Search Results (646)

Replication timing (RT), the temporal order of DNA replication during S phase, influences regional mutation rates, yet the mechanistic basis for RT-associated mutagenesis remains incompletely defined. To identify drivers of RT-dependent mutation biases, we analyzed whole-genome sequencing data from cells with disruptions in DNA replication/repair genes or exposed to mutagenic compounds. Mutation distributions between early- and late-replicating regions were compared using bootstrapping and statistical modeling. We identified 14 genes that exhibit differential effects in early- or late-replicating regions, encompassing multiple DNA repair pathways, including mismatch repair (MLH1, MSH2, MSH6, PMS1, and PMS2), trans-lesion DNA synthesis (REV1) and double-strand break repair (DCLRE1A and PRKDC), DNA polymerases (POLB, POLE3, and POLE4), and other genes central to genomic instability (PARP1 and TP53). Similar analyses of mutagenic compounds revealed 19 compounds with differential effects on replication timing. These results establish replication timing as a critical modulator of mutagenesis, with distinct DNA repair pathways and exogenous agents exhibiting replication timing-specific effects on genomic instability. Our systematic bioinformatics approach identifies new DNA repair genes and mutagens that exhibit differential activity during the S phase. These findings pave the way for further investigation of factors that contribute to genome instability during cancer transformation. Full article

Sustainability in the construction sector has become a fundamental objective for mitigating escalating environmental challenges; given that concrete is the most widely used man-made material, extending its service life is therefore critical. Among durability concerns, magnesium sulfate (MgSO₄) attack is particularly deleterious to concrete structures. Therefore, this study investigates the short- and long-term performance of concrete produced with copper slag (CS)—a massive waste generated by copper mining activities worldwide—employed as a supplementary cementitious material (SCM), together with recycled coarse aggregate (RCA), obtained from concrete construction and demolition waste, when exposed to MgSO₄. CS was used as a 15 vol% cement replacement, while RCA was incorporated at 0%, 20%, 50%, and 100 vol%. Compressive strength, bulk density, water absorption, and porosity were measured after water curing (7–388 days) and following immersion in a 5 wt.% MgSO₄ solution for 180 and 360 days. Microstructural characteristics were assessed using scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis with its differential thermogravimetric derivative (TG-DTG), and Fourier transform infrared spectroscopy (FTIR) techniques. The results indicated that replacing 15% cement with CS reduced 7-day strength by ≤10%, yet parity with the reference mix was reached at 90 days. Strength losses increased monotonically with RCA content. Under MgSO₄ exposure, all mixtures experienced an initial compressive strength gain during the short-term exposures (28–100 days), attributed to the pore-filling effect of expansive sulfate phases. However, at long-term exposure (180–360 days), a clear strength decline was observed, mainly due to internal cracking, brucite formation, and the transformation of C–S–H into non-cementitious M–S–H gel. Based on these findings, the combined use of CS and RCA at low replacement levels shows potential for producing environmentally friendly concrete with mechanical and durability performance comparable to those of concrete made entirely with virgin materials. Full article

Background/Objectives: The Motor Speech Hierarchy (MSH) Probe Words (PWs) have yet to be validated as effective in discriminating between children with impaired and children with typically developing speech motor control. This preliminary study first examined the effectiveness of the mandibular control subtest of the MSH-PWs in distinguishing between typically developing (TD) and speech sound-disordered (SSD) children aged between 3 years 0 months and 3 years 6 months. Secondly, we compared automatically derived kinematic measures of jaw range and control with MSH-PW consensus scoring to assist in identifying deficits in mandibular control. Methods: Forty-one children with TD speech and 13 with SSD produced the 10 words of the mandibular stage of the MSH-PWs. A consensus team of speech pathologists observed video recordings of the words to score motor speech control and phonetic accuracy, as detailed in the MSH-PW scoring criteria. Specific measures of jaw and lip movements during speech were also extracted to derive the objective measurements, with agreement between the perceptual and objective measures of jaw range and jaw control evaluated. Results: A significant difference between TD and SSD groups was found for jaw range (p = 0.006), voicing transitions (p = 0.004) and total mandibular scores (p = 0.015). SSD and TD group discrimination was significant (at alpha = 0.01) with a balanced classification accuracy of 0.79. Initial analysis indicates objective kinematic measures using facial tracking show good agreement with perceptual judgements of jaw range and jaw control. Conclusions: The preliminary data indicate the MSH-PWs can discriminate TD speech from SSD at the level of mandibular control and can be used by clinicians to assess motor speech control. Further investigation of objective measures to support perceptual scoring is indicated. Full article

Background: Lynch syndrome (LS) is an autosomal dominant disease caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene. LS patients harboring genetic variants in one of the MMR genes display a heterogeneous phenotype in terms of cancer penetrance (lifetime cancer risk) and expressivity (malignancies in gastrointestinal or other specific organs). Methods: DNA samples from the index cases of Family 1 and Family 2 were analyzed using a next-generation sequencing (NGS) multigene panel comprising 25 genes involved in major hereditary cancer predisposition syndromes. This NGS analysis revealed a variant of uncertain significance (VUS) in the PMS2 gene (NM_000535.7: c.184G>A; p.Gly62Arg) of both index cases, which was validated by Sanger sequencing. The structural and functional impact of this VUS was evaluated in silico using twelve different prediction tools and by immunohistochemical analysis of MMR proteins. Results: Based on the personal and family history of the two families, tumor pathology, and protein in silico analysis, the novel PMS2 gene variant described in this study may be associated with hereditary LS. Considering the low penetrance of PMS2 gene variants in LS-associated tumors and the intrafamilial variability of the associated clinical phenotypes, the multidisciplinary approach proposed in this study could significantly support the evaluation of suspected LS cases carrying PMS2 variants. Full article

Background: This study is the first to investigate the association between colorectal cancer (CRC) risk and the hMLH1 −93G>A and hMSH2 1032G>A polymorphisms of mismatch repair (MMR) genes in the Azerbaijani population. Methods: Peripheral blood samples containing EDTA were collected from the study subjects (134 patients and 137 controls), and genomic DNA was extracted using the non-enzymatic salting-out method. Genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and the results were visualized through agarose gel electrophoresis. Results: Overall, no statistically significant correlation was observed between CRC risk and the hMLH1 −93G>A polymorphism in the heterozygous GA (OR = 0.760; 95% CI = 0.374–1.542; p = 0.446), the mutant AA (OR = 1.474; 95% CI = 0.738–2.945; p = 0.270), or the A allele (OR = 1.400; 95% CI = 0.984–1.995; p = 0.062). However, in contrast to the dominant model, a statistically significant association was found between the recessive model and an increased CRC risk, with an odds ratio of 1.788 (95% CI = 1.102–2.900; p = 0.018). The hMLH1 −93G>A polymorphism was identified at a significantly higher frequency across the TNM stages, with the distribution showing statistical significance (p < 0.05). Additionally, no statistically significant association was observed between the hMSH2 1032G>A polymorphism and CRC risk. Conclusions: Although no overall association was observed for hMLH1 −93G>A, our findings suggest a potential link with increased colorectal cancer risk under the recessive model in the Azerbaijani population. Further studies are warranted to confirm this model-specific association and investigate the underlying biological mechanisms. Full article

The progressive proliferation of sensor deployment in distribution networks (DNs), propelled by the dual drivers of power automation and ubiquitous IoT infrastructure development, has precipitated exponential growth in real-time data generated by multisource heterogeneous (MSH) sensors within multilayer grid architectures. This phenomenon presents dual implications: large-scale datasets offer an enhanced foundation for reliability assessment and dispatch planning in DNs; the dramatic escalation in data volume imposes demands on the computational precision and response speed of traditional evaluation approaches. The identification of critical influencing factors under extreme operating conditions, coupled with dynamic assessment and prediction of DN reliability through MSH data approaches, has emerged as a pressing challenge to address. Through a brief analysis of existing technologies and algorithms, this article reviews the technological development of MSH data analysis in DNs. By integrating the stability advantages of conventional approaches in practice with the computational adaptability of artificial intelligence, this article focuses on discussing key approaches for MSH data processing and assessment. Based on the characteristics of DN data, e.g., diverse sources, heterogeneous structures, and complex correlations, this article proposes several practical future directions. It is expected to provide insights for practitioners in power systems and sensor data processing that offer technical inspirations for intelligent, reliable, and stable next-generation DN construction. Full article

The DNA mismatch repair (MMR) system plays a crucial role in repairing DNA damage and regulating cell cycle arrest induced by cadmium (Cd) stress. To elucidate the mechanism by which miRNAs target AtMSH2 in regulating Arabidopsis’ response to Cd stress, the wild-type Arabidopsis, Atmsh2 mutant, and three miRNA-overexpressing transgenic lines were grown hydroponically in half-strength MS solution containing cadmium (Cd) at concentrations of 0, 0.5, 1, 2, and 3 mg/L for 5 days. miRNA-seq analysis, bioinformatics prediction, dual-luciferase reporter assays, and qRT-PCR results demonstrated that miR5651, miR170-3p, and miR171a-3p specifically targeted AtMSH2 and their expression levels showed a significant negative correlation. Compared to wild-type (WT) Arabidopsis, Cd stress tolerance was significantly enhanced in miRNA-overexpressing transgenic lines. Moreover, exogenous application of these three miRNAs in half-strength MS liquid medium also markedly improved Cd stress tolerance in wild-type Arabidopsis. Furthermore, the expression of these three miRNAs expression was further upregulated by Cd stress in a dose-dependent manner. Additionally, DNA damage response in miRNA-overexpressing transgenic lines was promoted based on the expression of DNA repair, DNA damage signaling, and cell cycle genes, which differed from both wild-type and Atmsh2 plants. Taken together, miR5651, miR170-3p, and miR171a-3p participated in Cd stress response and improved plant Cd tolerance by mediating the expression of AtMSH2. Our study provides novel insights into the epigenetic mechanisms of Cd tolerance in plants, which sheds light on breeding for stress resilience in phytoremediation. Full article

Breast, colon, and ovarian cancers are among the most prevalent malignancies worldwide, with distinct clinical features. This study aims to identify key proteins as common biomarkers for breast, colon, and ovarian cancer through protein analysis, molecular mechanisms, and patient sample validation. Data mining from curated databases identified 483 proteins for breast cancer, 521 for colon cancer, and 223 for ovarian cancer. Interaction network analysis revealed shared clusters involved in cancer progression, DNA repair, and cell proliferation. A core set of 27 proteins was found to be common across all three cancer types, participating in key biological processes such as DNA damage response, cell proliferation, and apoptosis. Notably, these proteins are implicated in KEGG pathways linked to multiple cancers. Differential gene expression analysis revealed significant alterations in the expressions of MSH2 and KIT across the three cancers, suggesting their potential as common biomarkers. The high expression of these proteins was associated with better survival outcomes, highlighting their potential as common biomarkers for breast, colon, and ovarian cancers. The in-silico methodology integrated various bioinformatic tools—including cluster identification, gene expression profiling, protein network visualization, and biomarker prediction—enhancing the understanding of shared molecular mechanisms and potential therapeutic targets. Full article

Background/Objectives: Proximal interphalangeal joint (PIJ) arthrodesis is a common surgical intervention for patients with PIJ osteoarthritis or trauma-related joint destruction. The objective of this study was to evaluate the biomechanical stability of various arthrodesis techniques under forces comparable to activities of daily living (ADL) to assess their suitability for early active movement protocols. Methods: In this in vitro study, composite cylinders simulating PIJ arthrodesis were subjected to standardized fusion angles of 40° using different fixation techniques, including crossed K-wires, compression screws, cerclage wires, tension band wiring, anatomical fixation plates, and locking grid plates. Forces representing ADLs such as typing, holding a pencil, carrying weight, and opening a jar were applied using a universal testing machine in a four-point bending setup. Micromotion and gap clearance were calculated and analyzed. Results: Techniques involving compression, such as compression screws, tension bands, and cerclage wires, exhibited lower micromotion and gap clearance under forces up to 17 N, suggesting potential suitability for early active movement protocols. In contrast, fixation plates demonstrated structural failure or excessive clearance during early active motion ADLs. K-wires showed intermediate results with moderate gap clearance and micromotion. Conclusions: Compression-based fixation techniques for PIJ arthrodesis may permit early active movement without external stabilization, while fixation plates are prone to failure under ADL forces. Further dynamic biomechanical testing and clinical studies are recommended to confirm these findings. Full article

Machine learning (ML) algorithms hold the potential to outperform the selection of patients for immunotherapy (ICIs) compared to previous biomarker studies. We analyzed the predictive performance of ML models and compared them to traditional clinical biomarkers (TCBs) in the field of gastrointestinal (GI) cancers. The study has been registered in PROSPERO (number: CRD42023465917). A systematic search of PubMed was conducted to identify studies applying different ML algorithms to GI cancer patients treated with ICIs using tumor RNA gene expression profiles. The outcomes included were response to immunotherapy (ITR) or survival. Additionally, we compared the ML methodology details and predictive power inherent in the published gene sets using 5-fold cross-validation and logistic regression (LR), on an available well-defined ICI-treated metastatic gastric cancer (GC) cohort (n = 45). A set of standard clinical ICI biomarkers (MLH, MSH, and CD8 genes, plus PMS2 and PD-L1)) and de-novo calculated principal components (PCs) of the original datasets were also included as additional points of comparison. Nine articles were identified as eligible to meet the inclusion criteria. Three were pan-cancer studies, five assessed GC, and one studied colorectal cancer (CRC). Classification and regression models were used to predict ICI efficacy. Next, using LR, we validated the predictive power of applied ML algorithms on RNA signatures, using their reported receiver operating characteristics (ROC) analysis area under the curve (AUC) values on a well-defined ICI-treated gastric cancer (GC) dataset (n = 45). In two cases our method has outperformed the published results (reported/LR comparison: 0.74/0.831, 0.67/0.735). Besides the published studies, we have included two benchmarks: a set of TCBs and using principal components based on the whole dataset (PCA, 99% explained variance, 40 components). Interestingly, a study using a selected gene set (immuno-oncology panel) with AUC = 0.83 was the only one that outperformed the TCB (AUC = 0.8) and the PCA (AUC =0.81) results. Cross-validation of the predictive performance of these genes on the same GC dataset and an investigation of their prognostic role on a collated multi-cohort GC dataset of n = 375 resected, or chemotherapy-treated patients revealed that genes mannose-6-phosphate receptor (M6PR), Indoleamine 2,3-Dioxygenase 1 (IDO1), Neuropilin-1 (NRP1), and MAGEA3 performed similarly, or better than established biomarkers like PD-L1 and MSI. We found an immuno-oncology panel with an AUC = 0.83 that outperformed the clinical benchmark or the PC results. We recommend further investigation and experimental validation in the case of M6PR, IDO1, NRP1, and MAGEA3 expressions based on their strong predictive power in GC ITR. Well-designed studies with larger sample sizes and nonlinear ML models might help improve biomarker selections. Full article

This study investigates the effects of the combined addition of MgO expansive agent (MEA) and rice husk ash (RHA) on the performance of concrete. Results show that MEA absorbs water and competes with superplasticizers for adsorption, reducing early-age fluidity. In the later stages, its reaction with RHA generates M-S-H gel, accelerating slump loss. At early ages (up to 7 days), due to the slow hydration of MEA and partial replacement of cement, fewer hydration products are formed. Additionally, the pozzolanic reaction of RHA has not yet developed, resulting in the low early strength of concrete. In the later stages, Mg(OH)₂ fills pores and enhances compactness, while the pozzolanic reaction of RHA further optimizes the pore structure. The internal curing effect also provides the moisture needed for continued MEA hydration, significantly improving later-age strength. Moreover, in the post-cast strip of a tall building, the internal curing effect of RHA ensures the effective shrinkage compensation by MEA under low water-to-cement ratio conditions. The restraint provided by reinforcement enhances the pore-filling effect of Mg(OH)₂, improving concrete compactness and crack resistance, ultimately boosting long-term strength and durability. Full article

This study investigated the potential cosmetic properties of the ethyl acetate (EtOAc) fraction obtained from the roots of Astilboides tabularis (Hemsl.) Engl., focusing on skin-whitening, antiwrinkle, and moisturizing effects using cell-based assays and three-dimensional (3D) artificial skin models (Neoderm-ED and Neoderm-ME). The EtOAc fraction showed significant dose-dependent inhibitory activity against tyrosinase (TYR) (72.0% inhibition at 50 µg/mL), comparable to that of kojic acid. In α-melanocyte-stimulating hormone (α-MSH)-stimulated Neoderm-ME artificial skin containing melanocytes, the EtOAc fraction reduced melanin synthesis at concentrations of 50 and 75 µg/mL and decreased melanogenesis-related gene expression, including TYR, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and TRP-2. In the antiwrinkle assays, the EtOAc fraction effectively inhibited elastase activity (41.5% inhibition at 10 µg/mL), exceeding the efficacy of ursolic acid. In the Neoderm-ED artificial skin model, the EtOAc fraction reversed structural damage induced by particulate matter (PM10), restoring epidermal thickness and dermal density. This improvement was supported by the increased expression of skin barrier and antiwrinkle genes, including filaggrin, hyaluronic acid synthase-1 (HAS-1), HAS-2, aquaporin-3 (AQP-3), collagen type I alpha 1 chain (COL1A1), elastin, tissue inhibitor of metalloproteinases-1 (TIMP-1), and TIMP-2, as well as decreased expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-9). Our results indicate that the EtOAc fraction from A. tabularis root has considerable potential as a multifunctional cosmetic. Full article

Background/Objectives: Many patients assigned to adjuvant radiotherapy for non-metastatic breast cancer already received taxane-based chemotherapy, which can cause peripheral neuropathy (PNP). This study investigated potential associations between moderate-to-severe or mild PNP and distress. Methods: Ninety-eight breast cancer patients who received taxane-based chemotherapy and completed the National Comprehensive Cancer Network Distress Thermometer were included in this retrospective study. The severity of PNP plus 17 factors were evaluated for associations with distress. Results: Mean distress scores (higher scores representing higher levels of distress) were 6.17 (SD ± 2.41) in patients with moderate-to-severe PNP, 4.21 (SD ± 2.54) in patients with mild PNP and 4.04 (SD ± 2.24) in patients without PNP. On univariable analyses, higher distress scores were significantly associated with moderate-to-severe PNP (vs. mild or no PNP, p < 0.001), Karnofsky performance score ≤ 80 (p = 0.001), history of autoimmune disease (p = 0.035), and hypertension (p = 0.002). Trends were found for age ≥65 years (p = 0.056), type of chemotherapy (p = 0.078), and beta-blocker medication (p = 0.072). On multivariable analysis, moderate-to-severe PNP (p = 0.036), Karnofsky performance score ≤ 80 (p = 0.013), and hypertension (p = 0.045) were significant. Conclusions: Since moderate-to-severe chemotherapy-induced PNP was associated with a significantly higher level of distress when compared to mild or nor PNP, these patients should be offered early psychological support and personalized monitoring. Full article

The aim of this study was to evaluate the influence of filler type, filler content, and filler silanization on the flexural strength (FX), elastic modulus (E_m), shore D hardness (SDH), and two-body wear (2BW) of polyaryletherketone (PAEK) compounds. Specimens (40 wt% PEEK, 40 wt% PEK) with different filler types: 20 wt%: fumed silica (FS), calcium silicate (CS), feldspar (FP), magnesium silicate hydrate (MSH), no filler (NF); different filler content: 20, 25 or 30 wt% CS; different filler silanization: 20 wt% CS silanized with alkylsilane/aminosilane, FP silanized with methylsilane/ vinylsilane, no silanization; and PEEK₂₀ (BioHPP) or PEEK₂₅ (BioHPP plus) controls were fabricated and tested for FX, E_m, and SDH. Two-body wear (4 × 100,000 cycles, 50 N, 2.5 Hz) with composite resin antagonists was measured with PAEK_i (35 wt% PEEK, 35 wt% PEK, 30 wt% CS), PAEK_ii (70 wt% PEEK, 30 wt% CS), PAEK_iii (70 wt% PEEK, 25 wt% CS, 5 wt% FP), and PEEK₂₀ controls. Data were analyzed with Kolmogorov–Smirnov-, Kruskal–Wallis-H-, post hoc Scheffé test, pairwise comparisons, Bonferroni correction, one-way ANOVA, and Spearman rho (α = 0.05). An abrasion area analysis was performed. Adding filler increased FX, E_m, and SDH, with CS and MSH showing the highest values for FX and E_m. Adding 30 wt% CS increased FX, E_m, and SDH compared with 20 wt%. Silanization with methylsilane increased FX, E_m, and SDH. Silanization with aminosilane increased FX and SDH. PEEK₂₀ showed the lowest 2BW compared with all EPCs. No material losses were detected on the antagonists. PAEK compounds with 25 to 30 wt% CS increased FX and E_m compared to lower contents, no filler, or PEEK₂₀. Higher values of FX and E_m did not lead to lower 2BW. Full article

In the Netherlands, around 52,000 dairy cows die on the primary farm each year due to natural death, euthanasia, or on-farm emergency slaughter (OFES). The decision as to what is the best option is made by the farmer, often after consulting a veterinarian, a livestock trader, or a slaughterhouse operator. To determine which factors play a role in this decision-making process, semi-structured interviews were conducted with dairy farmers, private veterinary practitioners, livestock traders, and slaughterhouse operators in the Netherlands. Dairy cattle culling decisions are influenced and limited by strict enforcement of livestock transport regulations and limited options for on-farm killing methods. Requirements regarding mortality rates imposed by the dairy industry and private quality labels for raw milk also influence culling decisions in the Netherlands. Most participants stated that restrictive conditions regarding OFES and mobile slaughterhouses (MSHs) appear to have (unintended) negative effects on cow welfare and meat salvage in general. Different interests, such as cow welfare, food safety, economic concerns of various stakeholders, the reputational interests of the dairy and beef industries, and sustainability objectives such as meat salvage can be conflictive. The results of this study show that the decision-making process regarding culling or (prolonged) veterinary treatment of dairy cattle is complex because various factors, interests, and uncertainties must be weighed. This weighing can vary between individual dairy farms and individual dairy farmers. Full article