Search Results (48)

The human genome has a profound impact on human health and disease detection. Carcinoma (cancer) is one of the prominent diseases that majorly affect human health and requires the development of different treatment strategies and targeted therapies based on effective disease detection. Therefore, our research aims to identify biomarkers associated with distinct cancer types (gastric, lung, and breast) using machine learning. In the current study, we have analyzed the human genomic data of gastric cancer, breast cancer, and lung cancer patients using XGB-BIF (i.e., XGBoost-Driven Biomarker Identification Framework for detecting cancer). The proposed framework utilizes feature selection via XGBoost (eXtreme Gradient Boosting), which captures feature interactions efficiently and takes care of the non-linear effects in the genomic data. The research progressed by training XGBoost on the full dataset, ranking the features based on the Gain measure (importance), followed by the classification phase, which employed support vector machines (SVM), logistic regression (LR), and random forest (RF) models for classifying cancer-diseased and non-diseased states. To ensure interpretability and transparency, we also applied SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME), enabling the identification of high-impact biomarkers contributing to risk stratification. Biomarker significance is discussed primarily via pathway enrichment and by studying survival analysis (Kaplan–Meier curves, Cox regression) for identified biomarkers to strengthen translational value. Our models achieved high predictive performance, with an accuracy of more than 90%, to classify and link genomic data into diseased (cancer) and non-diseased states. Furthermore, we evaluated the models using Cohen’s Kappa statistic, which confirmed strong agreement between predicted and actual risk categories, with Kappa scores ranging from 0.80 to 0.99. Our proposed framework also achieved strong predictions on the METABRIC dataset during external validation, attaining an AUC-ROC of 93%, accuracy of 0.79%, and Kappa of 74%. Through extensive experimentation, XGB-BIF identified the top biomarker genes for different cancer datasets (gastric, lung, and breast). CBX2, CLDN1, SDC2, PGF, FOXS1, ADAMTS18, POLR1B, and PYCR3 were identified as important biomarkers to identify diseased and non-diseased states of gastric cancer; CAVIN2, ADAMTS5, SCARA5, CD300LG, and GIPC2 were identified as important biomarkers for breast cancer; and CLDN18, MYBL2, ASPA, AQP4, FOLR1, and SLC39A8 were identified as important biomarkers for lung cancer. XGB-BIF could be utilized for identifying biomarkers of different cancer types using genetic data, which can further help clinicians in developing targeted therapies for cancer patients. Full article

The construction industry is a major contributor to global carbon emissions, driving the need for sustainable solutions. Ultra-lightweight structures have emerged as an effective approach to reducing material usage and energy consumption. This study explores the potential of ultra-lightweight architectural systems through a learning-by-doing methodology, integrating innovative composite materials, PolRe, and knitting techniques to enhance tensegrity structures for sustainable, deployable, and efficient structural designs. Combining physical modeling, inspired by Frei Otto and Heinz Isler, with digital simulations using Kangaroo 2 and Python, this research employs form-finding and finite element analysis to validate structural performance. A 1:5 scale prototype was constructed using a manual knitting machine adapted from traditional knitting techniques. The integration of elastic meshes and rigid joints produced modular tensegrity systems that balance tension and compression, creating reversible, deployable, and material-efficient solutions. This study bridges conceptual aesthetics with structural efficiency, providing a template for sustainable, ultra-lightweight, textile-based structures. Full article

Background/Objectives: Diabetes mellitus is one of the most common chronic diseases worldwide. In addition to short-term and long-term complications, diabetes has a detrimental effect on the patients’ mood. The main psychiatric disorder occurring among diabetic patients is depression. The rates of depression in the developed and developing countries are 15% and 11%, respectively. This study aimed to determine the prevalence of depressive symptoms among patients with type 1 and type 2 diabetes and prediabetes in Poland using the example of the Podlaskie Province and taking into account selected sociodemographic variables. Methods: A total of 874 patients participated in the study, including 448 women (55.8%) and 386 men (44.2%). The study was conducted from July 2022 to July 2023 among the participants of the “Zatrzymaj cukrzycę! Polski Rejestr Diabetologiczny PolRed” (“Stop Diabetes! Polish Diabetes Registry (PolRed)”) project or those hospitalised in the Department of Endocrinology, Diabetology and Internal Medicine at the University Clinical Hospital in Bialystok. The study used a diagnostic survey method using a survey questionnaire developed by the authors and the Beck Depression Inventory (BDI). Results: The highest severity of depressive symptoms according to the Beck Depression Inventory was found in patients with type 2 diabetes (M = 12.18; SD ± 9.48) and the lowest in those with type 1 diabetes (M = 8.11; SD ± 7.55). The assessment of the differences in the severity of depressive symptoms according to the Beck Depression Inventory showed that participants with type 1 diabetes differed statistically significantly (p < 0.001) from those with type 2 diabetes and from those in a prediabetic state. In the group of type 2 diabetes (r = 0.336; p < 0.001) patients and prediabetic state patients (r = 0.231; p < 0.01), there were positive correlations of age with the severity of depressive symptoms. In the group of participants with type 2 diabetes, a statistically significant relationship (p < 0.001) was observed between age and the severity of depressive symptoms. Conclusions: The prevalence of mood disorders in patients with type 1 and type 2 diabetes and diagnosed prediabetes from the Podlaskie Province depends on the type of hyperglycaemic disorder. The prevalence of depressive symptoms among patients with type 1 and type 2 diabetes and prediabetes is determined by specific socio-demographic factors, including, above all, age and gender. The highest severity of a disturbed emotional state according to the Beck Depression Inventory is found in individuals with type 2 diabetes and the lowest in those with type 1 diabetes. Full article

Background: Diabetes mellitus is one of the greatest public health challenges worldwide and one of the major conditions contributing to a poorer quality of life. The main factors that may deteriorate quality of life among patients with diabetes include age, financial status, educational background, quality of healthcare services and presence of disease complications. This study aimed to assess the quality of life among patients with type 1 and type 2 diabetes and prediabetes in Poland using the example of the Podlaskie Province, taking into account selected sociodemographic variables. Methods: A total of 874 patients participated in the study, including 448 women (55.8%) and 386 men (44.2%). The study was conducted from July 2022 to July 2023 among participants of the “Zatrzymaj cukrzycę! Polski Rejestr Diabetologiczny PolReD” (“Stop Diabetes! Polish Diabetes Registry (PolRed)”) project or those hospitalised in the Department of Endocrinology, Diabetology and Internal Medicine at the University Clinical Hospital in Bialystok. The study used a diagnostic survey method using a survey questionnaire developed by the authors and the 36-Item Short Form Survey (SF-36). Results: The overall study group had the highest level of quality of life assessment in the domains of social functioning (M = 69.48; SD ± 28.07), physical functioning (M = 64.54; SD ± 31.57) and role limitations due to emotional problems (M = 62.40; SD ± 45.21), and the lowest level of quality of life in the domain of general health perceptions (M = 42.21; SD ± 12.77). Age was found to be negatively correlated in all quality of life domains analysed (r = −0.438; p < 0.001)—quality of life decreased with age in all investigated domains. Men had a statistically significantly (p < 0.05) higher quality of life in each analysed domain (M = 43.52–74.08; SD ± 12.68–44.09) compared to women (M = 41.18–65.88; SD ± 12.76–46.08). Place of residence also exhibited a statistically significant (p < 0.05) differentiated quality of life in terms of physical functioning. Conclusions: The assessment of quality of life among patients with type 1 and type 2 diabetes and those diagnosed with prediabetes from the Podlaskie Province depends on the type of hyperglycaemic disorder. The assessment of quality of life among patients with type 1 and type 2 diabetes and prediabetes is determined by specific socio-demographic factors, including, above all, age and gender. Respondents with type 1 diabetes have a higher quality of life in terms of role limitations due to physical health, role limitations due to emotional problems, pain (bodily pain) and general health compared to respondents with type 2 diabetes. Full article

High temperatures present considerable challenges to global fish growth and production, yet the genetic basis of heat tolerance remains underexplored. This study combines quantitative trait locus (QTL) mapping and genome-wide association studies (GWAS) to examine the genetics of heat tolerance in Larimichthys polyactis. As a result, a genetic linkage map was constructed with 3237 bin markers spanning 24 linkage groups and totaling 1900.84 centimorgans, using genotyping-by-sequencing of a full-sib family comprising 120 progeny and their two parents. Based on this genetic linkage map, QTL mapping identified four QTLs associated with heat tolerance, which encompassed 18 single nucleotide polymorphisms and harbored 648 genes within the QTL intervals. The GWAS further disclosed 76 candidate genes related to heat tolerance, 56 of which overlapped with the QTL results. Enrichment analysis indicated that these genes are involved in immune response, development, lipid metabolism, and endocrine regulation. qPCR validation of 14 prioritized genes, which were simultaneously enriched in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways, confirmed significant upregulation of smpd5, polr3d, rab11fip2, and gfpt1, along with downregulation of gpat4 and grk5 after 6 h of heat stress. These findings demonstrate their responsiveness to elevated high temperatures. This meta-analysis of QTL mapping and GWAS has successfully identified functional genes related to heat tolerance, enhancing understanding of the genetic architecture underlying this critical trait in L. polyactis. It also provides a molecular breeding tool to improve genetic traits associated with heat tolerance in cultured L. polyactis. Full article

Background: Eukaryotic RNA polymerase I consists of 12 or 11 core subunits and three dissociable subunits, Rrn3, A34, and A49. The A34 and A49 subunits exist as a heterodimer. In silico analysis of the A34 family of transcription factors demonstrates a commonly shared domain structure despite a lack of sequence conservation, as well as N–terminal and C-terminal disordered regions. The common structure of A34 has an N–terminal disordered region followed by a dimerization domain that, in conjunction with A49, contributes to a fold that resembles the TFIIF core. This in turn is followed by a short region that cryo-EM demonstrates resembles an arm and intimately interacts with the PolR1A, PolR1B, and PolR1C subunits of Pol I. Analyses: This Pol I–binding domain is then followed by a region that is not resolved in cryo-EM and is predicted to be intrinsically disordered. Interestingly, the size/length of this disordered structure increases from yeast to humans, and is composed of repeats with unique sequence and biochemical features that also increase in number. Further analyses of the A34 CTD (carboxy–terminal domain) indicate that it has a high probability of undergoing liquid–liquid phase separation. Conclusions: We suggest that this intrinsically disordered domain found in the A34 family of Pol I transcription factors serves a function similar to the CTD of the PolR2A subunit in coordinating transcription initiation and elongation and RNA processing. Lastly, we propose that dynamic acetylation of PAF49 may regulate interactions of the intrinsically disordered CTD and thereby specify liquid–liquid phase separations. Overall, we propose a new paradigm for a repeat-containing CTD in Pol I transcription. Full article

Small nucleolar RNAs (snoRNAs) are non-coding RNAs (ncRNAs) that regulate many cellular processes. Changes in the profiles of cellular ncRNAs and those secreted in exosomes are observed during viral infection. In our study, we analysed differences in expression profiles of snoRNAs isolated from exosomes of influenza (IAV)-infected and non-infected MDCK cells using high-throughput sequencing. The analysis revealed 133 significantly differentially regulated snoRNAs (131 upregulated and 2 downregulated), including 93 SNORD, 38 SNORA, and 2 SCARNA. The most upregulated was SNORD58 (log2FoldChange = 9.61), while the only downregulated snoRNAs were SNORD3 (log2FC = −2.98) and SNORA74 (log2FC = −2.67). Several snoRNAs previously described as involved in viral infections were upregulated, including SNORD27, SNORD28, SNORD29, SNORD58, and SNORD44. In total, 533 interactors of dysregulated snoRNAs were identified using the RNAinter database with an assigned confidence score ≥ 0.25. The main groups of predicted interactors were transcription factors (TFs, 169 interactors) and RNA-binding proteins (RBPs, 130 interactors). Among the most important were pioneer TFs such as POU5F1, SOX2, CEBPB, and MYC, while in the RBP category, notable interactors included Polr2a, TNRC6A, IGF2BP3, and FMRP. Our results suggest that snoRNAs are involved in pro-viral activity, although follow-up studies including experimental validation would be beneficial. Full article

In Indonesia, one of the main causes of death for both young and elderly people is heart attacks, and the main cause of heart attacks is non-communicable diseases such as hypertension. Deaths due to heart attacks caused by non-communicable diseases, namely hypertension, rank first in Indonesia. Therefore, predictions of the risk of having a heart attack caused by hypertension need serious attention. Further, for determining whether a patient is experiencing a heart attack, an effective method of prediction is required. One efficient approach is to use statistical models. This study discusses predicting risk of heart attack via modeling and classifying hypertension risk based on factors that influence it, namely, age, cholesterol levels, and triglyceride levels by using the spline estimator of the Nonparametric Ordinal Logistic Regression (NOLR) model. In this study, we assume an ordinal scale response variable with q categories to have an asymmetric distribution, namely, a multinomial distribution. The data used in this study are secondary data from medical records of cardiac poly patients at the Haji General Hospital in Surabaya, Indonesia. The results show that the proposed model approach has the greatest classification accuracy and sensitivity values compared to NOLR model approach using GAM, and the classical model approach, namely the Parametric Ordinal Logistic Regression (POLR) model. This means that the NOLR model approach is suitable for predicting hypertension and heart attack risks. Also, the NOLR model estimated using the LS-Spline estimator obtained is valid for predicting the risk of heart attack with accuracy value of 85% and sensitivity value of 100%. Full article

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder with variable penetrance and high genetic and phenotypic heterogeneity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, and POLR1B genes, and its major characteristic features are malar and mandibular hypoplasia, downward slanting of the palpebral fissures, and conductive hearing loss. In this study, five patients (two males and three females, age range from 2 to 29 years) with TCS were tested by Next-Generation Sequencing (NGS)-based sequencing and clinically characterized. Genetic analyses detected two deletions and one insertion in the TCOF1 gene and one missense variant in the POLR1D gene. Two novel mutations, c.1371_1372insT (p.Lys458*) in the TCOF1 gene and c.295 G>C (p.Gly99Arg) in the POLR1D gene, were identified. Moreover, two already known mutations, c.4369_4373del (p.Lys1457Glufs*12) and c.2103_2106del (p.Ser701Argfs*9) in the TCOF1 gene, were detected. The novel TCOF1 c.1371_1372insT mutation was associated with mild craniofacial manifestations and very rare symptoms of TCS, i.e., developmental delay and moderate intellectual disability. Although incomplete penetrance is a known phenomenon in TCS, surprisingly, the majority of our patients inherited the disease-causing variants from an asymptomatic mother. The unique feature of our study is the observation of causative mutation transmission between asymptomatic family members. Our results expanded the clinical and mutational spectrum of TCS and further confirmed the inter- and intra-familial variability of this disorder. Full article

Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies. Our strategy aims at the identification of diseased cells as early as possible to intercept progression of the disease prior to severe clinical impairment and irreversible tissue damage. Full article

Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (Polr1d, Rpl11; Rpl35; Nhp2); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage. Full article

One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC. Full article

Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann–Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann–Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann–Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders. Full article

Long non-coding RNAs’ HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016, and HULC rs7763881 are progressively reported having a close genetic affinity with esophageal carcinogenesis in the East. Nonetheless, their correlation with variables already endorsed as significant prognostic factors in terms of staging, guiding treatment and predicting recurrence, metastasis, and survival have yet to be explored. Herein, we investigated their prognostic value by correlating them with clinicopathological and laboratory prognostic markers in esophageal cancer in the West. Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated on for esophageal cancer between 2014 and 2018 were compared with 121 healthy community controls. HULC was not detected differently in any of the cancer prognostic subgroups. LINC00951 was underrepresented in Ca19.9 elevated subgroup. HOTAIR was more frequent in both worse differentiation grade and positive Signet-Ring-Cell and Ca19.9 subgroups. POLR2E was identified less frequently in Adenocarcinoma, Signet-Ring-Cell, and Diffuse histologies, as well as in Perineural, Lymphovascular, and Perivascular Invasion positive, while it was overrepresented in CEA positive subgroup. These lncRNAs polymorphisms may hold great potential not only as future therapeutic agents but also as novel markers for predictive analysis of esophageal cancer risk, clinical outcome, and survival. Clinical implications of these findings need to be validated with prospective larger sample-size studies. Full article

The progression and metastasis of oral squamous cell carcinoma (OSCC) are highly influenced by cancer stem cells (CSCs) due to their unique self-renewal and plasticity. In this study, data were obtained from a single-cell RNA-sequencing dataset (GSE172577) in the GEO database, and LASSO-Cox regression analysis was performed on 1344 CSCs-related genes to establish a six-gene prognostic signature (6-GPS) consisting of ADM, POLR1D, PTGR1, RPL35A, PGK1, and P4HA1. High-risk scores were significantly associated with unfavorable survival outcomes, and these features were thoroughly validated in the ICGC. The results of nomograms, calibration plots, and ROC curves confirmed the good prognostic accuracy of 6-GPS for OSCC. Additionally, the knockdown of ADM or POLR1D genes may significantly inhibit the proliferation, migration, and invasion of OSCC cells through the JAK/HIF-1 pathway. Furthermore, cell-cycle arrest occurred in the G1 phase by suppressing Cyclin D1. In summary, 6-GPS may play a crucial role in the occurrence and development of OSCC and has the potential to be developed further as a diagnostic, therapeutic, and prognostic tool for OSCC. Full article