) composition between males and females, which may impact the quality and organoleptic characteristics of the meat. The integration of different omics technologies is a relevant approach for investigating biological and genetic mechanisms associated with complex traits. Here, the perirenal tissue of six male and six female Assaf suckling lambs was evaluated using RNA sequencing and whole-genome bisulfite sequencing (WGBS). A multiomic discriminant analysis using multiblock (s)PLS-DA allowed the identification of 314 genes and 627 differentially methylated regions (within these genes), which perfectly discriminate between males and females. These candidate genes overlapped with previously reported QTLs for carcass fat volume and percentage of different FAs in milk and meat from sheep. Additionally, differentially coexpressed (DcoExp) modules of genes between males (nine) and females (three) were identified that harbour 22 of these selected genes. Interestingly, these DcoExp were significantly correlated with fat percentage in different deposits (renal, pelvic, subcutaneous and intramuscular) and were associated with relevant biological processes for adipogenesis, adipocyte differentiation, fat volume and FA composition. Consequently, these genes may potentially impact adiposity and meat quality traits in a sex-specific manner, such as juiciness, tenderness and flavour.
Where are rooted networks in digital political ecologies?
Authors: Hawkins Roberta , Nelson Ingrid L.
Published: November 2022

This perspective piece contends that political-ecological relations are already digital and that feminist analyses help reveal their often-overlooked power relations. We argue that as digital political ecologies research grows in popularity, there is widespread omission and forgetting of key epistemological lessons from feminist political ecologies, such as rooted networks. Here, we remind readers of rooted networks lessons, and we distill them into suggested writing strategies for researchers. Such rooted network writing strategies may seem inefficient and may take up space and time, but as feminist political ecologists concerned with digital relations, we see them as necessary.
Combining all-trans retinoid acid treatment targeting myeloid-derived suppressive cells with cryo-thermal therapy enhances antitumor immunity in breast cancer
Authors: Lou Yue , Peng Peng , Wang Shicheng , Wang Junjun , Du Peishan , Zhang Zelu , Zheng Jiamin , Liu Ping , Xu Lisa X.
Published: November 2022

Targeting myeloid-derived suppressive cells (MDSCs) has been considered a potential strategy in tumor therapy. However, a single drug targeting MDSCs remains a challenge in the clinic. An increasing number of studies have shown that combination agents targeting MDSCs and immunotherapy may provide exciting new insights and avenues to explore in tumor therapy. In our previous study, a novel cryo-thermal therapy was developed for metastatic tumors that systematically activate innate and adaptive immunity. Moreover, cryo-thermal therapy was shown to dramatically decrease the levels of MDSCs and induce their differentiation toward potent antigen-presenting cells. However, the therapeutic effects of cryo-thermal therapy on the 4T1 mouse breast cancer model were still not satisfactory because of the high level of MDSCs before and after treatment. Therefore, in this study, we combined cryo-thermal therapy with all-trans retinoid acid (ATRA), a small molecule drug that can induce the inflammatory differentiation of MDSCs. We found that combination therapy notably upregulated the long-term survival rate of mice. Mechanically, combination therapy promoted the phenotype and functional maturation of MDSCs, efficiently decreasing suppressive molecule expression and inhibiting glutamine and fatty acid metabolism. Moreover, MDSCs at an early stage after combination therapy significantly decreased the proportions of Th2 and Treg subsets, which eventually resulted in Th1-dominant CD4+ T-cell differentiation, as well as enhanced cytotoxicity of CD8+ T cells and natural killer cells at the late stage. This study suggests a potential therapeutic strategy for combination ATRA treatment targeting MDSCs with cryo-thermal therapy to overcome the resistance of MDSC-induced immunosuppression in the clinic.
A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients
Authors: Tardiveau Claire , Monneret Guillaume , Lukaszewicz Anne-Claire , Cheynet Valérie , Cerrato Elisabeth , Imhoff Katia , Peronnet Estelle , Bodinier Maxime , Kreitmann Louis , Blein Sophie , Llitjos Jean-François , Conti Filippo , Gossez Morgane , Buisson Marielle , Yonis Hodane , Cour Martin , Argaud Laurent , Delignette Marie-Charlotte , Wallet Florent , Dailler Frederic , Monard Céline , Brengel-Pesce Karen , Venet Fabienne ,   the RICO study group
Published: November 2022

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients’ age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.
Environmentally-triggered contraction of the norovirus virion determines diarrheagenic potential
Authors: Helm Emily W. , Peiper Amy M. , Phillips Matthew , Williams Caroline G. , Sherman Michael B. , Kelley Theresa , Smith Hong Q. , Jacobs Sorin O. , Shah Dhairya , Tatum Sarah M. , Iyer Neha , Grodzki Marco , Morales Aparicio Joyce C. , Kennedy Elizabeth A. , Manzi Mikayla S. , Baldridge Megan T. , Smith Thomas J. , Karst Stephanie M.
Published: November 2022

Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they are a major cause of disease in all age groups, infections in the very young can be quite severe with annual estimates of 50,000-200,000 fatalities in children under 5 years old. In spite of the remarkable disease burden associated with norovirus infections in people, very little is known about the pathogenic mechanisms underlying norovirus diarrhea, principally because of the lack of tractable small animal models. We recently demonstrated that wild-type neonatal mice are susceptible to murine norovirus (MNV)-induced acute self-resolving diarrhea in a time course mirroring human norovirus disease. Using this robust pathogenesis model system, we demonstrate that virulence is regulated by the responsiveness of the viral capsid to environmental cues that trigger contraction of the VP1 protruding (P) domain onto the particle shell, thus enhancing receptor binding and infectivity. The capacity of a given MNV strain to undergo this contraction positively correlates with infection of cells expressing low abundance of the virus receptor CD300lf, supporting a model whereby virion contraction triggers infection of CD300lflo cell types that are responsible for diarrhea induction. These findings directly link environmentally-influenced biophysical features with norovirus disease severity.
Effect of the m6ARNA gene on the prognosis of thyroid cancer, immune infiltration, and promising immunotherapy
Authors: Xia Minqi , Wang Shuo , Ye Yingchun , Tu Yi , Huang Tiantian , Gao Ling
Published: November 2022

Background

Accumulating evidence suggests that N6-methyladenosine (m6A) RNA methylation plays an important role in tumor proliferation and growth. However, its effect on the clinical prognosis, immune infiltration, and immunotherapy response of thyroid cancer patients has not been investigated in detail.

Methods

Clinical data and RNA expression profiles of thyroid cancer were extracted from the Cancer Genome Atlas-thyroid carcinoma (TCGA-THCA) and preprocessed for consensus clustering. The risk model was constructed based on differentially expressed genes (DEGs) using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. The associations between risk score and clinical traits, immune infiltration, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), immune infiltration, and immunotherapy were assessed. Immunohistochemistry was used to substantiate the clinical traits of our samples.

Results

Gene expression analysis showed that 17 genes, except YHTDF2, had significant differences (vs healthy control, P<0.001). Consensus clustering yielded 2 clusters according to their clinical features and estimated a poorer prognosis for Cluster 1 (P=0.03). The heatmap between the 2 clusters showed differences in T (P<0.01), N (P<0.001) and stage (P<0.01). Based on univariate Cox and LASSO regression, a risk model consisting of three high-risk genes (KIAA1429, RBM15, FTO) was established, and the expression difference between normal and tumor tissues of three genes was confirmed by immunohistochemical results of our clinical tissues. KEGG and GSEA analyses showed that the risk DEGs were related mainly to proteolysis, immune response, and cancer pathways. The levels of immune infiltration in the high- and low-risk groups were different mainly in iDCs (P<0.05), NK cells (P<0.05), and type-INF-II (P<0.001). Immunotherapy analysis yielded 30 drugs associated with the expression of each gene and 20 drugs associated with the risk score.

Conclusions

Our risk model can act as an independent marker for thyroid cancer and provides promising immunotherapy targets for its treatment.
Vancomycin-induced gut microbiota dysbiosis aggravates allergic rhinitis in mice by altered short-chain fatty acids
Authors: Chen Zhen , Xu Qingqing , Liu Yang , Wei Yihan , He Shancai , Lin Wei , Wang Yingge , Li Li , Xu Yuanteng
Published: November 2022

Objective

This study aims to explore how gut microbiota dysbiosis affects allergic rhinitis (AR) and whether short-chain fatty acids (SCFAs) play a role in this process.

Methods

A mouse gut microbiota dysbiosis model was established by adding vancomycin to drinking water for 2 weeks before ovalbumin (OVA) sensitization. Then an OVA-alum AR mouse model was established by intraperitoneal OVA injection followed by nasal excitation. Hematoxylin and eosin (H&E) staining was performed to observe pathological changes in nasal and colon tissues of AR mice. Serum levels of total-IgE, OVA-sIgE, IL-4, IL-5, IL-10, and TGF-β1 were measured. The composition and diversity of the mouse gut microbiota were observed by 16S rDNA sequencing. Levels of SCFAs in feces were determined using SCFA-targeted metabolomics. Sodium butyrate (NaB) was added daily to mice on a low-fiber basal diet 2 weeks before the first sensitization, until the end of the study.

Results

After gut microbiota dysbiosis, serum levels of the total IgE, OVA-sIgE, IL-4, and IL-5 in AR mice were significantly increased, compared with the control group. The composition and diversity of gut microbiota were significantly altered after gut microbiota dysbiosis, with the fecal SCFAs significantly reduced as well. The reduced bacterial genera after gut microbiota dysbiosis, such as Ruminococcus and Lactobacillus, were significantly and positively correlated with SCFAs. In contrast, the increased genera in the Van group, such as Escherichia-Shigella and Klebsiella, were significantly negatively correlated with SCFAs in feces. NaB treatment significantly reduced total-IgE, OVA-sIgE, IL-4, and IL-5 levels in serum, and inflammatory infiltration of the nasal and colon mucosa. In addition, serum levels of IL-10 and TGF-β1 increased significantly after NaB treatment. Foxp3 protein in the colon was upregulated considerably after NaB intervention.

Conclusion

Vancomycin-induced gut microbiota dysbiosis increased susceptibility and severity of AR, which is significantly related to reduced SCFA-producing bacteria, fecal SCFAs, and specific bacterial taxa. In addition, it was found that NaB alleviated low dietary fiber base-fed symptoms and immune status in AR mice.
Change in composition and potential functional genes of microbial communities on carbonatite rinds with different weathering times
Authors: Chen Jin , Li Fangbing , Zhao Xiangwei , Wang Yang , Zhang Limin , Yan Lingbin , Yu Lifei
Published: November 2022

Organisms and time are important factors for rock weathering to form soils. However, weathering time is usually difficult to quantitatively study, and the potential microorganisms involved in rock weathering are difficult to identify qualitatively. Currently, there is no clear conclusion on how ecological strategies of carbonatite weathering rind microorganisms change with weathering time, and how the microbial composition and functional genes involved in element cycling change over two century-scale weathering time. In this study, we selected abandoned carbonate tombstones as the subject and used the date when the tombstones were erected by humans as the onset of weathering. Using metagenome sequencing methods, we investigated the trends in the composition of fungal, bacterial and archaeal communities of carbonate weathering rind and related elemental cycle functional genes during a weathering time of 19 to 213 years. The results showed that: (1) with the increase in weathering time, at the phylum level, microbial taxa gradually shifted from r-strategists (faster turnover rates, higher mortality rates, higher reproduction, lower competition rate) to K-strategists (slower turnover rates, lower mortality rates, lower reproduction, higher competition rate), which correspondingly increased the abundance of functional genes related to C and N cycles. (2) The properties of the parent rock layer determines the colonization and distribution of weathering rind microorganisms (especially prokaryotic microorganisms) and the corresponding functional gene abundance. Our study provides new insights into the weathering process of carbonate rocks.
Gut microbiome of captive wolves is more similar to domestic dogs than wild wolves indicated by metagenomics study
Authors: Chen Lei , Sun Mengyao , Xu Di , Gao Zenghao , Shi Yuying , Wang Shen , Zhou Yiping
Published: November 2022

Adaptation during the domestication from wolves (Canis lupus) to dogs (Canis lupus familiaris) is a debated ecological topic. Changes in food and environment are major divergences in the domestication of dogs. Gut microbes play an important role in animal adaptation to the food and environmental changes. In this study, shotgun sequencing was performed to compare the species diversity and functional diversity of gut microbes in wild wolves (group CLW, n = 3), captive wolves (group CLC, n = 4), and domestic dogs (group CLF, n = 4). The results found that Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria and Actinobacteria were the most abundant phyla and Bacteroides, Fusobacterium, Prevotella, Megamonas, Paraprevotella, Faecalibacterium, Clostridium were the most abundant genera in the gut of wolves and dogs. Groups CLW, CLC and CLF have shown significant difference in gut microbial species diversity and functional diversity. Bacteroides, Fusobacterium and Faecalibacterium were most abundant genera in groups CLW, CLC and CLF, respectively. Their abundance varied significantly among groups. Compared to the wild wolves, the intestinal microbiol genes of domestic dogs were significantly enriched in the carbohydrate metabolism pathway of KEGG database. One hundred and seventy-seven enzymes were detected with significantly higher abundance in group CLF than that in group CLW, and 49 enzymes showed extremely significant higher abundance in group CLF than that in group CLW (q < 0.01) base on the function abundance annotated in CAZy database. It is noteworthy that there were also significant differences in the abundance of 140 enzymes between groups CLC and CLW (q < 0.05). Clustering analysis based on both the species and the function abundance of intestinal microbiota all found that groups CLC and CLF clustered into one branch, while samples from group CLW clustered into the other branch. This result suggests that captive wolves are more similar to domestic dogs than wild wolves in both species composition and function composition of intestinal microbiota.
Metagenomic analysis provides bases on individualized shift of colon microbiome affected by delaying colostrum feeding in neonatal calves
Authors: Song Yang , Wen Shubo , Li Fuyong , Fischer-Tlustos Amanda , He Zhixiong , Guan Le Luo , Steele Michael
Published: November 2022

This study investigated the effect of colostrum feeding time on the colon digesta microbiome of 2-day-old dairy calves using whole-genome-based metagenome sequencing, aiming to understand the dynamic changes of the colon microbiome when the colostrum feeding is delayed. In total, 24 male Holstein calves were grouped to different pasteurized colostrum feeding time treatments randomly: TRT0h (45 min after birth,n = 7); TRT6h (6 h after birth,n = 8); and TRT12h (12 h after birth,n = 9). Bacteria, archaea, eukaryotes, and viruses were identified in the colon microbiome, with bacteria (99.20%) being the most predominant domain.Streptococcus,Clostridium,Lactobacillus,Ruminococcus, andEnterococcuswere the top five abundant bacteria genera. For colon microbiome functions, 114 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, with nutrients metabolism-related functions “carbohydrate metabolism,” “amino acid metabolism,” “metabolism of cofactors and vitamins,” “metabolism of terpenoids and polyketides,” and “metabolism of other amino acids” being the top five secondary level of KEGG hierarchy functions. When colon microbiomes were compared, they were not affected by delaying first colostrum feeding at both taxonomic and functional levels. However, distinct clusters of colon microbiome profiles were shown based on PERMANOVA analysis despite of different colostrum feeding treatment, suggesting the individualized responses. Moreover, the relative abundance of microbial taxa, microbial functions, and differentially expressed genes was compared between the two distinct clusters, and different relationships were observed among host differentially expressed genes, differential levels of microbial taxa, and microbial functions between the two clusters. Our results suggest that the host may play an important role in shaping the colon microbiome of neonatal dairy calves in response to the early life feeding management. Whether the observed colon microbiome shifts affect gut health and function in the long term requires further research.
Effect of different organic acid additives on the fermentation quality and bacterial community of paper mulberry (Broussonetia papyrifera) silage
Authors: Li Mengxin , Yu Qiang , Xu Jinyi , Sun Hong , Cheng Qiming , Xie Yixiao , Wang Chunmei , Li Ping , Chen Chao , Zheng Yulong
Published: November 2022

To investigate the effects of different organic acid additives and their concentrations on the fermentation quality and bacterial community of paper mulberry silage, paper mulberry was left untreated (control) or was treated with ethylenediaminetetraacetic acid (EDTA), propionic acid (PA) or citric acid (CA), the amount of each additive was 2 g.kg−1 FM, 5 g.kg−1 FM and g.kg−1 FM. All groups were ensiled for 3, 7, 15, 30 and 60 days. Compared to the control, adding EDTA reduced protein breakdown, preserved more water-soluble carbohydrates of the silages (WSCs, 24.74 g.kg−1 DM), and high concentrations of EDTA inhibited the activity of undesirable microorganisms. Adding PA increased the abundance of Lactiplantibacillus and decreased the abundance of Enterococcus, and it caused a rapid decrease in the pH of the silage at an early stage (from 6.50 to 5.31) while altering the microbiota, and low concentrations of PA resulted in high LA (66.22 g.kg−1 DM) concentration and low PA (9.92 g.kg−1 DM) concentration at 60 days of ensiling. Different concentrations of additives altered the microbial community of paper mulberry to different degrees. High concentrations of PA and CA can increase the abundance of Lactiplantibacillus. High concentrations of CA resulted in a rapid decrease in silage pH at an early stage and higher WSC concentration. These results suggest that EDTA, PA and CA can be used as additives to improve the quality of paper mulberry silage.
The vascular protective effect of matrix Gla protein during kidney injury
Authors: Kida Yujiro , Yamaguchi Ikuyo
Published: November 2022

Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this “Hypothesis and Theory” article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.
Small-molecule drugs development for Alzheimer's disease
Authors: Yao Weiwei , Yang Huihui , Yang Jinfei
Published: November 2022

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no effective therapeutic drugs currently. The complicated pathophysiology of AD is not well understood, although beta-amyloid (Aβ) cascade and hyperphosphorylated tau protein were regarded as the two main causes of AD. Other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitters, mitochondrial dysfunction, and inflammation, were also proposed and studied as targets in AD. This review aims to summarize the small-molecule drugs that were developed based on the pathogenesis and gives a deeper understanding of the AD. We hope that it could help scientists find new and better treatments to gradually conquer the problems related to AD in future.
5-HT1B receptor agonist enhances breakpoint for cocaine on a progressive ratio (PR) schedule during maintenance of self-administration in female rats but reduces breakpoint for sucrose
Authors: Scott Samantha N. , Ruscitti Brielle A. , Garcia Raul , Nguyen Toan T. , Blattner Kevin M. , Blass Benjamin E. , Neisewander Janet L.
Published: November 2022

Background: Previous research showed that the 5-HT1B receptor agonist CP94253 enhanced cocaine reinforcement rate during maintenance of daily self-administration (SA), but inhibited reinforcement rate after 21 days of abstinence in male rats. Here we examined whether female rats show similar effects of CP94253 during maintenance as males across estrous cycle phases.

Methods: Female rats trained on a fixed ratio 5 (FR5) cocaine reinforcement schedule were tested for the effects of CP94253 (5.6 mg/kg, s.c.) on cocaine reinforcement rate during each phase of the estrous cycle, with access to either low (0.075 and 0.1875) or high (0.375 and 0.75) cocaine doses available for 1 h sequentially in descending dose order. Other female and male rats trained on a progressive ratio (PR) schedule of cocaine or sucrose reinforcement were tested for CP94253 (0, 3.2, 5.6, and 10 mg/kg, s.c.) effects on reinforcement rate in 3-h sessions. CP94253 effects on responding during sucrose cue-reactivity were also examined post-abstinence.

Results: Regardless of sex, CP94253 enhanced breakpoints on the PR schedule during maintenance of cocaine SA but attenuated breakpoints for sucrose reinforcement and decreased responding during sucrose cue-reactivity. FR results showed that CP94253 attenuated cocaine reinforcement rate during all estrous cycle phases except metestrus.

Conclusions: Overall, we suggest that CP94253 increased incentive motivation for cocaine during maintenance of SA in female and male rats, yet decreased motivation for sucrose. We also suggest that 5-HT1BRs modulate motivation similarly across sexes except when females are in metestrus.
Forebrain control of breathing: Anatomy and potential functions
Authors: Schottelkotte Karl M. , Crone Steven A.
Published: November 2022

The forebrain plays important roles in many critical functions, including the control of breathing. We propose that the forebrain is important for ensuring that breathing matches current and anticipated behavioral, emotional, and physiological needs. This review will summarize anatomical and functional evidence implicating forebrain regions in the control of breathing. These regions include the cerebral cortex, extended amygdala, hippocampus, hypothalamus, and thalamus. We will also point out areas where additional research is needed to better understand the specific roles of forebrain regions in the control of breathing.