Search Results (424)

The mechanisms by which SARS-CoV-2 infection lead to neuroinflammation and cognitive impairment in COVID-19 and Long COVID are unclear. Cerebrovascular Wnt/β-catenin pathway activity is suppressed in association with neuroinflammation and cognitive impairment in a mouse model of COVID-19. In this study, we asked whether SARS-CoV-2 (NY Iota strain) infection of astrocytes would result in cell-autonomous changes in Wnt/β-catenin pathway components. We report that induced pluripotent stem cell (hiPSC)-derived human astrocytes (iAs) are susceptible to sustained infection with SARS-CoV-2 in vitro. Real-time PCR revealed that SARS-CoV-2 infection of iAs decreased transcripts for Wnt3a, Wnt10b, and the downstream pathway effectors β-catenin and TCF3. Wnt7b was increased, as was the proinflammatory chemokine CXCL10. No changes were noted in Wnt3, Wnt7a, TCF1, TCF4, or LEF1. These data indicate that SARS-CoV-2 infection differentially influences Wnt/β-catenin pathway components in astrocytes. These data could have implications for the mechanistic basis of COVID-19 and Long COVID. Full article

Background/Objectives: Type 2 diabetes (T2D) is a clinically and genetically heterogeneous disease. In this study, we aimed to stratify patients with T2D from the Volga-Ural region of Eurasia into distinct subgroups based on clinical characteristics and to investigate the genetic underpinnings of these clusters. Methods: A total of 254 Tatar individuals with T2D and 361 ethnically matched controls were recruited. Clinical clustering was performed using k-means and hierarchical algorithms on five variables: age at diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), and β-cell function (HOMA-B). Genetic association analysis was conducted using logistic regression under an additive model, adjusted for age and sex, and corrected for multiple comparisons using the Benjamini–Hochberg method. Results: Four distinct T2D subtypes were identified—mild age-related diabetes (MARD, n = 25), mild obesity-related diabetes (MOD, n = 72), severe insulin-resistant diabetes (SIRD, n = 66), and severe insulin-deficient diabetes (SIDD, n = 52)—each with unique clinical and comorbidity profiles. SIDD patients exhibited the highest burden of microvascular complications and lowest estimated glomerular filtration rate. Nine genetic variants showed significant associations with T2D and/or specific subtypes, including loci in genes related to neurotransmission (e.g., HTR1B, CHRM5), appetite regulation (NPY2R), insulin signaling (TCF7L2, PTEN), and other metabolic pathways. Some variants demonstrated subtype-specific associations, underscoring the genetic heterogeneity of T2D. Conclusions: Our findings support the utility of clinical clustering in uncovering biologically and clinically meaningful T2D subtypes and reveal genetic variants that may contribute to this heterogeneity. These insights may inform future precision medicine approaches for T2D diagnosis and management. Full article

Colorectal cancer (CRC) remains a major global challenge, with growing attention to its pathogenesis as mediated by the gut microbiome and epigenetic regulation. Despite therapeutic progress, clinical management remains difficult. CRC accounts for ~10% of cancers and is the second leading cause of cancer death worldwide. Romania bears a substantial burden, with many diagnoses at advanced stages. Etiology—Integrated Genetic, Environmental, and Microbial Determinants. Hereditary syndromes explain 10–15% of cases; most are sporadic, with hypermutated MSI/POLE (~15%), non-hypermutated chromosomal instability (~85%), and a CpG island methylator phenotype (~20%). GWAS implicate loci near SMAD7, TCF7L2, and CDH1; in Romania, SMAD7 rs4939827 associates with risk. Lifestyle exposures—high red/processed meat, low fiber, adiposity, alcohol, and smoking—shape susceptibility. Microbiome–Epigenome Interactions. Dysbiosis promotes carcinogenesis via genotoxins (e.g., colibactin), hydrogen sulfide, activation of NF-κB/STAT3, barrier disruption, and epigenetic remodeling of DNA methylation and microRNAs. Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks⁺ Escherichia coli exemplifies these links. Population-Specific Risk—Romania within Lifestyle–Microbiome Evidence. Incidence is rising, including early-onset disease. Romania lacks CRC-specific microbiome datasets. However, metabolic cohorts show loss of butyrate producers, enrichment of pathobionts, and SCFA imbalance—patterns that mirror European CRC cohorts—and exhibit regional heterogeneity. Beyond Fusobacterium nucleatum. Additional oncobacteria shape tumor biology. Peptostreptococcus stomatis activates integrin α6/β4→ERBB2–MAPK and can bypass targeted inhibitors, while Parvimonas micra enhances WNT/β-catenin programs and Th17-skewed immunity. Together, these data support a systems view in which microbial cues and host epigenetic control jointly drive CRC initiation, progression, metastasis, and treatment response. Full article

Introduction: Recent randomized evidence suggests that stage II–IV non metastatic esophageal adenocarcinoma is best managed with perioperative chemotherapy (CHT) and surgery. Intensification of neoadjuvant chemotherapy and radiochemotherapy are proposed before surgery in high-volume centers with the aim of increasing both systemic and locoregional control. However, few data comparing intensified RTCHT, CHT plus RTCHT and perioperative CHT with FLOT in real-life scenarios are available. Methods: This is a multicenter, retrospective series, including three cohorts of patients treated for esophageal adenocarcinoma: Cohort A: nRTCHT; Cohort B: TCF plus RTCHT, defined as triplet chemotherapy followed by dose-reduced triplet therapy + RT; Cohort C: perioperative chemotherapy with FLOT regimen. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were pathologic complete response (pCR), pathologic lymph-node complete response (ypN0), overall survival (OS), and perioperative acute toxicity. Results: From January 2013 to December 2023, 142 patients were identified. All patients received multimodal therapy with radical esophagectomy. A total of 95% of patients were male; the majority of patients presented with stage cT3cN1. A total of 63 patients were treated in Cohort A (31 cases with doublet 5FU-CDDP concurrent to 50.4 Gy and 32 cases with CROSS regimen), 36 in Cohort B, and 43 in Cohort C. After a median FU of 36 months, the 3-year DFS resulted 58.6%. pCR occurred in 26 cases (18.6%). Three-year OS had a value of 72%. At univariate analysis, ypN0 was related to better DFS; cN+ disease was related with worse OS. The treatment cohort did not impact survival outcomes; however, an effect on CR was shown, with pCR in 15% (A), 36.3% (B), 11% (C) of cases, respectively (χ: 0.008). A total of 67% of patients in Cohort B experienced a ypN0. Two treatment-related deaths occurred (one in Cohort A and one in C) with a slight increase in G3 toxicity in cohort C. Conclusions: In this real-life multicenter series, oncological results were adequate for all three neoadjuvant strategies. TCF plus RTCHT guaranteed a higher pCR and ypN0 rate without increasing toxicity. An intensified neoadjuvant schedule, such as TCF plus RTCHT, may be useful in cases where higher tumor and nodal responses are needed. Taken together, our data highlight that further investigation is warranted before abandoning radiotherapy-based neoadjuvant approaches in esophageal and GEJ adenocarcinoma. Full article

The expression of the Secreted Protein, Acidic and Rich in Cysteine (SPARC) gene in human melanoma increases during progression and is associated with epithelial-to-mesenchymal transition (EMT), which is a major determinant of metastasis in melanoma patients. However, the underlying molecular mechanisms that control SPARC expression in this context remain elusive. Herein, we identified Paired-related homeobox 1 (PRRX1), an EMT transcription factor, as a transcriptional activator of SPARC by direct binding to the promoter, thereby increasing its activity. Moreover, we found a strong positive correlation between SPARC and PRRX1 expression levels in clinical samples and cell lines. Furthermore, the switch from the proliferative/melanocytic phenotype toward the invasive/mesenchymal-like phenotype favors the expression of TCF7L2, a β-catenin cofactor, which, together with Sp1, binds to the proximal SPARC promoter, thereby bolstering protein expression. We also show that SPARC is a target of the miR-29 family, whose members are expressed in clinical melanoma samples and cell lines. Indeed, we found that miR-29b1~a expression is inversely correlated with SPARC levels, and it is significantly reduced in samples with a mesenchymal-like phenotype. Taken together, SPARC expression in melanoma cells relies on transcriptional activation by PRRX1/TCF7L2-Sp1 and is modulated through miR-29b1~a, which provides fine-tuning regulation over the switch between phenotypic states. Full article

Cold stress severely limits legume productivity, threatening global food security, particularly in climate-vulnerable regions. This review synthesizes advances in understanding and enhancing cold tolerance in key legumes (chickpea, soybean, lentil, and cowpea), addressing three core questions: (1) molecular/physiological foundations of cold tolerance; (2) how emerging technologies accelerate stress dissection and breeding; and (3) integration strategies and deployment challenges. Legume cold tolerance involves conserved pathways (e.g., ICE-CBF-COR, Inducer of CBF Expression, C-repeat Binding Factor, Cold-Responsive genes) and species-specific mechanisms like soybean’s GmTCF1a-mediated pathway. Multi-omics have identified critical genes (e.g., CaDREB1E in chickpea, NFR5 in pea) underlying adaptive traits (membrane stabilization, osmolyte accumulation) that reduce yield losses by 30–50% in tolerant genotypes. Technologically, AI and high-throughput phenotyping achieve >95% accuracy in early cold detection (3–7 days pre-symptoms) via hyperspectral/thermal imaging; deep learning (e.g., CNN-LSTM hybrids) improves trait prediction by 23% over linear models. Genomic selection cuts breeding cycles by 30–50% (to 3–5 years) using GEBVs (Genomic estimated breeding values) from hundreds of thousands of SNPs (Single-nucleotide polymorphisms). Advanced sensors (LIG-based, LoRaWAN) enable real-time monitoring (±0.1 °C precision, <30 s response), supporting precision irrigation that saves 15–40% water while maintaining yields. Key barriers include multi-omics data standardization and cost constraints in resource-limited regions. Integrating molecular insights with AI-driven phenomics and multi-omics is revolutionizing cold-tolerance breeding, accelerating climate-resilient variety development, and offering a blueprint for sustainable agricultural adaptation. Full article

Background: Metabolic diseases, like type 2 diabetes mellitus and obesity, show a growing public health concern in Sri Lanka. Genetic predisposition and diet contribute to metabolic disease risk, but there are limited investigations into the impact of gene–diet interactions on metabolic disease risk in the Sri Lankan population. In this study, we examined whether a metabolic genetic risk score (GRS), constructed from 10 single nucleotide polymorphisms (SNPs), interacts with dietary factors to influence metabolic health indicators in Sri Lankan adults. Methods: This cross-sectional study included 105 generally healthy adults aged 25–50 years from the GOOD (Genetics of Obesity and Diabetes) study. Anthropometric, biochemical, and dietary data using food frequency questionnaires were collected using validated methods. Genotyping was performed using the KASP^® assay. The unweighted GRS was calculated by summing risk alleles across 10 SNPs in the TCF7L2, CAPN10, FTO KCNJ11, and MC4R genes. Gene–diet interaction analysis was conducted using regression models adjusted for confounders. Results: A statistically significant interaction was identified between the 10-SNP metabolic GRS and polyunsaturated fatty acid (PUFA) intake on waist circumference (P_{(interaction)} = 0.00009). Participants with a high GRS (≥6 risk alleles) and higher PUFA intake (≥3.1 g/day) exhibited significantly lower waist circumference (p = 0.047). Conclusions: This study provides novel insights to understand gene–diet interactions affecting metabolic traits in Sri Lankans. The findings suggest that higher PUFA intake may mitigate genetic susceptibility to central obesity, highlighting the importance of personalized dietary recommendations for metabolic disease prevention. Further studies in larger cohorts are warranted to confirm this finding. Full article

Background: Increased hip-flexion gait (HFgait) has been shown to promote increased aerobic demands by increasing peak swing-phase hip-flexion angles while walking at comfortable speeds. Biomechanically, HFgait produces a gait pattern similar to walking, while removing the flight phase from running and reducing tibial accelerations. We sought to identify knee joint contact forces between HFgait and common exercise modalities, including running, walking, and cycling, across intensity levels. Methods: Ten healthy participants completed two bouts (low and high intensity) of four different exercises: treadmill running, walking, HFgait, and cycling. Tibiofemoral joint compressive force (TCF) was estimated using a static optimization-based approach. Results: Peak TCF was greater in running compared to HFgait, walking, and cycling; greater in HFgait compared to cycling; and greater in walking compared to cycling. The integral of TCF (iTCF) was greater in running compared to cycling, greater in HFgait compared to running, walking, and cycling, and greater in walking compared to running and cycling. Conclusions: HFgait produced lower knee joint loading than running, comparable joint loading to walking, and greater joint loading than cycling. Thus, HFgait may serve as an exercise modality for populations where joint loading is of particular concern, while achieving aerobic demands similar to running or increased functional demands compared to stationary cycling. Full article

Acute lymphoblastic leukemia (ALL) represents the most common type of cancer in the pediatric population. The (1;19)(q23;p13) translocation is a primary chromosomal abnormality present in 3–12% of ALL cases. The current study aims to develop a label-free innovative nanodevice for the ultrasensitive diagnosis of the TCF3-PBX1 chimeric oncogene, featuring simplified operation and rapid analysis using minimal sample volumes, which positions it as a superior alternative for clinical diagnostics and early leukemia identification. The biosensor system was engineered on a nanostructured platform composed of polypyrrole (PPy) and a novel chemically functionalized hybrid nanocomposite of platinum nanospheres and titanium dioxide nanoparticles (TiO₂@Pt). Single-stranded oligonucleotide sequences were chemically immobilized on the nanoengineered transducer to enable biospecific detection. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), ultraviolet-visible spectroscopy (UV-Vis), and atomic force microscopy (AFM) were used to characterize each stage of the biotechnological device fabrication process. The analytical properties of the sensing tool were explored using recombinant plasmids containing the TCF3-PBX1 oncogenic sequence and clinical specimens from pediatric patients with B-cell ALL. After exposing the molecular monitoring system to the genetic target, significant variations were observed in the voltammetric oxidation current (∆I = 33.08% ± 0.28 to 124.91% ± 17.08) and in the resistance to charge transfer (ΔR_CT = 19.73% ± 0.96 to 83.51% ± 0.84). Data analysis revealed high reproducibility, with a relative standard deviation of 3.66%, a response range from 3.58 aM to 357.67 fM, a detection limit of 19.31 aM, and a limit of quantification of 64.39 aM. Therefore, a novel nanosensor for multiparametric electrochemical screening of the TCF3-PBX1 chimeric oncogene was described for the first time, potentially improving the quality of life for leukemic patients. Full article

Background/Objectives: The transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism has been strongly associated with type 2 diabetes mellitus (T2DM) in various populations; however, its impact on different ethnic groups is not fully understood. Given the distinct minor allele frequency in Chinese populations, this study aimed to analyze the association of rs7903146 with the risk of T2DM in a Han Chinese cohort and its relationship with relevant clinical parameters. Methods: We conducted a case–control study including 600 patients with type 2 diabetes mellitus (T2DM) and 511 sex-matched non-diabetic controls of Han Chinese descent. The TCF7L2 rs7903146 (C/T) polymorphism was genotyped using a TaqMan™ SNP assay. Clinical parameters, including body mass index (BMI), fasting plasma glucose, hemoglobin A1c, lipid profile, and high-sensitivity C-reactive protein (hs-CRP), were compared between genotypes. Logistic regression analyses were performed under a dominant genetic model (CT/TT vs. CC), adjusting for age, sex, systolic and diastolic blood pressure, BMI, and smoking status. Subgroup analyses were conducted by sex, BMI category, age at diagnosis, and family history of T2DM. Given the exploratory nature of this study and the low frequency of the TT genotype, no formal correction for multiple testing was applied. Results: Frequencies of the CT and TT genotypes were higher in the diabetic group (p = 0.045) and were significantly associated with an increased risk of T2DM under a dominant genetic model (adjusted OR = 2.24, p = 0.025). Individuals with CT/TT genotypes had elevated fasting glucose and hs-CRP levels; these genotypes were also linked to higher BMI in the female T2DM patients. The T allele frequency varied across ethnic groups, being lowest in East Asians and highest in Latin (Brazilian/mixed ancestry) populations. Mechanistically, the T allele may contribute to T2DM via altered TCF7L2 expression, impaired insulin secretion, inflammation, and metabolic dysregulation. Conclusions: The TCF7L2 rs7903146 T allele was associated with an increased risk of T2DM and higher fasting glucose and hs-CRP levels in this Han Chinese cohort. The CT/TT genotypes were also associated with higher BMI in the female T2DM patients. While the findings are consistent with the known effects of this variant in other populations, mechanistic hypotheses such as the involvement of inflammatory or metabolic pathways remain hypothetical and warrant further functional validation. Full article

This study examines the impact of overall Environmental, Social, and Governance (ESG) performance and its pillars on the default probability of Australian-listed firms. Using a panel dataset spanning 2014 to 2022 and applying the Generalized Method of Moments (GMM) regression, we find that firms with higher ESG scores exhibit a significantly lower likelihood of default. Disaggregating the ESG components reveals that the Environmental and Social pillars have a negative association with default risk, suggesting a risk-mitigating effect. In contrast, the Governance pillar demonstrates a positive relationship with default probability, which may reflect potential greenwashing behavior or an excessive focus on formal governance mechanisms at the expense of operational and financial performance. Furthermore, the analysis identifies trade credit financing (TCF) as a partial mediator in the ESG–default risk nexus, indicating that firms with stronger ESG profiles rely less on external short-term financing, thereby reducing their default risk. These findings provide valuable insights for corporate management, investors, regulators, and policymakers seeking to enhance financial resilience through sustainable practices. Full article

Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related prognostic model—termed the AS score—using data from two independent sarcoma cohorts. Methods: A prognostic model was developed using a previously characterized cohort of 25 angiosarcoma samples. Candidate genes were identified via the Maxstat algorithm (Maxstat v0.7-25 for R), combined with log-rank testing. The AS score was then computed by weighing normalized gene expression levels according to Cox regression coefficients. For external validation, transcriptomic data from TCGA Sarcoma cohort (n = 253) were analyzed. The Immunoscore—which reflects the tumor immune microenvironment—was inferred using the ESTIMATE package (v1.0.13) in R. All statistical analyses were performed in RStudio (v 4.0.3). Results: Four genes—IGF1R, MAP2K1, SERPINE1, and TCF12—were ultimately selected to construct the prognostic model. The resulting AS score enabled the classification of angiosarcoma cases into two prognostically distinct groups (p = 0.00012). Cases with high AS score values, which included both cutaneous and non-cutaneous forms, exhibited significantly poorer outcomes, whereas cases with low AS scores were predominantly cutaneous. A significant association was observed between the AS score and the Immunoscore (p = 0.025), with higher Immunoscore values found in high-AS score tumors. Validation using TCGA sarcoma cohort confirmed the prognostic value of both the AS score (p = 0.0066) and the Immunoscore (p = 0.0029), with a strong correlation between their continuous values (p = 2.9 × 10⁻⁸). Further survival analysis, integrating categorized scores into four groups, demonstrated robust prognostic significance (p = 0.00021). Notably, in tumors with a low Immunoscore, AS score stratification was not prognostic. In contrast, among cases with a high Immunoscore, the AS score effectively distinguished outcomes (p < 0.0001), identifying a subgroup with poor prognosis but potential sensitivity to immunotherapy. Conclusions: This combined classification using the AS score and Immunoscore has prognostic relevance in sarcoma, suggesting that angiosarcomas with an immunologically active microenvironment (high Immunoscore) and poor prognosis (high AS score) may be prime candidates for immunotherapy and this approach warrants prospective validation. Full article

Background: Glioblastoma (GBM) is one of the most challenging malignancies in all of neoplasms. These malignancies are associated with unfavorable clinical outcomes and significantly compromised patient wellbeing. The immunological landscape within the tumor microenvironment (TME) plays a critical role in determining GBM prognosis. By mining data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and correlating them with immune responses in the TME, genes associated with the immune microenvironment with potential prognostic value were obtained. Method: We selected GSE16011 as the training set. Gene expression profiles were substrates scored by both ESTIMATE and xCell, and immune cell subpopulations in GBM were analyzed by CIBERSORT. Gene expression profiles associated with low immune scores were performed by lasso regression, Cox analysis and random forest (RF) to identify a prognostic model for the multiple genes associated with immune infiltration in GBM. Then we constructed a nomogram to optimize the prognostic model using GSE7696 and TCGA-GBM as validation sets and evaluated these data for gene mutation and gene enrichment analysis. Result: The prognostic correlation between the six genes (MEOX2, PHYHIP, RBBP8, ST18, TCF12, and THRB) and GBM was finally found by lasso regression, Cox regression, and RF, and the online database obtained that all six genes were differentially expressed in GBM. Therefore, a prognostic correlation model was constructed based on the six genes. Kaplan–Meier (KM) survival analysis showed that this prognostic model had excellent prognostic ability. Conclusions: Prognostic models based on tumor microenvironment and immune score stratification and the construction of related genes have potential applications for prognostic analysis of GBM patients. Full article

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine. Full article

The flexible transparent conductive films (TCFs) of a ZnS/Cu/Ag/TiO₂ multilayered structure were deposited on a flexible PET substrate with high surface roughness using magnetic sputtering, and the effects of structural characteristics on the performance of the films were analyzed. The TCFs with TiO₂/Cu/Ag/TiO₂ and ZnS/Cu/Ag/ZnS symmetric structures were also prepared for comparison. The TCF samples were deposited using ZnS, TiO₂, Cu and Ag targets, and they were analyzed using scanning electronic microscopy, atomic force microscopy, grazing incidence X-ray diffraction, spectrophotometry and a four-probe tester. The TCFs exhibit generally uniform surface morphology, excellent light transmittance and electrical conductivity with optimized structure. The optimal values are 84.40%, 5.52 Ω/sq and 33.19 × 10⁻³ Ω⁻¹ for the transmittance, sheet resistance and figure of merit, respectively, in the visible spectrum. The satisfactory properties of the asymmetric multilayered TCF deposited on a rough-surface substrate should be mainly attributed to the optimized structure parameters and reasonable interfacial compatibilities. Full article