Search Results (383)

Congenital cataracts (CCs) are a leading cause of preventable childhood blindness, with genetic factors playing a crucial role in their etiology. Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder associated with CCs but is often underdiagnosed due to variable expressivity, particularly in female carriers. Objective: This study aimed to explore the genetic landscape of CCs in a Swiss cohort, focusing on two novel NHS and one novel GJA8 variants and their phenotypic presentation. Methods: Whole-exome sequencing (WES) was conducted on 20 unrelated Swiss families diagnosed with CCs. Variants were analyzed for pathogenicity using genetic databases, and segregation analysis was performed. Clinical data, including cataract phenotype and associated systemic anomalies, were assessed to establish genotype–phenotype correlations. Results: Potentially pathogenic DNA sequence variants were identified in 10 families, including three novel variants, one in GJA8 (c.584T>C) and two NHS variants (c.250_252insA and c.484del). Additional previously reported variants were detected in CRYBA1, CRYGC, CRYAA, MIP, EPHA2, and MAF, reflecting genetic heterogeneity in the cohort. Notably, NHS variants displayed significant phenotypic variability, suggesting dose-dependent effects and X-chromosome inactivation in female carriers. Conclusions: NHS remains underdiagnosed due to its variable expressivity and the late manifestation of systemic features, often leading to misclassification as isolated CC. This study highlights the importance of genetic testing in unexplained CC cases to improve early detection of syndromic forms. The identification of novel NHS and GJA8 variants provides new insights into the genetic complexity of CCs, emphasizing the need for further research on genotype–phenotype correlations. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation—factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny. Full article

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article

This study explores the efficacy of magnetic abrasive finishing (MAF) with planetary kinematics for post-processing Inconel 939 components fabricated by laser powder bed fusion (LPBF). Given the critical limitations in surface quality of LPBF-produced parts—especially in hard-to-machine superalloys like Inconel 939—there is a pressing need for advanced, adaptable finishing techniques that can operate effectively on complex geometries. This research focuses on optimizing the process parameters—eccentricity, rotational speed, and machining time—to enhance surface integrity following preliminary vibratory machining. Custom-designed samples underwent sequential machining, including heat treatment and 4 h vibratory machining, before MAF was applied under controlled conditions using ferromagnetic Fe-Si abrasives. Surface roughness measurements demonstrated a significant reduction, achieving Ra values from 1.21 µm to below 0.8 µm in optimal conditions, representing more than a fivefold improvement compared to the as-printed state (5.6 µm). Scanning Electron Microscopy (SEM) revealed progressive surface refinement, with MAF effectively removing adhered particles left by prior processing. Statistical analysis confirmed the dominant influence of eccentricity on the surface profile parameters, particularly Rz. The findings validate the viability of MAF as a precise, controllable, and complementary finishing method for LPBF-manufactured Inconel 939 components, especially for geometrically complex or hard-to-reach surfaces. Full article

Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell dyscrasia. According to revised diagnostic criteria, pPCL is defined by the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood of patients with newly diagnosed multiple myeloma (NDMM). pPCL is characterized by a distinct cytogenetic profile, including frequent t(11;14), MAF/MAB translocations, 1q gain, and del(17p). While t(11;14) is generally associated with a favorable prognosis, the coexistence of multiple high-risk cytogenetic abnormalities is linked to poorer outcomes. Tandem autologous hematopoietic stem cell transplantation and novel anti-myeloma agents have improved survival in some patients; however, overall prognosis remains poor, particularly in those ineligible for transplantation. Venetoclax and emerging immunotherapies, such as CAR-T cells and bispecific antibodies, show promise and merit clinical trials focused on pPCL-enriched cohorts. Additionally, recent findings associating even minimal CPCs with adverse outcomes in NDMM support broader inclusion criteria in future trials. A deeper understanding of pPCL’s molecular pathology is critical for the development of effective targeted therapies. This article reviews recent advances in the molecular understanding of and treatment strategies for pPCL. Full article

Aquaculture has become a crucial component of global food production, yet catfish (10.8% of global finfish production) breeding programs often lack sufficient genetic data to fully utilize their production potential. In the last 15 years, there have been improvements in this field as two high-density (HD) single nucleotide polymorphism (SNP) arrays (250K and 690K) and low-density panels have been developed for North American channel catfish (Ictalurus punctatus) and blue catfish (Ictalurus furcatus). This lack of genomic tools hinders genetic improvement efforts in other commercially relevant catfish species besides them. Therefore, this review investigated the reason behind the lack of SNP chip usage in genetic-based selections in most catfish breeding programs and the cross-species applicability of the already existing high-density SNP arrays for genotyping members of the Clariidae, African catfish (Clarias gariepinu), and Siluridae, European catfish (Silurus glanis), families. This paper systematically reviews the literature of more than 16 SNP arrays, with 66 non-target species, and assesses the possibility of adapting catfish SNP arrays to the catfish families of interest. With lowered filtering (e.g., MAF > 0) thresholds, the Affymetrix Axiom 250K and Axiom Catfish 690K Genotyping Array could potentially be used on important market species like African and European catfishes. In the long term, chip development would be the solution for these species, but, until then, cross-application is a viable alternative. Despite low polymorphic SNPs (~1%) and call rates (~0%), this SNP array could aid researchers and breeders, improving catfish aquaculture and management. Full article

DNA and RNA nucleotide sequences are ubiquitous in all biological cells, serving as both a comprehensive library of capabilities for the cells and as an impressive regulatory system to control cellular function. The multi-alignment framework (MAF) provided in this study offers a user-friendly platform for sequence alignment and quantification. It is adaptable to various research needs and can incorporate different tools and parameters for in-depth analysis, especially in low read rate scenarios. This framework can be used to compare results from different alignment programs and algorithms on the same dataset, allowing for a comprehensive analysis of subtle to significant differences. This concept is demonstrated in a small RNA case study. MAF is specifically designed for the Linux platform, commonly used in bioinformatics. Its script structure streamlines processing steps, saving time when repeating procedures with various datasets. While the focus is on microRNA analysis, the templates provided can be adapted for all transcriptomic and genomic analyses. The template structure allows for flexible integration of pre- and post-processing steps. MicroRNA analysis indicates that STAR and Bowtie2 alignment programs are more effective than BBMap. Combining STAR with the Salmon quantifier or, with some limitations, the Samtools quantification, appears to be the most reliable approach. This method is ideal for scientists who want to thoroughly analyze their alignment results to ensure quality. The detailed microRNA analysis demonstrates the quality of three alignment and two quantification methods, offering guidance on assessing result quality and reducing false positives. Full article

Background/Objectives: Thyroid hormone (TH) deficiency during the pregnancy and lactation periods leads to enduring memory impairments in offspring. However, the mechanisms underlying the cognitive and memory deficits induced by developmental hypothyroidism remain largely unexplored. Methods: Mice were exposed to propylthiouracil (PTU) or purified water to detect changes in hippocampal neurogenesis and differentiation of their offspring to explain the pathogenesis of impaired learning and memory. In addition, HT22 cell line were used to investigate the regulation between Maf and Mef2c. Results: Our findings indicate that developmental exposure to PTU results in abnormalities of the preferential differentiation of GABAergic interneurons and a subsequent reduction in PV⁺ inhibitory interneurons in the hippocampus of mouse pups. More significantly, we also indicate that the downregulation of Maf and the consequent alteration of Mef2c are likely responsible for the mechanisms through which developmental hypothyroidism influences the differentiation and development of PV⁺ inhibitory interneurons in offspring. Conclusions: Consequently, the aberrant development of PV⁺ interneuron in the hippocampus of mice subjected to developmental hypothyroidism potentially contributes to memory deficits during adolescence and adulthood. Full article

Background/Objectives: The Tswana goat, an indigenous Botswana breed, remains genetically understudied despite its adaptation to local conditions. This study characterized its genetic diversity across regions, using Boer goats as a reference, to assess population structure, heterozygosity, and breeding patterns. Methods: Genomic DNA from Tswana goats (Southern, Central, Northwest, and research ranch populations) and Boer goats was genotyped using the Illumina Goat_IGGC_65K_v2 BeadChip. Data were analyzed in PLINK v1.9 and R v4.3.2 to compute genetic diversity indices. Results: Tswana goats showed higher genetic diversity than Boer goats, with greater minor allele frequency (MAF: 0.313 ± 0.127 vs. 0.287 ± 0.136) and expected and observed heterozygosity (Ho: 0.395 ± 0.019 vs. 0.367 ± 0.022, and He: 0.400 vs. 0.375). Regional variation emerged across the Central (Ho = 0.394, He = 0.401, and MAF = 0.320), Southern (Ho = 0.397, He = 0.399, and MAF = 0.318), Northwest (Ho = 0.364, He = 0.358, and MAF = 0.289), and research ranch populations (Ho = 0.394, He = 0.380, and MAF = 0.300). Inbreeding coefficients (F_IS) ranged from mild inbreeding (Central: 0.019) to heterozygote excess (research ranch: −0.038), reflecting managed breeding. Conclusion: Tswana goats have high genetic diversity, with regional variation linked to breeding practices. Although regional structure suggests genetic differentiation, no distinct ecotypes were identified. These findings emphasize the need for controlled breeding to preserve genetic diversity for the Tswana goat. Full article

The evaluation of external pelvimetry measurements and the genetic factors influencing them is essential for improving morphological characteristics and reproductive performance in cattle. This study represents the first comprehensive analysis of the association between single nucleotide polymorphisms (SNPs) and external pelvimetry traits in Romanian Simmental cattle, a breed recognized for its distinctive pelvic morphology. The relationship between single-nucleotide polymorphisms (SNPs) and external pelvimetry traits—including croup height (CH), buttock height (BH), croup width (CW), rump angle (RA), and croup length (CL)—was examined in Simmental cows. From an initial set of 110 SNPs, 33 markers were retained after applying quality control filters, including a minor allele frequency (MAF) greater than 0.05 and Hardy–Weinberg equilibrium. These SNPs, located on multiple chromosomes, were identified within intronic, exonic, or regulatory regions of relevant genes such as CLSTN2, DPYD, FBXL7, FBXL13, SEMA6A, RUNX2, FSTL4, DST, DCBLD2, FRMD6, CAV2.3, ABL2, SH3BP4, RSBN1L,and SAMD12, suggesting that these genetic variants may influence the development and morphology of the pelvic bones. Statistical analysis revealed significant relationships between certain allele variants and croup measurements, highlighting that the presence of alternative alleles can modify their morphological traits. Notably, the G allele in CLSTN2 reduced croup height by 5.74 cm (p = 0.0227), while the T allele in RUNX2 decreased rump angle by 4.49° (p = 0.0119). Full article

Under the 1960 Indus Water Treaty, Pakistan owned the Western rivers (Indus, Jhelum, and Chenab) and India the Eastern rivers (Ravi, Suleimanki, and Beas). Pakistan’s per capita water availability will reduce from 5260 m³ to less than 1000 m³ by 2025, causing water stress. The Indus Basin’s water availability was examined at inflow and outflow gauges between 1991 and 2015. The Indus Basin inflow and outflow gauges indicated exceptionally low and high flows before, during, and after floods. Lower flow values vary greatly for the Indus, Chenab, and Jhelum rivers. During Rabi and Kharif, the Indus and Chenab rivers behaved differently. Lower flows (Q90 to Q99) in Western Rivers are more periodic than higher flows (Q90 to Q99) and medium flows (Q90 to Q99). The outflow gauge Kotri reported 35% exceedance with zero flows during pre-flood and post-flood seasons and 50% during flood season, indicating seasonal concerns. Outflow and inflow both fell, particularly after the year 2000, according to data collected over a longer period (1976–2015). Low storage and regulating upstream capacity caused the Indus Basin outflow to reach 28 MAF (million acre feet) between 1976 and 2015, which is 70% more than the permitted 8.6 MAF downstream Kotri gauge. For 65 percent of the year, the Indus Basin does not release any water downstream of Kotri. As a result, the ecosystem relies on an annual influx of at least 123 MAF to sustain itself, and an outflow of 8.6 MAF from the Indus Basin necessitates an inflow of 113.51 MAF. At high-flow seasons, the Indus Basin experiences devastating floods, yet it dries out at a frightening rate before and after floods. The preservation of ecosystems and riparian zones downstream depends on the large environmental flows in eastern rivers. This is achievable only by fully implementing IWT and improving water management practices at western rivers. Full article

To solve the manufacturing problem of the efficient removal of multi-scale surface defects (wrinkles, cracks, scratches, etc.) on the inner wall of MP35N cobalt–chromium alloy vascular stents, this study proposes a collaborative optimization strategy of magnetic abrasive polishing (MAF) based on a new type of magnetic abrasive. In response to the unique requirements for the inner wall processing of high aspect ratio microtubes, metal-based Al₂O₃ magnetic abrasives with superior performance were prepared by the plasma melt powder spraying method. A special MAF system for the inner wall of the bracket was designed and constructed. The four-factor and three-level Box–Behnken response surface method was adopted to analyze the influences and interactions of tube rotational speed, magnetic pole feed rate, abrasive filling amount, and processing clearance on surface roughness (Ra). The significance order of each parameter for Ra is determined as follows: processing clearance > tube rotational speed > abrasive filling amount > magnetic pole feed rate. Using the established model and multiple regression equations, the optimal parameters were determined as follows: a tube rotational speed of 600 r/min, a magnetic pole feed rate of 150 mm/min, an abrasive filling amount of 0.50 g, and a processing clearance of 0.50 mm. The optimized model predicted an Ra value of 0.104 μm, while the average Ra value verified experimentally was 0.107 μm, with the minimum error being 2.9%. Compared with the initial Ra of 0.486 μm, directly measured by the ultra-depth-of-field 3D microscope of model DSX1000, the surface roughness was reduced by 77.98%. MAF effectively eliminates the surface defects and deteriorated layers on the inner wall of MP35N tubes, significantly improving the surface quality, which is of great significance for the subsequent preparation of high-quality vascular stents and their clinical applications. Full article

Low-coverage whole-genome sequencing (lcWGS) followed by imputation is emerging as a cost-effective method for generating a substantial number of single nucleotide polymorphism (SNP) in aquatic species with highly heterozygous and complex genomes. This study represents the first systematic investigation into the application of low-coverage whole-genome sequencing (lcWGS) combined with imputation for genotyping in Pacific abalone (Haliotis discus hannai) without a reference panel. We utilized 1059 Pacific abalone individuals sequenced at an average depth of 7.86×, as well as 16 individuals sequenced at 20×, as sample materials. To assess the genotype imputation accuracy for lcWGS without a reference panel, we simulated data with varying sequencing depths (0.5–4×) and examined the effects of sample size, chromosome length, and minor allele frequency (MAF) using BaseVar and STITCH strategies. Results showed that STITCH achieved high accuracy when the sample size exceeded 400, with a genotype correlation (R²) of 0.98 ± 0.002 and genotype concordance (GC) of 0.99 ± 0.001. Imputation accuracy plateaued when the sample size exceeded 400 and sequencing depth surpassed 1×. Chromosome length had minimal effects, with all three chromosomes achieving an accuracy of approximately 0.98. However, the accuracy for rare MAF (<0.05) was lower, falling below 0.99. A second imputation with Beagle significantly increased SNP detection by 3.9–8.3 folds for a sequencing depth of 0.5–4×, apparently without sacrificing accuracy. To our knowledge, this is the first study of lcWGS analysis conducted in abalone. The findings demonstrate that lcWGS with imputation can achieve high accuracy with moderate sample sizes (n ≥ 400) in Pacific abalone, offering a cost-effective approach for genotyping in aquaculture species. Full article

Natural or artificial selection could shape genetic architecture, e.g., the relationship between minor allele frequency (MAF) and the effect sizes of causal variants (CVs). This study aimed to investigate the impact of the MAF–effect size relationship (as a selection signature, S) on genomic prediction and heritability estimation in livestock, using both simulated data (Holstein) and real datasets (Holstein and pigs). We evaluated the performance of two models: (1) selection-adjusted genomic best linear unbiased prediction (GBLUP-S), and (2) MAF-stratified selection-adjusted genomic best linear unbiased prediction (GBLUP-SMS). Simulation results demonstrated that for traits under strong negative selection (S < −1), both GBLUP-S and GBLUP-SMS outperformed classic GBLUP. The prediction accuracy of GBLUP-S improved by 0.011–0.031, while GBLUP-SMS achieved a gain of 0.005–0.025. Furthermore, GBLUP-SMS exhibited lower sensitivity to variations in S-values, whereas GBLUP-S heavily relied on accurate S specification. When the true S was matched, GBLUP-SMS generated more unbiased (or comparable) heritability estimates and higher prediction accuracy relative to GBLUP-S. Critically, mismatched S in GBLUP-S led to increased bias in heritability estimates and reduced prediction accuracy. Cross-validation with real phenotypic data from Holsteins and pigs demonstrated that implementing selection-adjust methods improved prediction accuracy by 0.015 for FP in Holsteins and 0.01 for T1 in pigs, while enhancing the unbiasedness of heritability estimates across all traits. Negative selection signatures were identified for cattle (S = −0.5) and pig T1, T2, and T3 (S = −1.5, −1, and −2, respectively). These findings advance the theoretical framework of GBLUP-based genomic prediction and heritability estimation. Full article