bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying novel genetic loci associated with polycystic ovary syndrome based on its shared genetic architecture with type 2 diabetes
Authors: Li Xiaoyi , Xiao Han , Ma Yujia , Zhou Zechen , Chen Dafang
Published: August 2022

Genome-wide association studies (GWAS) have identified several common variants associated with polycystic ovary syndrome (PCOS). However, the etiology behind PCOS remains incomplete. Available evidence suggests a potential genetic correlation between PCOS and type 2 diabetes (T2D). The publicly available data may provide an opportunity to enhance the understanding of the PCOS etiology. Here, we quantified the polygenic overlap between PCOS and T2D using summary statistics of PCOS and T2D and then identified the novel genetic variants associated with PCOS behind this phenotypic association. A bivariate causal mixture model (MiXeR model) found a moderate genetic overlap between PCOS and T2D (Dice coefficient = 44.1% and after adjusting for body mass index, 32.1%). The conditional/conjunctional false discovery rate method identified 11 potential risk variants of PCOS conditional on associations with T2D, 9 of which were novel and 6 of which were jointly associated with two phenotypes. The functional annotation of these genetic variants supports a significant role for genes involved in lipid metabolism, immune response, and the insulin signaling pathway. An expression quantitative trait locus functionality analysis successfully repeated that 5 loci were significantly associated with the expression of candidate genes in many tissues, including the whole blood, subcutaneous adipose, adrenal gland, and cerebellum. We found that SCN2A gene is co-localized with PCOS in subcutaneous adipose using GWAS-eQTL co-localization analyses. A total of 11 candidate genes were differentially expressed in multiple tissues of the PCOS samples. These findings provide a new understanding of the shared genetic architecture between PCOS and T2D and the underlying molecular genetic mechanism of PCOS.
Exploring the mechanism of YangXue QingNao Wan based on network pharmacology in the treatment of Alzheimer’s disease
Authors: Zhang Yuying , Guo Kaimin , Zhang Pengfei , Zhang Mengying , Li Xiaoqiang , Zhou Shuiping , Sun He , Wang Wenjia , Wang Hui , Hu Yunhui
Published: August 2022

It is clinical reported that YangXue QingNao Wan (YXQNW) combined with donepezil can significantly improve the cognitive function of AD patients. However, the mechanism is not clear. A network pharmacology approach was employed to predict the protein targets and affected pathways of YXQNW in the treatment of AD. Based on random walk evaluation, the correlation between YXQNW and AD was calculated; while a variety of AD clinical approved Western drugs were compared. The targets of YXQNW were enriched and analyzed by using the TSEA platform and MetaCore. We proved that the overall correlation between YXQNW and AD is equivalent to clinical Western drugs, but the mechanism of action is very different. Firstly, YXQNW may promote cerebral blood flow velocity by regulating platelet aggregation and the vasoconstriction/relaxation signal pathway, which has been verified by clinical meta-analysis. Secondly, YXQNW may promote Aβ degradation in the liver by modulating the abnormal glucose and lipid metabolisms via the adiponectin-dependent pathway, RXR/PPAR-dependent lipid metabolism signal pathway, and fatty acid synthase activity signal pathway. We also verified whether YXQNW indeed promoted Aβ degradation in hepatic stellate cells. This work provides a novel scientific basis for the mechanism of YXQNW in the treatment of AD.
FGF/FGFR-related lncRNAs based classification predicts prognosis and guides therapy in gastric cancer
Authors: Chen Qiuxiang , Du Xiaojing
Published: August 2022

Fibroblast growth factor (FGF) and its receptor (FGFR) play crucial roles in gastric cancer (GC). Long non-coding RNAs (lncRNAs) are defined as RNA molecules of around 200 nucleotides or more, which are not translated into proteins. As well-known regulatory factors, lncRNAs are considered as biomarkers for prognosis and treatment response in GC. It is of importance to identify FGF/FGFR-related lncRNAs in GC. Here, some FGF/FGFR-related lncRNAs were identified in GC based on the data from public databases, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Then a four-lncRNAs (FGF10-AS1, MIR2052HG, POU6F2-AS2, and DIRC1) risk score (RS) model was established for predicting GC’s prognosis by using Cox analysis. According to the median value of RS, GC patients were divided into low and high RS group. Low RS group displayed high tumor mutation burden and infiltration of immune cells, as well as more sensitivity to immunotherapy or chemotherapy. High RS group showed high infiltration of stromal cells and more oncogenic signatures. In addition, a comprehensive analysis was carried out and found that high RS group may exhibit specific sensitivity to Panobinostat (histone deacetylases inhibitor) and Tivantinib (MET inhibitor). In summary, our study not only offers a novel personalized prognostication classification model according to FGF/FGFR-related lncRNAs, but also provides a new strategy for subclass-specific precision treatment in GC.
A novel prognostic signature based on cuproptosis-related lncRNA mining in colorectal cancer
Authors: Hou Dong , Tan Jia-nan , Zhou Sheng-ning , Yang Xu , Zhang Zhi-hong , Zhong Guang-yu , Zhong Lin , Yang Bin , Han Fang-hai
Published: August 2022

Background: Colorectal cancer (CRC) is a common malignant tumor that affects the large bowel or the rectum. Cuproptosis, recently discovered programmed cell death process, may play an important role in CRC tumorigenesis. Long non-coding RNAs (lncRNAs) can alter the proliferation of colorectal cancer cells through the control and activation of gene expression. To date, cuproptosis-related lncRNAs, have not been investigated as potential predictive biomarkers in colorectal cancer.

Methods: The mRNA and lncRNA expression data of colorectal cancer were gathered from The Tumor Genome Atlas (TCGA) database, and Pearson correlation analysis and univariate Cox regression analysis were used to identify the lncRNAs with differential prognosis. Colorectal cancer was classified using consistent clustering, and the clinical significance of different types, tumor heterogeneity, and immune microenvironment differences was investigated. The differential lncRNAs were further screened using LASSO regression to develop a risk scoring model, which was then paired with clinicopathological variables to create a nomogram. Finally, the copy number changes in the high-risk and low-risk groups were compared.

Results: Two clusters were formed based on the 28 prognostic cuproptosis-related lncRNAs, and the prognosis of cluster 2 was found to be significantly lower than that of cluster 1. Cluster 1 showed increased immune cell infiltration and immunological score, as well as strong enrichment of immune checkpoint genes. Next, LASSO regression was used to select 11 distinctive lncRNAs, and a risk score model was constructed using the training set to distinguish between high and low-risk groups. Patients in the high-risk group had a lower survival rate than those in the low-risk group, and both the test set and the total set produced consistent results. The AUC value of the ROC curve revealed the scoring model’s efficacy in predicting long-term OS in patients. Moreover, the model could be used as an independent predictor when combined with a multivariate analysis of clinicopathological features, and our nomogram could be used intuitively to predict prognosis.

Conclusion: Collectively, we developed a risk model using 11 differential lncRNAs and demonstrated that the model has predictive value as well as clinical and therapeutic implications for predicting prognosis in CRC patients.
A p53 transcriptional signature in primary and metastatic cancers derived using machine learning
Authors: Keshavarz-Rahaghi Faeze , Pleasance Erin , Kolisnik Tyler , Jones Steven J. M.
Published: August 2022

The tumor suppressor gene, TP53, has the highest rate of mutation among all genes in human cancer. This transcription factor plays an essential role in the regulation of many cellular processes. Mutations in TP53 result in loss of wild-type p53 function in a dominant negative manner. Although TP53 is a well-studied gene, the transcriptome modifications caused by the mutations in this gene have not yet been explored in a pan-cancer study using both primary and metastatic samples. In this work, we used a random forest model to stratify tumor samples based on TP53 mutational status and detected a p53 transcriptional signature. We hypothesize that the existence of this transcriptional signature is due to the loss of wild-type p53 function and is universal across primary and metastatic tumors as well as different tumor types. Additionally, we showed that the algorithm successfully detected this signature in samples with apparent silent mutations that affect correct mRNA splicing. Furthermore, we observed that most of the highly ranked genes contributing to the classification extracted from the random forest have known associations with p53 within the literature. We suggest that other genes found in this list including GPSM2, OR4N2, CTSL2, SPERT, and RPE65 protein coding genes have yet undiscovered linkages to p53 function. Our analysis of time on different therapies also revealed that this signature is more effective than the recorded TP53 status in detecting patients who can benefit from platinum therapies and taxanes. Our findings delineate a p53 transcriptional signature, expand the knowledge of p53 biology and further identify genes important in p53 related pathways.
Immunogenicity of COVID-19 vaccines in patients with diabetes mellitus: A systematic review
Authors: Boroumand Amir Bahador , Forouhi Mahtab , Karimi Farzaneh , Moghadam Arman Soltani , Naeini Leila Ghanbari , Kokabian Pajman , Naderi Delaram
Published: August 2022

Purpose

To evaluate the immunogenicity of COVID-19 vaccines in patients with diabetes mellitus (DM) through a systematic approach.

Method

A comprehensive search was conducted in PubMed, Scopus, and Web of Science with no time restrictions. The search was based on the three main concepts: Covid-19, Vaccine immunogenicity and Diabetes Mellitus.

Results

After excluding irrelevant studies, 16 studies remained for the quantitative assay. Among the sixteen studies, eleven had controls. Type of diabetes was specifically mentioned in six studies (T2DM; n=4, T1DM and T2DM; n=2). Twelve of the included studies were conducted on the immunogenicity of vaccines that included mRNA vaccines (i.e. BNT162b2 and mRNA-1273) in DM, five studies included vector-based vaccines (i.e. Ad5-nCoV and ChAdOx1-S), and five studies assessed the immunogenicity of vaccines in DM, including inactivated vaccines (i.e. BBV-152, CoronaVac, Sinopharm or SinoVac). Most of the current studies indicate lower antibody response in patients with DM compared to individuals without DM, after the second dose of vaccine and irrespective of vaccine type. Several studies have shown that higher age and higher BMI are associated with lower antibody response, while optimum glycemic control and higher GFR are associated with higher antibody response among patients with DM.

Conclusion

Immunogenicity of the vaccines has mostly been reported to be lower among patients with DM compared to healthy controls. There are also few studies assessing variables that significantly affect this association, including age, type of diabetes, BMI, glycemic control and eGFR. Investigating these associations could help us provide the most advantageous condition for patients with DM before, during and after vaccination for optimum antibody response. Many unresolved issues concerning potential factors affecting vaccine immunogenicity, including type of vaccine, numbers of administered doses, re-vaccination intervals and hyperglycemia in patients with DM need to be addressed through future research.
Exploring the multidimensional heterogeneities of glioblastoma multiforme based on sample-specific edge perturbation in gene interaction network
Authors: Zheng Jianglin , Qiu Yue , Wu Zhipeng , Wang Xuan , Jiang Xiaobing
Published: August 2022

Glioblastoma multiforme (GBM) is the most malignant brain cancer with great heterogeneities in many aspects, such as prognosis, clinicopathological features, immune landscapes, and immunotherapeutic responses. Considering that gene interaction network is relatively stable in a healthy state but widely perturbed in cancers, we sought to explore the multidimensional heterogeneities of GBM through evaluating the degree of network perturbations. The gene interaction network perturbations of GBM samples (TCGA cohort) and normal samples (GTEx database) were characterized by edge perturbations, which were quantized through evaluating the change in relative gene expression value. An unsupervised consensus clustering analysis was performed to identify edge perturbation-based clusters of GBM samples. Results revealed that the edge perturbation of GBM samples was stronger than that of normal samples. Four edge perturbation-based clusters of GBM samples were identified and showed prominent heterogeneities in prognosis, clinicopathological features, somatic genomic alterations, immune landscapes, and immunotherapeutic responses. In addition, a sample-specific perturbation of gene interaction score (SPGIScore) was constructed based on the differently expressed genes (DEGs) among four clusters, and exhibited a robust ability to predict prognosis. In conclusion, the bioinformatics approach based on sample-specific edge perturbation in gene interaction network provided a new perspective to understanding the multidimensional heterogeneities of GBM.
Gamma delta T-cell reconstitution after allogeneic HCT: A platform for cell therapy
Authors: Gaballa Ahmed , Arruda Lucas C. M. , Uhlin Michael
Published: August 2022

Allogeneic Hematopoietic stem cell transplantation (allo-HCT) is a curative platform for several hematological diseases. Despite its therapeutic benefits, the profound immunodeficiency associated with the transplant procedure remains a major challenge that renders patients vulnerable to several complications. Today, It is well established that a rapid and efficient immune reconstitution, particularly of the T cell compartment is pivotal to both a short-term and a long-term favorable outcome. T cells expressing a TCR heterodimer comprised of gamma (γ) and delta (δ) chains have received particular attention in allo-HCT setting, as a large body of evidence has indicated that γδ T cells can exert favorable potent anti-tumor effects without inducing severe graft versus host disease (GVHD). However, despite their potential role in allo-HCT, studies investigating their detailed reconstitution in patients after allo-HCT are scarce. In this review we aim to shed lights on the current literature and understanding of γδ T cell reconstitution kinetics as well as the different transplant-related factors that may influence γδ reconstitution in allo-HCT. Furthermore, we will present data from available reports supporting a role of γδ cells and their subsets in patient outcome. Finally, we discuss the current and future strategies to develop γδ cell-based therapies to exploit the full immunotherapeutic potential of γδ cells in HCT setting.
Identification of m6A modification patterns and development of m6A–hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer
Authors: Shen Xi , Zhong Jianxin , He Jinlan , Han Jiaqi , Chen Nianyong
Published: August 2022

Background

N6-methylation (m6A) modification of RNA has been found to have essential effects on aspects of the tumor microenvironment (TME) including hypoxia status and mobilization of immune cells. However, there are no studies to explore the combined effect of m6A modification and hypoxia on molecular heterogeneity and TME of triple-negative breast cancer (TNBC).

Methods

We collected The Cancer Genome Atlas (TCGA-TNBC, N=139), the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC-TNBC, N=297), the GSE103091, GSE21653, and GSE135565 series from the Gene Expression Omnibus (GEO-TNBC, N=247), and FUSCCTNBC (N=245) for our study. The non-negative matrix factorization algorithm was used to cluster TNBC samples. Immune cell infiltration was analyzed by the CIBERSORT algorithm. The enrichment scores were calculated by single-sample gene set enrichment analysis(ssGSEA) to characterize TME in TNBC samples. Immunohistochemistry (IHC) and qRT-PCR were performed to detect the gene expression.

Results

Based on the expression of m6A-related genes, we identified three distinct m6A clusters (denoted A, B, and C) in TNBC samples. Comparing the TME characteristics among the three clusters, we observed that cluster C was strongly related to hypoxia status and immune suppression, whereas clusters A and B displayed more immune cell infiltration. Therefore, we combine m6A and hypoxia related genes to classify two m6A-hypoxia clusters of TNBC and screened six prognostic genes by LASSO-Cox regression to construct a m6A-hypoxia signature(MHPS), which divided TNBC samples into high- and low-risk groups. We identified different TME features, immune cell infiltration between the two groups, and a better immunotherapy response was observed in the low-risk group. A nomogram was constructed with tumor size, lymph node, and risk score to improve clinical application of MHPS.

Conclusion

We identified distinct TME characteristics of TNBC based on three different m6A modification patterns. Then, we constructed a specific m6A–hypoxia signature for TNBC to evaluate risk and predict immunotherapy response of patients, to enable more accurate treatment in the future.
Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis
Authors: Zou Menglian , Yang Zihan , Fan Yue , Gong Liang , Han Ziying , Ji Li , Hu Xiaomin , Wu Dong
Published: August 2022

Background

Acute necrotizing pancreatitis (NP), a severe form of acute pancreatitis (AP), has higher mortality and worse outcome than non-necrotizing pancreatitis (non-NP). Infected NP is a devastating subgroup of NP. To date neither NP nor infected NP has robust prediction strategies, which may delay early recognition and timely intervention. Recent studies revealed correlations between disturbed gut microbiota and AP severity. Some features of intestinal microbiota have the potential to become biomarkers for NP prediction.

Methods

We performed 16S rRNA sequencing to analyze gut microbiota features in 20 healthy controls (HC), and 58 AP patients on hospital admission. The AP patients were later classified into NP and non-NP groups based on subsequent diagnostic imaging features. Random forest regression model and ROC curve were applied for NP and infected NP prediction. PIRCUSt2 was used for bacterial functional pathway prediction analysis.

Results

We found that the three groups (HC, NP, and non-NP) had distinct microorganism composition. NP patients had reduced microbial diversity, higher abundance of Enterobacteriales, but lower abundance of Clostridiales and Bacteroidales compared with the non-NP group. Correlation analyses displayed that intestine bacterial taxonomic alterations were related to severity, ICU admission, and prognosis. By pathway prediction, species more abundant in NP patients had positive correlation with synthesis and degradation of ketone bodies, and benzoate degradation. Enterococcus faecium (ASV2) performed best in discriminating NP and non-NP patients. Finegoldia magna (ASV3) showed the maximal prediction capacity among all ASVs and had comparable accuracy with Balthazar CT to detect patients with infected NP.

Conclusions

Our study suggests that NP patients have distinct intestinal microbiota on admission compared to non-NP patients. Dysbiosis of intestinal microbiota might influence NP progression through ketone body or benzoate metabolism. Enterococcus faecium and Finegoldia magna are potential predictors for NP and infected NP. Our findings explore biomarkers which may inform clinical decision-making in AP and shed light on further studies on NP pathophysiology and management.
Using dual water isotopes to quantify the mixing of water masses in the Pearl River Estuary and the adjacent northern South China Sea
Authors: Jian Xiaoyu , Zhang Shuwen , Lao Qibin , Chen Fajin , Huang Peng , Chen Chunqing , Zhu Qingmei
Published: August 2022

The mixing of different water masses is important for local physical and biogeochemical processes as well as for ecosystems in the ocean. In this study, a new dataset of stable water isotopes (δD and δ18O) combined with temperature–salinity profiles was used to quantitatively understand the mixing of water masses in the Pearl River Estuary (PRE) and the adjacent northern South China Sea (SCS). Based on hydrographic characteristics and the isotope–salinity relationships in the water column, three water masses, namely, low isotopic values (<1.5‰ for δD and <0‰ for δ18O) with a salinity of <33.20 for PRE water (PREW), high isotopic values (>2.0‰ for δD and >0.6‰ for δ18O) with a salinity of >34.60 for SCS Kuroshio Branch (SCSKB), and higher isotopic values (>3.0‰ for δD and <0.4‰ for δ18O) with a salinity of >33.30 for SCS water (SCSW), were identified in the PRE and the adjacent SCS. The mixing of the three water masses in the PRE and the adjacent SCS was mainly from SCSW (71%), followed by the SCSKB (23%), and the proportion of PREW only accounted for 6%. However, different water layers and regions are affected differently by these three water masses. The surface water is mainly influenced by the PREW, whereas the subsurface water is mainly influenced by the intrusion of SCSKB (100–300 m). The mixing process of water masses in the west side of the study area (<115°E) is mainly contributed by the SCSW (86%), whereas the contributions of PREW and SCSKB are only 4% and 10%, respectively. By contrast, the mixing of water masses in the east side (>115°E) is mainly influenced by the Kuroshio intrusion (50%). This study reveals that dual water isotopes are exquisitely sensitive to determine the complex hydrological process in the PRE and the adjacent SCS, and water masses on marine environment should deserve more attention.
Stress concentration of perforated cement sheath and the effect of cement sheath elastic parameters on its integrity failure during shale gas fracturing
Authors: Bu Yuhuan , Yang Heng , Zhao Lingyun , Guo Shenglai , Liu Huajie , Ma Xiaolong
Published: August 2022

Due to the extremely low porosity and permeability of shale, fracturing is often used to develop shale gas reservoirs. During shale fracturing, extremely high fracturing pressure may invalidate the integrity of the cement sheath and bring hidden dangers to the safe development of shale gas. This paper compares the stress state of the three-dimensional unperforated and perforated finite element models of casing-cement sheath-formation to obtain the influence of perforation on the stress concentration and failure area of the cement sheath. The stress state comparison incorporates three sets of perforation models with different hole densities and diameter verifies the stress concentration law of perforation on the cement sheath. By studying the effects of the elastic modulus and Poisson’s ratio of the cement sheath on the maximum tensile and compressive stresses of the cement sheath under fracturing pressure, the integrity failure form of the cement sheath and the measures for integrity failure are obtained. The results show that the peak stress concentration of the perforated cement sheath is about twice the normal value of the stress. The failure area is the two ends of the perforation, the shape is similar to the bottom surface of the elliptical cone, and the thickness is up to half of the wall thickness of the cement sheath. The line length of the largest failure area is 4.5 times the diameter of the hole. Under fracturing conditions, the cement sheath generally undergoes tensile failure. The lower the elastic modulus and Poisson’s ratio of the cement sheath, the smaller the tensile stress of the cement sheath, and the less likely it is to cause tensile failure.
Automatized lung disease quantification in patients with COVID-19 as a predictive tool to assess hospitalization severity
Authors: Guiot Julien , Maes Nathalie , Winandy Marie , Henket Monique , Ernst Benoit , Thys Marie , Frix Anne-Noelle , Morimont Philippe , Rousseau Anne-Françoise , Canivet Perrine , Louis Renaud , Misset Benoît , Meunier Paul , Charbonnier Jean-Paul , Lambermont Bernard
Published: August 2022

The pandemic of COVID-19 led to a dramatic situation in hospitals, where staff had to deal with a huge number of patients in respiratory distress. To alleviate the workload of radiologists, we implemented an artificial intelligence (AI) - based analysis named CACOVID-CT, to automatically assess disease severity on chest CT scans obtained from those patients. We retrospectively studied CT scans obtained from 476 patients admitted at the University Hospital of Liege with a COVID-19 disease. We quantified the percentage of COVID-19 affected lung area (% AA) and the CT severity score (total CT-SS). These quantitative measurements were used to investigate the overall prognosis and patient outcome: hospital length of stay (LOS), ICU admission, ICU LOS, mechanical ventilation, and in-hospital death. Both CT-SS and % AA were highly correlated with the hospital LOS, the risk of ICU admission, the risk of mechanical ventilation and the risk of in-hospital death. Thus, CAD4COVID-CT analysis proved to be a useful tool in detecting patients with higher hospitalization severity risk. It will help for management of the patients flow. The software measured the extent of lung damage with great efficiency, thus relieving the workload of radiologists.
Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments
Authors: Monaghan Marie , Takhar Pooja , Langlands Luke , Knuf Markus , Amin Sam
Published: August 2022

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.
Epidemiological features and spatial-temporal clustering of visceral leishmaniasis in mainland China from 2019 to 2021
Authors: Li Yuanyuan , Luo Zhuowei , Hao Yuwan , Zhang Yi , Yang Limin , Li Zhongqiu , Zhou Zhengbin , Li Shizhu
Published: August 2022

Background

Visceral leishmaniasis (VL) is a serious vector-borne disease in central and western China. In recent years, the number of VL cases increased gradually, particularly the mountain-type zoonotic visceral leishmaniasis (MT-ZVL). This study clarified the epidemiological features and spatial-temporal clustering of VL in China between 2019 and 2021, identified the risk areas for VL transmission, and provided scientific evidence for the prevention and control of VL.

Materials and methods

The information on VL cases in 2019–2021 was collected from the Infectious Disease Reporting Information Management System of the Chinese Center for Disease Control and Prevention. The epidemiological characteristics of VL cases were analyzed. The global Moran’s I and Getis-ORD Gi* statistical data were processed for spatial autocorrelation and hotspot analysis in ESRI ArcGIS software. Also, spatial-temporal clustering analysis was conducted with the retrospective space–time permutation scan statistics.

Results

A total of 608 VL cases were reported from 2019 to 2021, with 158, 213, and 237 cases reported each year, respectively. Of the 608 cases, there were 10 cases of anthroponotic visceral leishmaniasis (AVL), 20 cases of desert-type zoonotic visceral leishmaniasis (DT-ZVL), and 578 cases of MT-ZVL. The age of VL cases was mainly distributed in the group of subjects aged ≥ 15 years. Peasants and infants were the dominant high-risk population. The incidence peak season of VL occurred between March and May. The cases were mainly distributed in Shanxi (299 cases), Shaanxi (118 cases), and Gansu (106 cases) Provinces, accounting for 86.02% (523/608) of the total reported cases in China. Spatial analysis revealed that clustering of infection is mainly located in eastern Shanxi Province and Shaanxi–Shanxi border areas, as well as southern Gansu and northern Sichuan Province. In addition, new reemergence hotspots in Shanxi, Henan, and Hebei Provinces have been detected since 2020. Spatio-temporal clustering analysis revealed an increase in the degree of infection aggregation in eastern Shanxi Province and Shaanxi–Shanxi border areas.

Conclusion

The AVL and DT-ZVL were endemic at a lower level in western China, whereas MT-ZVL rebounded rapidly and showed a resurgence in historically endemic counties. The spatial-temporal clustering analysis displayed that the high-incidence areas of VL have shifted to central China, particularly in Shanxi and Shaanxi Provinces. Integrated mitigation strategies targeting high-risk populations are needed to control VL transmission in high-risk areas.
Molecular epidemiology and antibiotic resistance profiles of invasive Haemophilus influenzae from Norway 2017–2021
Authors: Tønnessen Ragnhild , García Ignacio , Debech Nadia , Lindstrøm Jonas Christoffer , Wester Astrid Louise , Skaare Dagfinn
Published: August 2022

Invasive Haemophilus influenzae (Hi) disease has decreased in countries that included Hi type b (Hib) vaccination in their childhood immunization programs in the 1990s. Non-typeable (NT) and non-b strains are now the leading causes of invasive Hi disease in Europe, with most cases reported in young children and the elderly. Concerningly, no vaccines toward such strains are available and beta-lactam resistance is increasing. We describe the epidemiology of invasive Hi disease reported to the Norwegian Surveillance System for Communicable Diseases (MSIS) (2017–2021, n = 407). Whole-genome sequencing (WGS) was performed on 245 isolates. We investigated the molecular epidemiology (core genome phylogeny) and the presence of antibiotic resistance markers (including chromosomal mutations associated with beta-lactam or quinolone resistance). For isolates characterized with both WGS and phenotypic antibiotic susceptibility testing (AST) (n = 113) we assessed correlation between resistance markers and susceptibility categorization by calculation of sensitivity, specificity, and predictive values. Incidence rates of invasive Hi disease in Norway ranged from 0.7 to 2.3 per 100,000 inhabitants/year (mean 1.5 per 100,000) and declined during the COVID-19 pandemic. The bacterial population consisted of two major phylogenetic groups with subclustering by serotype and multi-locus sequence type (ST). NTHi accounted for 71.8% (176). The distribution of STs was in line with previous European reports. We identified 13 clusters, including four encapsulated and three previously described international NTHi clones with blaTEM–1 (ST103) or altered PBP3 (rPBP3) (ST14/IIA and ST367/IIA). Resistance markers were detected in 25.3% (62/245) of the isolates, with blaTEM–1 (31, 50.0%) and rPBP3 (28, 45.2%) being the most frequent. All isolates categorized as resistant to aminopenicillins, tetracycline or chloramphenicol possessed relevant resistance markers, and the absence of relevant substitutions in PBP3 and GyrA/ParC predicted susceptibility to cefotaxime, ceftriaxone, meropenem and quinolones. Among the 132 WGS-only isolates, one isolate had PBP3 substitutions associated with resistance to third-generation cephalosporins, and one isolate had GyrA/ParC alterations associated with quinolone resistance. The detection of international virulent and resistant NTHi clones underlines the need for a global molecular surveillance system. WGS is a useful supplement to AST and should be performed on all invasive isolates.
MutDock: A computational docking approach for fixed-backbone protein scaffold design
Authors: Chauhan Varun M. , Pantazes Robert J.
Published: August 2022

Despite the successes of antibodies as therapeutic binding proteins, they still face production and design challenges. Alternative binding scaffolds of smaller size have been developed to overcome these issues. A subset of these alternative scaffolds recognizes target molecules through mutations to a set of surface resides, which does not alter their backbone structures. While the computational design of antibodies for target epitopes has been explored in depth, the same has not been done for alternative scaffolds. The commonly used dock-and-mutate approach for binding proteins, including antibodies, is limited because it uses a constant sequence and structure representation of the scaffold. Docking fixed-backbone scaffolds with a varied group of surface amino acids increases the chances of identifying superior starting poses that can be improved with subsequent mutations. In this work, we have developed MutDock, a novel computational approach that simultaneously docks and mutates fixed backbone scaffolds for binding a target epitope by identifying a minimum number of hydrogen bonds. The approach is broadly divided into two steps. The first step uses pairwise distance alignment of hydrogen bond-forming areas of scaffold residues and compatible epitope atoms. This step considers both native and mutated rotamers of scaffold residues. The second step mutates clashing variable interface residues and thermodynamically unfavorable residues to create additional strong interactions. MutDock was used to dock two scaffolds, namely, Affibodies and DARPins, with ten randomly selected antigens. The energies of the docked poses were minimized and binding energies were compared with docked poses from ZDOCK and HADDOCK. The top MutDock poses consisted of higher and comparable binding energies than the top ZDOCK and HADDOCK poses, respectively. This work contributes to the discovery of novel binders based on smaller-sized, fixed-backbone protein scaffolds.
AKT and SGK kinases regulate cell migration by altering Scar/WAVE complex activation and Arp2/3 complex recruitment
Authors: Singh Shashi Prakash , Paschke Peggy , Tweedy Luke , Insall Robert H.
Published: August 2022

Cell polarity and cell migration both depend on pseudopodia and lamellipodia formation. These are regulated by coordinated signaling acting through G-protein coupled receptors and kinases such as PKB/AKT and SGK, as well as the actin cytoskeletal machinery. Here we show that both Dictyostelium PKB and SGK kinases (encoded by pkbA and pkgB) are dispensable for chemotaxis towards folate. However, both are involved in the regulation of pseudopod formation and thus cell motility. Cells lacking pkbA and pkgB showed a substantial drop in cell speed. Actin polymerization is perturbed in pkbA- and reduced in pkgB- and pkbA-/pkgB- mutants. The Scar/WAVE complex, key catalyst of pseudopod formation, is recruited normally to the fronts of all mutant cells (pkbA-, pkgB- and pkbA-/pkgB-), but is unexpectedly unable to recruit the Arp2/3 complex in cells lacking SGK. Consequently, loss of SGK causes a near-complete loss of normal actin pseudopodia, though this can be rescued by overexpression of PKB. Hence both PKB and SGK are required for correct assembly of F-actin and recruitment of the Arp2/3 complex by the Scar/WAVE complex during pseudopodia formation.
Identification and verification of ferroptosis-related genes in the synovial tissue of osteoarthritis using bioinformatics analysis
Authors: Xia Lin , Gong Ningji
Published: August 2022

Background: Osteoarthritis (OA) is a major factor causing pain and disability. Studies performed to date have suggested that synovitis is possibly a critical OA-related pathological change. Ferroptosis represents a novel type of lipid peroxidation-induced iron-dependent cell death. However, its effect on OA remains largely unclear.

Objective: This work focused on identifying and validating the possible ferroptosis-related genes (FRGs) involved in synovitis of OA through bioinformatics analysis.

Materials and Methods: The microarray dataset GSE55235 was downloaded in the database Gene Expression Omnibus (GEO). By the Venn diagram and GEO2R, differentially expressed genes (DEGs) and ferroptosis DEGs (FDEGs) were detected. DEGs were screened by GO and KEGG enrichment analysis, as well as protein-protein interaction (PPI) analysis. Besides, the software Cytoscape and database STRING were utilized to construct hub gene networks. Moreover, this study used the database NetworkAnalyst to predict the target miRNAs of the hub genes. Finally, the hub genes were confirmed by analysis of the receiver operating characteristic (ROC) curve on the GSE12021 and GSE1919 databases. Considering the relationship between ferroptosis and immunity, this study applied CIBERSORTx to analyze the immune infiltration in OA in addition.

Results: This work discovered seven genes, including ATF3, IL6, CDKN1A, IL1B, EGR1, JUN, and CD44, as the hub FDEGs. The ROC analysis demonstrated that almost all hub genes had good diagnostic properties in GSE12021 and GSE 1919.

Conclusion: This study discovered seven FDEGs to be the possible diagnostic biomarkers and therapeutic targets of synovitis during OA, which sheds more light on the pathogenesis of OA at the transcriptome level.
Innervation of human superficial fascia
Authors: Fede Caterina , Petrelli Lucia , Pirri Carmelo , Neuhuber Winfried , Tiengo Cesare , Biz Carlo , De Caro Raffaele , Schleip Robert , Stecco Carla
Published: August 2022

The superficial fascia has only recently been recognized as a specific anatomical structure. Furthermore, whereas it is actually recognized that the innervation of the deep/muscular fascia plays a key role in proprioception and nociception, there are very few studies that have analyzed these characteristics in the superficial fascia. In this work, our group analyzed two different anatomical districts (abdomen and thigh), from volunteer patients, undergoing surgery procedures. Each sample was processed for histological analysis by Hematoxylin&Eosin, and by immunohistochemistry stainings (in 5-micron-paraffin embedded section and in cryosectioned free floating samples), with antibodies specific for nerve fibers: S100 antibody for myelinating and non-myelinating Schwann cells, PGP9.5 antibody as pan-neuronal marker, tyrosine hydroxylase for autonomic innervation. The results revealed a huge innervation: the nervous structures were found above all around blood vessels and close to adipocytes, but they penetrated also in the connective tissue itself and are found in the midst of fibro-adipose tissue. The tissue is pervaded by both thin (mean diameter of 4.8 ± 2.6 μm) and large nerve fiber bundles of greater diameter (21.1 ± 12.2 μm). The ratio S100/TH positivity was equal to 2.96, with a relative percentage of autonomic innervation with of 33.82%. In the light of these findings is evident that the superficial fasciae have a clear and distinct anatomical identity and a specific innervation, which should be considered to better understand their role in thermoregulation, exteroception and pain perception. The knowledge of the superficial fascia may improve grading and developing of different manual approach for treatments of fascial dysfunctions, and the understanding of how some factors like temperature or manual therapies can have an impact on sensitivity of the fascia.
Contralaterally controlled neuromuscular electrical stimulation-induced changes in functional connectivity in patients with stroke assessed using functional near-infrared spectroscopy
Authors: Guo Chuan , Sui Youxin , Xu Sheng , Zhuang Ren , Zhang Mingming , Zhu Shizhe , Wang Jin , Zhang Yushi , Kan Chaojie , Shi Ye , Wang Tong , Shen Ying
Published: August 2022

Contralaterally controlled neuromuscular electrical stimulation (CCNMES) is an innovative therapy in stroke rehabilitation which has been verified in clinical studies. However, the underlying mechanism of CCNMES are yet to be comprehensively revealed. The main purpose of this study was to apply functional near-infrared spectroscopy (fNIRS) to compare CCNMES-related changes in functional connectivity (FC) within a cortical network after stroke with those induced by neuromuscular electrical stimulation (NMES) when performing wrist extension with hemiplegic upper extremity. Thirty-one stroke patients with right hemisphere lesion were randomly assigned to CCNMES (n = 16) or NMES (n = 15) groups. Patients in both groups received two tasks: 10-min rest and 10-min electrical stimulation task. In each task, the cerebral oxygenation signals in the prefrontal cortex (PFC), bilateral primary motor cortex (M1), and primary sensory cortex (S1) were measured by a 35-channel fNIRS. Compared with NMES, FC between ipsilesional M1 and contralesional M1/S1 were significantly strengthened during CCNMES. Additionally, significantly higher coupling strengths between ipsilesional PFC and contralesional M1/S1 were observed in the CCNMES group. Our findings suggest that CCNMES promotes the regulatory functions of ipsilesional prefrontal and motor areas as well as contralesional sensorimotor areas within the functional network in patients with stroke.
Cross-site scripting attack detection based on a modified convolution neural network
Authors: Yan Huyong , Feng Li , Yu You , Liao Weiling , Feng Lei , Zhang Jingyue , Liu Dan , Zou Ying , Liu Chongwen , Qu Linfa , Zhang Xiaoman
Published: August 2022

Cross-site scripting (XSS) attacks are currently one of the most threatening network attack methods. Effectively detecting and intercepting XSS attacks is an important research topic in the network security field. This manuscript proposes a convolutional neural network based on a modified ResNet block and NiN model (MRBN-CNN) to address this problem. The main innovations of this model are to preprocess the URL according to the syntax and semantic characteristics of XSS attack script encoding, improve the ResNet residual module, extract features from three different angles, and replace the full connection layer in combination with the 1*1 convolution characteristics. Compared with the traditional machine learning and deep learning detection models, it is found that this model has better performance and convergence time. In addition, the proposed method has a detection rate compared to a baseline of approximately 75% of up to 99.23% accuracy, 99.94 precision, and a 98.53% recall value.
Circadian Synchrony: Sleep, Nutrition, and Physical Activity
Authors: Healy Kelly L. , Morris Andrew R. , Liu Andrew C.
Published: August 2022

The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral and physiological processes. The cellular clock mechanism involves a transcriptional negative feedback loop that gives rise to circadian rhythms in gene expression with an approximately 24-h periodicity. To maintain system robustness, clocks throughout the body must be synchronized and their functions coordinated. In mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained to the light/dark cycle through photic signal transduction and subsequent induction of core clock gene expression. The SCN in turn relays the time-of-day information to clocks in peripheral tissues. While the SCN is highly responsive to photic cues, peripheral clocks are more sensitive to non-photic resetting cues such as nutrients, body temperature, and neuroendocrine hormones. For example, feeding/fasting and physical activity can entrain peripheral clocks through signaling pathways and subsequent regulation of core clock genes and proteins. As such, timing of food intake and physical activity matters. In an ideal world, the sleep/wake and feeding/fasting cycles are synchronized to the light/dark cycle. However, asynchronous environmental cues, such as those experienced by shift workers and frequent travelers, often lead to misalignment between the master and peripheral clocks. Emerging evidence suggests that the resulting circadian disruption is associated with various diseases and chronic conditions that cause further circadian desynchrony and accelerate disease progression. In this review, we discuss how sleep, nutrition, and physical activity synchronize circadian clocks and how chronomedicine may offer novel strategies for disease intervention.