bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of Potential miRNA Biomarkers and Prediction for Ovarian Cancer Using Artificial Intelligence
Authors: Hamidi Farzaneh , Gilani Neda , Belaghi Reza Arabi , Sarbakhsh Parvin , Edgünlü Tuba , Santaguida Pasqualina
Published: December 2021

Ovarian cancer is the second most dangerous gynecologic cancer with a high mortality rate. The classification of gene expression data from high-dimensional and small-sample gene expression data is a challenging task. The discovery of miRNAs, a small non-coding RNA with 18–25 nucleotides in length that regulates gene expression, has revealed the existence of a new array for regulation of genes and has been reported as playing a serious role in cancer. By using LASSO and Elastic Net as embedded algorithms of feature selection techniques, the present study identified 10 miRNAs that were regulated in ovarian serum cancer samples compared to non-cancer samples in public available dataset GSE106817: hsa-miR-5100, hsa-miR-6800-5p, hsa-miR-1233-5p, hsa-miR-4532, hsa-miR-4783-3p, hsa-miR-4787-3p, hsa-miR-1228-5p, hsa-miR-1290, hsa-miR-3184-5p, and hsa-miR-320b. Further, we implemented state-of-the-art machine learning classifiers, such as logistic regression, random forest, artificial neural network, XGBoost, and decision trees to build clinical prediction models. Next, the diagnostic performance of these models with identified miRNAs was evaluated in the internal (GSE106817) and external validation dataset (GSE113486) by ROC analysis. The results showed that first four prediction models consistently yielded an AUC of 100%. Our findings provide significant evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.
TGF-Beta Induced Key Genes of Osteogenic and Adipogenic Differentiation in Human Mesenchymal Stem Cells and MiRNA–mRNA Regulatory Networks
Authors: Du Genfa , Cheng Xinyuan , Zhang Zhen , Han Linjing , Wu Keliang , Li Yongjun , Lin Xiaosheng
Published: December 2021

Background: The clinical efficacy of osteoporosis therapy is unsatisfactory. However, there is currently no gold standard for the treatment of osteoporosis. Recent studies have indicated that a switch from osteogenic to adipogenic differentiation in human bone marrow mesenchymal stem cells (hMSCs) induces osteoporosis. This study aimed to provide a more comprehensive understanding of the biological mechanisms involved in this process and to identify key genes involved in osteogenic and adipogenic differentiation in hMSCs to provide new insights for the prevention and treatment of osteoporosis.

Methods: Microarray and bioinformatics approaches were used to identify the differentially expressed genes (DEGs) involved in osteogenic and adipogenic differentiation, and the biological functions and pathways of these genes were analyzed. Hub genes were identified, and the miRNA–mRNA interaction networks of these hub genes were constructed.

Results: In an optimized microenvironment, transforming growth factor-beta (TGF-beta) could promote osteogenic differentiation and inhibit adipogenic differentiation of hMSCs. According to our study, 98 upregulated genes involved in osteogenic differentiation and 66 downregulated genes involved in adipogenic differentiation were identified, and associated biological functions and pathways were analyzed. Based on the protein–protein interaction (PPI) networks, the hub genes of the upregulated genes (CTGF, IGF1, BMP2, MMP13, TGFB3, MMP3, and SERPINE1) and the hub genes of the downregulated genes (PPARG, TIMP3, ANXA1, ADAMTS5, AGTR1, CXCL12, and CEBPA) were identified, and statistical analysis revealed significant differences. In addition, 36 miRNAs derived from the upregulated hub genes were screened, as were 17 miRNAs derived from the downregulated hub genes. Hub miRNAs (hsa-miR-27a/b-3p, hsa-miR-128-3p, hsa-miR-1-3p, hsa-miR-98-5p, and hsa-miR-130b-3p) coregulated both osteogenic and adipogenic differentiation factors.

Conclusion: The upregulated hub genes identified are potential targets for osteogenic differentiation in hMSCs, whereas the downregulated hub genes are potential targets for adipogenic differentiation. These hub genes and miRNAs play important roles in adipogenesis and osteogenesis of hMSCs. They may be related to the prevention and treatment not only of osteoporosis but also of obesity.
Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies
Authors: Sakaria Rishika P. , Zaveri Parul G. , Holtrop Shannon , Zhang Jie , Brown Chester W. , Pivnick Eniko K.
Published: December 2021

Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C > T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.
Impact of Liability to Periodontitis on Glycemic Control and Type II Diabetes Risk: A Mendelian Randomization Study
Authors: Shah Parth D. , Schooling C. M. , Borrell Luisa N.
Published: December 2021

While the association of periodontitis with Type II diabetes (T2DM) is well-established, the causal relationship remains uncertain. We examined the causal association of periodontitis with glycemic traits (HbA1c, fasting glucose, and fasting insulin) and T2DM using Mendelian randomization (MR) taking advantage of large genome-wide association studies of European and East Asian adults, i.e., the UK Biobank (n ≈ 350,000) (HbA1c), trans-ancestral MAGIC (HbA1c, fasting glucose, and insulin), and DIAMANTE (74,124 cases/824,006 controls), and AGEN for T2DM in Europeans and East Asians, respectively. Periodontitis was instrumented using single-nucleotide polymorphisms (SNPs), strongly and independently predicting liability to periodontitis in each ancestry group. SNP-specific Wald estimates were combined using inverse variance weighting. Sensitivity analyses were performed using the weighted median and MR-Egger with meta-analysis of MR estimates for Europeans and East Asians. Genetically instrumented liability to periodontitis was not associated with glycemic traits or T2DM in either ancestry or when ancestry specific estimates were meta-analyzed. Our findings do not support a causal association of liability to periodontitis with glycemic traits or T2DM. However, further research is required confirming these findings among other racial/ethnic groups, especially groups who carry a heavy burden of both periodontitis and T2DM.
NPM1 is a Novel Therapeutic Target and Prognostic Biomarker for Ewing Sarcoma
Authors: Zhou Yangfan , Fang Yuan , Zhou Junjie , Liu Yulian , Wu Shusheng , Xu Bin
Published: December 2021

Ewing sarcoma (ES) is a cancer that may originate from stem mesenchymal or neural crest cells and is highly prevalent in children and adolescents. In recent years, targeted therapies against immune-related genes have shown good efficacy in a variety of cancers. However, effective targets for immunotherapy in ES are yet to be developed. In our study, we first identified the immune-associated differential hub gene NPM1 by bioinformatics methods as a differentially expressed gene, and then validated it using real time-PCR and western blotting, and found that this gene is not only closely related to the immune infiltration in ES, but also can affect the proliferation and apoptosis of ES cells, and is closely related to the survival of patients. The results of our bioinformatic analysis showed that NPM1 can be a hub gene in ES and an immunotherapeutic target to reactivate immune infiltration in patients with ES. In addition, treatment with NPM1 promoted apoptosis and inhibited the proliferation of ES cells. The NPM1 inhibitor NSC348884 can induce apoptosis of ES cells in a dose-dependent manner and is expected to be a potential therapeutic agent for ES.
Exploring Pathway-Based Group Lasso for Cancer Survival Analysis: A Special Case of Multi-Task Learning
Authors: Malenová Gabriela , Rowson Daniel , Boeva Valentina
Published: December 2021

Motivation: The Cox proportional hazard models are widely used in the study of cancer survival. However, these models often meet challenges such as the large number of features and small sample sizes of cancer data sets. While this issue can be partially solved by applying regularization techniques such as lasso, the models still suffer from unsatisfactory predictive power and low stability.

Methods: Here, we investigated two methods to improve survival models. Firstly, we leveraged the biological knowledge that groups of genes act together in pathways and regularized both at the group and gene level using latent group lasso penalty term. Secondly, we designed and applied a multi-task learning penalty that allowed us leveraging the relationship between survival models for different cancers.

Results: We observed modest improvements over the simple lasso model with the inclusion of latent group lasso penalty for six of the 16 cancer types tested. The addition of a multi-task penalty, which penalized coefficients in pairs of cancers from diverging too greatly, significantly improved accuracy for a single cancer, lung squamous cell carcinoma, while having minimal effect on other cancer types.

Conclusion: While the use of pathway information and multi-tasking shows some promise, these methods do not provide a substantial improvement when compared with standard methods.
Epigenetic Alteration and its Association With Downregulated FOXP3 Gene in Indian Breast Cancer Patients
Authors: Sadaf  , Akhter Naseem , Alharbi Raed A. , Sindi Abdulmajeed A. A. , Najm Mohammad Zeeshan , Alhumaydhi Fahad A. , Khan Mohammad Aasif , Deo S.V.S , Husain Syed Akhtar
Published: December 2021

Background:FOXP3 gene, known to be a potential tumor suppressor, has been identified to interact with HER2 in mammary cancer. Moreover, the high expression of FOXP3 serves as a good predictor of the survival of patients in breast cancer, prostate cancer, and gastric cancer. The expression and epigenetic alterations were evaluated in female breast cancer patients.

Material and Methods: Expression studies at the mRNA level and protein level were conducted in 140 breast cancer cases by real-time PCR and immunohistochemistry, respectively. Epigenetic studies were also conducted by analyzing the methylation status at the promoter region of the gene using MS-PCR.

Results:FOXP3 mRNA expression and protein expression were downregulated in breast cancer patients. The absence of FOXP3 protein expression is significantly associated with promoter methylation, where 70 methylated cases exhibited protein loss (70/95, 73.6%). Statistically, we also found a significant correlation between FOXP3 protein expression and TNM stage, promoter methylation, and histological grade. The methylated FOXP3 cases that did not express protein were also significantly associated with positive lymph node metastasis and HER-2 status.

Conclusion: The expression profile of FOXP3 may serve as a prognostic factor. In short, FOXP3 may stand in the most crucial list of biomarkers for breast cancer, bringing compelling results in terms of treatment and management of the disease.
Identification of TNFAIP8 as an Immune-Related Biomarker Associated With Tumorigenesis and Prognosis in Cutaneous Melanoma Patients
Authors: Sun Yuliang , Zhao Jianxiong , Sun Xiaoru , Ma Guangxin
Published: December 2021

Tumor necrosis factor-α–induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which is associated with inflammation and tumorigenesis. The potential role of TNFAIP8 in a tumor immune microenvironment in skin cutaneous melanoma (SKCM) has not yet been investigated. The TNFAIP8 expression was evaluated via gene expression profiling interactive analysis (GEPIA). We also evaluated the influence of TNFAIP8 on overall survival via GEPIA and PrognoScan. After GO and KEGG pathway analyses, the correlation between the TNFAIP8 expression level and immune cells or gene markers of the immune infiltration level was explored by R-language. The result showed the TNFAIP8 expression was significantly reduced in SKCM in comparison with normal control. In SKCM, the TNFAIP8 expression in higher levels was associated with the better overall survival. The high expression of TNFAIP8 was positively correlated with the immune score and promoted immune cell infiltration in SKCM patients. TNFAIP8 can be a positive prognosis marker or new immunotherapy target in SKCM.
Metabolomic and Proteomic Analyses of Persistent Valvular Atrial Fibrillation and Non-Valvular Atrial Fibrillation
Authors: Hu Bo , Ge Wen , Wang Yuliang , Zhang Xiaobin , Li Tao , Cui Hui , Qian Yongjun , Zhang Yangyang , Li Zhi
Published: December 2021

Atrial fibrillation (AF) is an abnormal heart rhythm related to an increased risk of heart failure, dementia, and stroke. The distinction between valvular and non-valvular AF remains a debate. In this study, proteomics and metabolomics were integrated to describe the dysregulated metabolites and proteins of AF patients relative to sinus rhythm (SR) patients. Totally 47 up-regulated and 41 down-regulated proteins in valvular AF, and 59 up-regulated and 149 down-regulated proteins in non-valvular AF were recognized in comparison to SR patients. Moreover, 58 up-regulated and 49 significantly down-regulated metabolites in valvular AF, and 47 up-regulated and 122 down-regulated metabolites in persistent non-valvular AF patients were identified in comparison to SR patients. Based on analysis of differential levels of metabolites and proteins, 15 up-regulated and 22 down-regulated proteins, and 13 up-regulated and 122 down-regulated metabolites in persistent non-valvular AF were identified relative to valvular AF. KEGG pathway enrichment analysis showed the altered proteins and metabolites were significantly related to multiple metabolic pathways, such as Glycolysis/Gluconeogenesis. Interestingly, the enrichment pathways related to non-valvular AF were obviously different from those in valvular AF. For example, valvular AF was significantly related to Glycolysis/Gluconeogenesis, but non-valvular AF was more related to Citrate cycle (TCA cycle). Correlation analysis between the differentially expressed proteins and metabolites was also performed. Several hub proteins with metabolites were identified in valvular AF and non-valvular AF. For example, Taurine, D-Threitol, L-Rhamnose, and DL-lactate played crucial roles in valvular AF, while Glycerol-3-phosphate dehydrogenase, Inorganic pyrophosphatase 2, Hydroxymethylglutaryl-CoAlyase, and Deoxyuridine 5-triphosphate nucleotidohydrolase were crucial in non-valvular AF. Then two hub networks were recognized as potential biomarkers, which can effectively distinguish valvular AF and non-valvular persistent AF from SR samples, with areas under curve of 0.75 and 0.707, respectively. Hence, these metabolites and proteins can be used as potential clinical molecular markers to discriminate two types of AF from SR samples. In summary, this study provides novel insights to understanding the mechanisms of AF progression and identifying novel biomarkers for prognosis of non-valvular AF and valvular AF by using metabolomics and proteomics analyses.
Identification and Validation of a Novel Six-Gene Expression Signature for Predicting Hepatocellular Carcinoma Prognosis
Authors: Yan Zongcai , He Meiling , He Lifeng , Wei Liuxia , Zhang Yumei
Published: December 2021

Background

Hepatocellular carcinoma (HCC) is a highly lethal disease. Effective prognostic tools to guide clinical decision-making for HCC patients are lacking.

Objective

We aimed to establish a robust prognostic model based on differentially expressed genes (DEGs) in HCC.

Methods

Using datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the International Genome Consortium (ICGC), DEGs between HCC tissues and adjacent normal tissues were identified. Using TCGA dataset as the training cohort, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analyses to identify a multi-gene expression signature. Proportional hazard assumptions and multicollinearity among covariates were evaluated while building the model. The ICGC cohort was used for validation. The Pearson test was used to evaluate the correlation between tumor mutational burden and risk score. Through single-sample gene set enrichment analysis, we investigated the role of signature genes in the HCC microenvironment.

Results

A total of 274 DEGs were identified, and a six-DEG prognostic model was developed. Patients were stratified into low- or high-risk groups based on risk scoring by the model. Kaplan–Meier analysis revealed significant differences in overall survival and progression-free interval. Through univariate and multivariate Cox analyses, the model proved to be an independent prognostic factor compared to other clinic-pathological parameters. Time-dependent receiver operating characteristic curve analysis revealed satisfactory prediction of overall survival, but not progression-free interval. Functional enrichment analysis showed that cancer-related pathways were enriched, while immune infiltration analyses differed between the two risk groups. The risk score did not correlate with levels of PD-1, PD-L1, CTLA4, or tumor mutational burden.

Conclusions

We propose a six-gene expression signature that could help to determine HCC patient prognosis. These genes may serve as biomarkers in HCC and support personalized disease management.
Transcriptome Analysis of Host Inflammatory Responses to the Ectoparasitic Mite Sarcoptes scabiei var. hominis
Authors: Shehwana Huma , Ijaz Sadaf , Fatima Abeera , Walton Shelley , Sheikh Zafar Iqbal , Haider Waseem , Naz Shumaila
Published: December 2021

Scabies, a human skin infestation caused by the ectoparasitic mite Sarcoptes scabiei var. hominis, affects more than 200 million people globally. The prevailing knowledge of the disease process and host immune response mechanisms is limited. A better understanding of the host-parasite relationship is essential for the identification of novel vaccine and drug targets. Here we aimed to interrogate the transcriptomic profiles of mite-infested human skin biopsies with clinical manifestations of ordinary scabies subjects (“OS”; n = 05) and subjects naive to scabies (“control”; n = 03) using RNASeq data analysis. A combined clustering, network, and pathway mapping approach enabled us to identify key signaling events in the host immune and pro-inflammatory responses to S. scabiei infestation. The clustering patterns showed various differentially expressed genes including inflammatory responses and innate immunity genes (DEFB4A, IL-19, CXCL8, CSF3, SERPINB4, S100A7A, HRNR) and notably upregulation of the JAK-STAT pathway in scabies-infested samples. Mite-infested human skin biopsies (GSE178563) were compared with an ex-vivo porcine infested model (E-MTAB-6433) and human skin equivalents (GSE48459). Marked enrichment of immune response pathways (JAK-STAT signaling, IL-4 and IL-13 pathway, and Toll receptor cascade), chemokine ligands and receptors (CCL17, CCL18, CCL3L1, CCL3L3, CCR7), and cytokines (IL-13 and IL-20) were observed. Additionally, genes known for their role in psoriasis and atopic dermatitis were upregulated, e.g., IL-19. The detailed transcriptomic profile has provided an insight into molecular functions, biological processes, and immunological responses and increased our understanding about transcriptomic regulation of scabies in human.
Population Dynamics Reveal a Core Community of the Common Bottlenose Dolphin (Tursiops truncatus) in Open Waters of the South-Western Gulf of Mexico
Authors: Bolaños-Jiménez Jaime , Morteo Eduardo , Delfín-Alfonso Christian A. , Fruet Pedro F. , Secchi Eduardo R. , Bello-Pineda Javier
Published: December 2021

The presence of transient and temporary individuals in capture-mark-recapture studies may violate the assumption on equal catchability, and thus yield biased estimates. We investigated the effects of residency patterns on population parameters of bottlenose dolphins inhabiting the coastal waters off the Alvarado Lagoon System (ALS), Veracruz, Mexico. We hypothesized that this population is open but there exists a “core community” that behaves as a closed population. Between 2006 and 2010, we conducted 75 photo-identification surveys and recorded 263 dolphin group encounters, in which 231 dolphins were identified. Individuals present during only one season, classified as transients (n= 85), were excluded from the study, and a standardized residency index (IH4) was computed for each dolphin that remained in the sample (n= 146). We used the K-means clustering method to split the sample into groups based on individual (seasonal, annual) IH4values. These clusters were named as regular residents (RR,n= 55), occasional residents (OR,n= 45), and occasional visitors (OV,n= 46). The cumulative frequency of newly identified individuals displayed an asymptotic trend for the whole sample and all clusters, indicating that most of the individuals present in the study area during the study period were identified. The assumption of demographic closure was tested to define the core community, and was rejected for the whole sample and the OV cluster (p< 0.001 in both cases), indicating that the population is open. The closure assumption was not rejected for RR and OR clusters (χ2= 6.88, DF = 13,p= 0.91, and χ2= 17.8, DF = 16,p= 0.33, respectively), indicating that these clusters were demographically closed over the 5-year period. Thus, we defined this aggregation of individuals as the “core community”. The closed population model Mthindicated that the total abundance of this core community was 123 individuals (95% CI: 114–133). Our results provide quantitative evidence of the existence of a core community in open waters of the Gulf of Mexico, and points toward residency pattern as a main driver of population dynamics. These results highlight the importance of considering residency patterns when dealing with heterogeneity in the sample of a highly mobile species.
Antibiotic Prescribing and Doctor-Patient Communication During Consultations for Respiratory Tract Infections: A Video Observation Study in Out-of-Hours Primary Care
Authors: Colliers Annelies , Bombeke Katrien , Philips Hilde , Remmen Roy , Coenen Samuel , Anthierens Sibyl
Published: December 2021

Objective: Communication skills can reduce inappropriate antibiotic prescribing, which could help to tackle antibiotic resistance. General practitioners often overestimate patient expectations for an antibiotic. In this study, we describe how general practitioners and patients with respiratory tract infections (RTI) communicate about their problem, including the reason for encounter and ideas, concerns, and expectations (ICE), and how this relates to (non-)antibiotic prescribing in out-of-hours (OOH) primary care.

Methods: A qualitative descriptive framework analysis of video-recorded consultations during OOH primary care focusing on doctor-patient communication.

Results: We analyzed 77 videos from 19 general practitioners. General practitioners using patient-centered communication skills received more information on the perspective of the patients on the illness period. For some patients, the reason for the encounter was motivated by their belief that a general practitioner (GP) visit will alter the course of their illness. The ideas, concerns, and expectations often remained implicit, but the concerns were expressed by the choice of words, tone of voice, repetition of words, etc. Delayed prescribing was sometimes used to respond to implicit patient expectations for an antibiotic. Patients accepted a non-antibiotic management plan well.

Conclusion: Not addressing the ICE of patients, or their reason to consult the GP OOH, could drive assumptions about patient expectations for antibiotics early on and antibiotic prescribing later in the consultation.
Incidence and Risk Factors of Dry Eye in Children and Adolescents With Diabetes Mellitus: A 3-Year Follow-Up Study
Authors: Chen Zhangling , Xiao Ying , Qian Yu , Lin Qiurong , Xiang Zhaoyu , Cui Lipu , Sun Jiaqi , Li Sicong , Qin Xinran , Yang Chenhao , Zou Haidong
Published: December 2021

Purpose: To investigate the incidence and risk factors of dry eye in children with diabetes mellitus (DM) over a period of 3 years.

Methods: Children and adolescents with DM (age: 3–14 years) from the Shanghai Children and Adolescent Diabetes Eye (SCADE) study cohort who did not have dry eye in January 2018 were followed-up for 3 years and re-examined in January 2021, and the incidence rate and risk factors for dry eye were calculated.

Results: Forty children and adolescents with DM came for follow-up in 2021. Nine of them were diagnosed with dry eye, resulting in a 3-year incidence rate of 22.5% and an annual mean incidence rate of 7.5% for dry eye. Univariate regression analysis confirmed that decreased corneal sensation (OR [Odds Ratio] = 25.60; 95%CI [Confidence Interval] = 1.31~501.69; P = 0.03) was the risk factor for dry eye incidence. Long course of DM (OR = 1.80; 95%CI = 0.96~3.38; P = 0.07), eye pain (OR = 12.27; 95%CI = 0.65~231.48; P = 0.09), and dry eye in parents (OR = 15.99; 95%CI = 0.76~337.75; P = 0.08) may interfere with the incidence of dry eye in them.

Conclusions: The incidence of dry eye in children and adolescents with DM is high.
Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation
Authors: Ren Zhen , Perkins Stephen J. , Love-Gregory Latisha , Atkinson John P. , Java Anuja
Published: December 2021

Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation. Our objective was to evaluate the clinicopathologic significance of genetic variants in TMA and C3G in a kidney transplant cohort. We used whole exome next-generation sequencing to analyze complement genes in 76 patients, comprising 60 patients with a TMA and 16 with C3G. Ten variants in complement factor H (CFH) were identified; of these, four were known to be pathogenic, one was likely benign and five were classified as a VUS (I372V, I453L, G918E, T956M, L1207I). Each VUS was subjected to a structural analysis and was recombinantly produced; if expressed, its function was then characterized relative to the wild-type (WT) protein. Our data indicate that I372V, I453L, and G918E were deleterious while T956M and L1207I demonstrated normal functional activity. Four common polymorphisms in CFH (E936D, N1050Y, I1059T, Q1143E) were also characterized. We also assessed a family with a pathogenic variant in membrane cofactor protein (MCP) in addition to CFH with a unique clinical presentation featuring valvular dysfunction. Our analyses helped to determine disease etiology and defined the recurrence risk after kidney transplant, thereby facilitating clinical decision making for our patients. This work further illustrates the limitations of the prediction models and highlights the importance of conducting functional analysis of genetic variants particularly in a complex clinicopathologic scenario such as kidney transplantation.
Rapid Progression of Angioimmunoblastic T Cell Lymphoma Following BNT162b2 mRNA Vaccine Booster Shot: A Case Report
Authors: Goldman Serge , Bron Dominique , Tousseyn Thomas , Vierasu Irina , Dewispelaere Laurent , Heimann Pierre , Cogan Elie , Goldman Michel
Published: December 2021

Since nucleoside-modified mRNA vaccines strongly activate T follicular helper cells, it is important to explore the possible impact of approved SARS-CoV-2 mRNA vaccines on neoplasms affecting this cell type. Herein, we report and discuss unexpected rapid progression of lymphomatous lesions after administration of a BNT162b2 mRNA vaccine booster in a man recently diagnosed with AITL.
Effects of Ocean Acidification on Resident and Active Microbial Communities of Stylophora pistillata
Authors: Barreto Marcelle Muniz , Ziegler Maren , Venn Alexander , Tambutté Eric , Zoccola Didier , Tambutté Sylvie , Allemand Denis , Antony Chakkiath Paul , Voolstra Christian R. , Aranda Manuel
Published: December 2021

Ocean warming and ocean acidification (OA) are direct consequences of climate change and affect coral reefs worldwide. While the effect of ocean warming manifests itself in increased frequency and severity of coral bleaching, the effects of ocean acidification on corals are less clear. In particular, long-term effects of OA on the bacterial communities associated with corals are largely unknown. In this study, we investigated the effects of ocean acidification on the resident and active microbiome of long-term aquaria-maintained Stylophora pistillata colonies by assessing 16S rRNA gene diversity on the DNA (resident community) and RNA level (active community). Coral colony fragments of S. pistillata were kept in aquaria for 2 years at four different pCO2 levels ranging from current pH conditions to increased acidification scenarios (i.e., pH 7.2, 7.4, 7.8, and 8). We identified 154 bacterial families encompassing 2,047 taxa (OTUs) in the resident and 89 bacterial families including 1,659 OTUs in the active communities. Resident communities were dominated by members of Alteromonadaceae, Flavobacteriaceae, and Colwelliaceae, while active communities were dominated by families Cyclobacteriacea and Amoebophilaceae. Besides the overall differences between resident and active community composition, significant differences were seen between the control (pH 8) and the two lower pH treatments (7.2 and 7.4) in the active community, but only between pH 8 and 7.2 in the resident community. Our analyses revealed profound differences between the resident and active microbial communities, and we found that OA exerted stronger effects on the active community. Further, our results suggest that rDNA- and rRNA-based sequencing should be considered complementary tools to investigate the effects of environmental change on microbial assemblage structure and activity.
Extensive Drug-Resistant Salmonella enterica Isolated From Poultry and Humans: Prevalence and Molecular Determinants Behind the Co-resistance to Ciprofloxacin and Tigecycline
Authors: Abd El-Aziz Norhan K. , Tartor Yasmine H. , Gharieb Rasha M. A. , Erfan Ahmed M. , Khalifa Eman , Said Mahmoud A. , Ammar Ahmed M. , Samir Mohamed
Published: December 2021

The emergence of extensive drug-resistant (XDR) Salmonella in livestock animals especially in poultry represents a serious public health and therapeutic challenge. Despite the wealth of information available on Salmonella resistance to various antimicrobials, there have been limited data on the genetic determinants of XDR Salmonella exhibiting co-resistance to ciprofloxacin (CIP) and tigecycline (TIG). This study aimed to determine the prevalence and serotype diversity of XDR Salmonella in poultry flocks and contact workers and to elucidate the genetic determinants involved in the co-resistance to CIP and TIG. Herein, 115 Salmonella enterica isolates of 35 serotypes were identified from sampled poultry (100/1210, 8.26%) and humans (15/375, 4.00%), with the most frequent serotype being Salmonella Typhimurium (26.96%). Twenty-nine (25.22%) Salmonella enterica isolates exhibited XDR patterns; 25 out of them (86.21%) showed CIP/TIG co-resistance. Exposure of CIP- and TIG-resistant isolates to the carbonyl cyanide 3-chlorophenylhydrazone (CCCP) efflux pump inhibitor resulted in an obvious reduction in their minimum inhibitory concentrations (MICs) values and restored the susceptibility to CIP and TIG in 17.24% (5/29) and 92% (23/25) of the isolates, respectively. Molecular analysis revealed that 89.66% of the isolates contained two to six plasmid-mediated quinolone resistance genes with the predominance of qepA gene (89.66%). Mutations in the gyrA gene were detected at codon S83 (34.62%) or D87 (30.77%) or both (34.62%) in 89.66% of XDR Salmonella. The tet(A) and tet(X4) genes were detected in 100% and 3.45% of the XDR isolates, respectively. Twelve TIG-resistant XDR Salmonella had point mutations at codons 120, 121, and 181 in the tet(A) interdomain loop region. All CIP and TIG co-resistant XDR Salmonella overexpressed ramA gene; 17 (68%) out of them harbored 4-bp deletion in the ramR binding region (T-288/A-285). However, four CIP/TIG co-resistant isolates overexpressed the oqxB gene. In conclusion, the emergence of XDR S. enterica exhibiting CIP/TIG co-resistance in poultry and humans with no previous exposure to TIG warrants an urgent need to reduce the unnecessary antimicrobial use in poultry farms in Egypt.
Coordinated Regulation of Protoperithecium Development by MAP Kinases MAK-1 and MAK-2 in Neurospora crassa
Authors: Lan Nan , Ye Shuting , Hu Chengcheng , Chen Zhiling , Huang Jun , Xue Wei , Li Shaojie , Sun Xianyun
Published: December 2021

Mitogen-activated protein (MAP) kinase pathways function as signaling hubs that are integral for many essential cellular processes, including sexual development. The molecular mechanisms and cross-talk between PR and CWI MAP kinase pathways have been extensively studied during asexual development. However, if these can be extended to sexual development remains elusive. By analyzing genome-wide transcriptional responses to deletion of each of two MAP kinase coding genes mak-2 (PR-MAP kinase pathway) and mak-1 (CWI-MAP kinase pathway) in Neurospora crassa during protoperithecium formation, 430 genes co-regulated by the MAK-1 and MAK-2 proteins were found, functionally enriched at integral components of membrane and oxidoreductase. These genes include 13 functionally known genes participating in sexual development (app, poi-2, stk-17, fsd-1, vsd-8, and NCU03863) and melanin synthesis (per-1, pkh-1, pkh-2, mld-1, scy-1, trn-2, and trn-1), as well as a set of functionally unknown genes. Phenotypic analysis of deletion mutants for the functionally unknown genes revealed that 12 genes were essential for female fertility. Among them, single-gene deletion mutants for NCU07743 (named as pfd-1), NCU02250 (oli), and NCU05948 (named as pfd-2) displayed similar protoperithecium development defects as the Δmak-1 and Δmak-2 mutants, failing to form protoperithecium. Western blotting analysis showed that both phosphorylated and total MAK-1 proteins were virtually abolished in the Δnrc-1, Δmek-2, and Δmak-2 mutants, suggesting that the posttranscriptional regulation of MAK-1 is dependent on the PR-MAP kinase pathway during the protoperithecium development. Taken together, this study revealed the regulatory roles and cross-talk between PR and CWI-MAP kinase pathways during protoperithecium development.
Human and Animal RNA Virus Diversity Detected by Metagenomics in Cameroonian Clams
Authors: Bonny Patrice , Schaeffer Julien , Besnard Alban , Desdouits Marion , Ngang Jean Justin Essia , Le Guyader Françoise S.
Published: December 2021

Many recent pandemics have been recognized as zoonotic viral diseases. While their origins remain frequently unknown, environmental contamination may play an important role in emergence. Thus, being able to describe the viral diversity in environmental samples contributes to understand the key issues in zoonotic transmission. This work describes the use of a metagenomic approach to assess the diversity of eukaryotic RNA viruses in river clams and identify sequences from human or potentially zoonotic viruses. Clam samples collected over 2years were first screened for the presence of norovirus to verify human contamination. Selected samples were analyzed using metagenomics, including a capture of sequences from viral families infecting vertebrates (VirCapSeq-VERT) before Illumina NovaSeq sequencing. The bioinformatics analysis included pooling of data from triplicates, quality filtering, elimination of bacterial and host sequences, and a deduplication step before de novo assembly. After taxonomic assignment, the viral fraction represented 0.8–15% of reads with most sequences (68–87%) remaining un-assigned. Yet, several mammalian RNA viruses were identified. Contigs identified as belonging to the Astroviridae were the most abundant, with some nearly complete genomes of bastrovirus identified. Picobirnaviridae sequences were related to strains infecting bats, and few others to strains infecting humans or other hosts. Hepeviridae sequences were mostly related to strains detected in sponge samples but also strains from swine samples. For Caliciviridae and Picornaviridae, most of identified sequences were related to strains infecting bats, with few sequences close to human norovirus, picornavirus, and genogroup V hepatitis A virus. Despite a need to improve the sensitivity of our method, this study describes a large diversity of RNA virus sequences from clam samples. To describe all viral contaminants in this type of food, and being able to identify the host infected by viral sequences detected, may help to understand some zoonotic transmission events and alert health authorities of possible emergence.
Application of Stem Cell-Derived Extracellular Vesicles as an Innovative Theranostics in Microbial Diseases
Authors: Keshavarz Alikhani Hani , Shokoohian Bahare , Rezasoltani Sama , Hossein-khannazer Nikoo , Yadegar Abbas , Hassan Moustapha , Vosough Massoud
Published: December 2021

Extracellular vesicles (EVs), as nano-/micro-scale vehicles, are membranous particles containing various cargoes including peptides, proteins, different types of RNAs and other nucleic acids, and lipids. These vesicles are produced by all cell types, in which stem cells are a potent source for them. Stem cell-derived EVs could be promising platforms for treatment of infectious diseases and early diagnosis. Infectious diseases are responsible for more than 11 million deaths annually. Highly transmissible nature of some microbes, such as newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), drives researcher’s interest to set up different strategies to develop novel therapeutic strategies. Recently, EVs-based diagnostic and therapeutic approaches have been launched and gaining momentum very fast. The efficiency of stem cell-derived EVs on treatment of clinical complications of different viruses and bacteria, such as SARS-CoV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Staphylococcus aureus, Escherichia coli has been demonstrated. On the other hand, microbial pathogens are able to incorporate their components into their EVs. The microbe-derived EVs have different physiological and pathological impacts on the other organisms. In this review, we briefly discussed biogenesis and the fate of EVs. Then, EV-based therapy was described and recent developments in understanding the potential application of stem cell-derived EVs on pathogenic microorganisms were recapitulated. Furthermore, the mechanisms by which EVs were exploited to fight against infectious diseases were highlighted. Finally, the deriver challenges in translation of stem cell-derived EVs into the clinical arena were explored.
Functional Integrity of Executive Control Network Contributed to Retained Executive Abilities in Mild Cognitive Impairment
Authors: Liu Wan , Liu Li , Cheng Xinxin , Ge Honglin , Hu Guanjie , Xue Chen , Qi Wenzhang , Xu Wenwen , Chen Shanshan , Gao Run , Rao Jiang , Chen Jiu
Published: December 2021

Background: Mild cognitive impairment (MCI) is considered to be a transitional state between normal aging and Alzheimer's dementia (AD). Recent studies have indicated that executive function (EF) declines during MCI. However, only a limited number of studies have investigated the neural basis of EF deficits in MCI. Herein, we investigate the changes of regional brain spontaneous activity and functional connectivity (FC) of the executive control network (ECN) between high EF and low EF groups.

Methods: According to EF composite score (ADNI-EF) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we divided MCI into two groups, including the MCI-highEF group and MCI-lowEF group. Resting-state functional MRI was utilized to investigate the fractional amplitude of low-frequency fluctuation (fALFF) and ECN functional connectivity across 23 healthy controls (HC), 11 MCI-highEF, and 14 MCI-lowEF participants. Moreover, a partial correlation analysis was carried out to examine the relationship between altered fALFF or connectivity of the ECN and the ADNI-EF.

Results: Compared to HC, the MCI-highEF participants demonstrated increased fALFF in the left superior temporal gyrus (STG), as well as decreased fALFF in the right precentral gyrus, right postcentral gyrus, and left middle frontal gyrus (MFG). The MCI-lowEF participants demonstrated increased fALFF in the cerebellar vermis and decreased fALFF in the left MFG. Additionally, compared to HC, the MCI-highEF participants indicated no significant difference in connectivity of the ECN. Furthermore, the MCI-lowEF participants showed increased ECN FC in the left cuneus and left MFG, as well as decreased ECN functional connectivity in the right parahippocampal gyrus (PHG). Notably, the altered fALFF in the left MFG was positively correlated to ADNI-EF, while the altered fALFF in cerebellar vermis is negatively correlated with ADNI-EF across the two MCI groups and the HC group. Altered ECN functional connectivity in the right PHG is negatively correlated to ADNI-EF, while altered ECN functional connectivity in the left cuneus is negatively correlated to ADNI-EF across the three groups.

Conclusions: Our current study demonstrates the presence of different patterns of regional brain spontaneous activity and ECN FC in the MCI-highEF group and MCI-lowEF group. Furthermore, the ECN FC of the MCI-highEF group was not disrupted, which may contribute to retained EF in MCI.
Acupuncture Can Regulate the Distribution of Lymphocyte Subsets and the Levels of Inflammatory Cytokines in Patients With Mild to Moderate Vascular Dementia
Authors: Zhi Hui , Wang Yao , Chang Shichen , Pan Pan , Ling Zhenzhen , Zhang Zhen , Ma Zhinan , Wang Runmin , Zhang Xuezhu
Published: December 2021

Background: Vascular dementia (VD) is the second most common type of dementia after Alzheimer’s disease, but there is a lack of definitive treatment for VD. Acupuncture treatment is effective in improving the cognitive impairment and behavioral capacity of patients with VD. In recent years, more studies indicated that peripheral inflammation and abnormal peripheral immune function may aggravate neuroinflammation and cognitive dysfunction. However, there are few studies about the acupuncture and the abnormal peripheral immune function of VD. Also, few studies concern the regulating effect of acupuncture on peripheral immunity of patients with VD.

Objective: The aim of this study was to explore the effect of the “sanjiao” acupuncture method on peripheral immunity of patients with mild to moderate VD.

Methods: A total of 30 patients with VD were involved in the acupuncture group (AG), which was treated with the “sanjiao” acupuncture method once a day for six times a week and lasted for 12 weeks, and 30 healthy elderly people were assigned to the normal group (NG), which had no treatment. The distribution of lymphocyte subsets and the levels of some inflammatory cytokines in the peripheral blood of subjects were evaluated using the flow cytometry (FCM) and the enzyme-linked immunosorbent assay (ELISA).

Results: A total of 60 subjects were involved in this study, while 58 subjects completed the entire trial. Before treatment, the levels of CD3+ T, CD4+ T cells, CD4+/CD8+, Tregs, B cells, IFN-γ, and IL-10 in patients with VD were significantly decreased compared with the normal group (all P < 0.05 or P < 0.01). The level of TNF-α in peripheral blood of patients with VD was significantly increased (P < 0.01). After acupuncture treatment, the levels of CD3+ T, CD4+ T cells, and IFN-γ were significantly increased (all P < 0.05 or P < 0.01). The level of TNF-α was significantly decreased (P < 0.01). The proportion of Tregs was increased (P < 0.01), but it was still lower than that of the normal group (P < 0.05).

Conclusion: The acupuncture method can increase the proportion of CD3+, CD4+ T cells, and Tregs in peripheral blood of patients with VD. And, it reduces the levels of pro-inflammatory factor TNF-α, which achieves the anti-inflammatory effects and immunostimulation. It suggests that acupuncture can improve the peripheral immune dysfunction of patients with VD by regulating the distribution of lymphocyte subsets and the levels of inflammatory cytokines.

Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR-IOR-17012052].
Neural Substrates of Visual Perception and Working Memory: Two Sides of the Same Coin or Two Different Coins?
Authors: Roussy Megan , Mendoza-Halliday Diego , Martinez-Trujillo Julio C.
Published: December 2021

Visual perception occurs when a set of physical signals emanating from the environment enter the visual system and the brain interprets such signals as a percept. Visual working memory occurs when the brain produces and maintains a mental representation of a percept while the physical signals corresponding to that percept are not available. Early studies in humans and non-human primates demonstrated that lesions of the prefrontal cortex impair performance during visual working memory tasks but not during perceptual tasks. These studies attributed a fundamental role in working memory and a lesser role in visual perception to the prefrontal cortex. Indeed, single cell recording studies have found that neurons in the lateral prefrontal cortex of macaques encode working memory representations via persistent firing, validating the results of lesion studies. However, other studies have reported that neurons in some areas of the parietal and temporal lobe—classically associated with visual perception—similarly encode working memory representations via persistent firing. This prompted a line of enquiry about the role of the prefrontal and other associative cortices in working memory and perception. Here, we review evidence from single neuron studies in macaque monkeys examining working memory representations across different areas of the visual hierarchy and link them to studies examining the role of the same areas in visual perception. We conclude that neurons in early visual areas of both ventral (V1-V2-V4) and dorsal (V1-V3-MT) visual pathways of macaques mainly encode perceptual signals. On the other hand, areas downstream from V4 and MT contain subpopulations of neurons that encode both perceptual and/or working memory signals. Differences in cortical architecture (neuronal types, layer composition, and synaptic density and distribution) may be linked to the differential encoding of perceptual and working memory signals between early visual areas and higher association areas.