Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro-computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 (CX3C motif chemokine receptor 1/chemokine [CX3C motif] ligand 1) signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity. RESULTS: Histological and expression profiles of CCM neurovascular lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) in male and female mice found that sustained mild hypoxia (12% O2, 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis. CONCLUSIONS: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness.

One label is all you need: Interpretable AI-enhanced histopathology for oncology.

Artificial Intelligence (AI)-enhanced histopathology presents unprecedented opportunities to benefit oncology through interpretable methods that require only one overall label per hematoxylin and eosin (H&E) slide with no tissue-level annotations. We present a structured review of these methods organized by their degree of verifiability and by commonly recurring application areas in oncological characterization. First, we discuss morphological markers (tumor presence/absence, metastases, subtypes, grades) in which AI-identified regions of interest (ROIs) within whole slide images (WSIs) verifiably overlap with pathologist-identified ROIs. Second, we discuss molecular markers (gene expression, molecular subtyping) that are not verified via H&E but rather based on overlap with positive regions on adjacent tissue. Third, we discuss genetic markers (mutations, mutational burden, microsatellite instability, chromosomal instability) that current technologies cannot verify if AI methods spatially resolve specific genetic alterations. Fourth, we discuss the direct prediction of survival to which AI-identified histopathological features quantitatively correlate but are nonetheless not mechanistically verifiable. Finally, we discuss in detail several opportunities and challenges for these one-label-per-slide methods within oncology. Opportunities include reducing the cost of research and clinical care, reducing the workload of clinicians, personalized medicine, and unlocking the full potential of histopathology through new imaging-based biomarkers. Current challenges include explainability and interpretability, validation via adjacent tissue sections, reproducibility, data availability, computational needs, data requirements, domain adaptability, external validation, dataset imbalances, and finally commercialization and clinical potential. Ultimately, the relative ease and minimum upfront cost with which relevant data can be collected in addition to the plethora of available AI methods for outcome-driven analysis will surmount these current limitations and achieve the innumerable opportunities associated with AI-driven histopathology for the benefit of oncology.

A common resequencing-based genetic marker data set for global maize diversity.

Maize (Zea mays ssp. mays) populations exhibit vast ranges of genetic and phenotypic diversity. As sequencing costs have declined, an increasing number of projects have sought to measure genetic differences between and within maize populations using whole-genome resequencing strategies, identifying millions of segregating single-nucleotide polymorphisms (SNPs) and insertions/deletions (InDels). Unlike older genotyping strategies like microarrays and genotyping by sequencing, resequencing should, in principle, frequently identify and score common genetic variants. However, in practice, different projects frequently employ different analytical pipelines, often employ different reference genome assemblies and consistently filter for minor allele frequency within the study population. This constrains the potential to reuse and remix data on genetic diversity generated from different projects to address new biological questions in new ways. Here, we employ resequencing data from 1276 previously published maize samples and 239 newly resequenced maize samples to generate a single unified marker set of approximately 366 million segregating variants and approximately 46 million high-confidence variants scored across crop wild relatives, landraces as well as tropical and temperate lines from different breeding eras. We demonstrate that the new variant set provides increased power to identify known causal flowering-time genes using previously published trait data sets, as well as the potential to track changes in the frequency of functionally distinct alleles across the global distribution of modern maize.

Effectiveness of DArTseq markers application in genetic diversity and population structure of indigenous chickens in Eastern Province of Rwanda.

BACKGROUND: The application of biotechnologies which make use of genetic markers in chicken breeding is developing rapidly. Diversity Array Technology (DArT) is one of the current Genotyping-By-Sequencing techniques allowing the discovery of whole genome sequencing. In livestock, DArT has been applied in cattle, sheep, and horses. Currently, there is no study on the application of DArT markers in chickens. The aim was to study the effectiveness of DArTSeq markers in the genetic diversity and population structure of indigenous chickens (IC) and SASSO in the Eastern Province of Rwanda. METHODS: In total 87 blood samples were randomly collected from 37 males and 40 females of indigenous chickens and 10 females of SASSO chickens purposively selected from 5 sites located in two districts of the Eastern Province of Rwanda. Genotyping by Sequencing (GBS) using DArTseq technology was employed. This involved the complexity reduction method through digestion of genomic DNA and ligation of barcoded adapters followed by PCR amplification of adapter-ligated fragments. RESULTS: From 45,677 DArTseq SNPs and 25,444 SilicoDArTs generated, only 8,715 and 6,817 respectively remained for further analysis after quality control. The average call rates observed, 0.99 and 0.98 for DArTseq SNPs and SilicoDArTs respectively were quite similar. The polymorphic information content (PIC) from SilicoDArTs (0.33) was higher than that from DArTseq SNPs (0.22). DArTseq SNPs and SilicoDArTs had 34.4% and 34% of the loci respectively mapped on chromosome 1. DArTseq SNPs revealed distance averages of 0.17 and 0.15 within IC and SASSO chickens respectively while the respective averages observed with SilicoDArTs were 0.42 and 0.36. The average genetic distance between IC and SASSO chickens was moderate for SilicoDArTs (0.120) compared to that of DArTseq SNPs (0.048). The PCoA and population structure clustered the chicken samples into two subpopulations (1 and 2); 1 is composed of IC and 2 by SASSO chickens. An admixture was observed in subpopulation 2 with 12 chickens from subpopulation 1. CONCLUSIONS: The application of DArTseq markers have been proven to be effective and efficient for genetic relationship between IC and separated IC from exotic breed used which indicate their suitability in genomic studies. However, further studies using all chicken genetic resources available and large big sample sizes are required.

Evaluation of HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1 polymorphisms associated with prostate cancer in samples of patients from HUPE-UERJ.

PURPOSE: Prostate cancer (PCa) is the leading cause of death among men in 48 countries. Genetic alterations play a significant role in PCa carcinogenesis. For the hypothesis of this research, five unique polymorphisms (SNP) were investigated in different genes that showed to be associated in different ways with PCa: rs4430796, rs2735839, rs4792311, rs12329760, and rs28931588, respectively for the genes HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1. PATIENTS AND METHODS: Blood samples from 426 subjects were evaluated: 290 controls (161 females and 129 males) and 136 PCa patients. SNP were determined by real-time polymerase chain reaction. TaqMan SNP genotyping assay. In the control samples, the SNPs were defined in association with the self-reported ethnicity, and in 218 control samples with markers with ancestry indicators. The genes were in Hardy-Weinberg equilibrium. One hundred and seventy control samples were matched by ethnicity for comparison with the PCa samples. RESULTS: The G allele at rs28931588 was monomorphic in both patients and controls studied. Significant differences were observed in allelic and genotypic frequencies between the control and Pca samples in rs2735839 (KLK3; p = 0.002 and χ2 = 8.73 and p = 0.01, respectively), by the global frequency and in the dominant model rs2735839_GG (odds ratio [OR] = 0.51, p = 0.02). AA and GA genotypes at rs4792311 (ELAC2) were more frequent in patients with Gleason 7(4 + 3), 8, and 9 (n = 37%-59.7%) compared to patients with Gleason 6 and 7(3 + 4) (n = 26%-40.0%) conferring a protective effect on the GG genotype (OR = 0.45, p = 0.02). The same genotype showed an OR = 2.71 (p = 0.01) for patients with low severity. The HNF1B-KLK3-ELAC2-TMPRSS2-ERG haplotypes: GAAT, AAAT, GAGT, and AAGT were more frequent in patients with Pca with OR ranging from 4.65 to 2.48. CONCLUSIONS: Higher frequencies of risk alleles were confirmed in the SNPs, KLK3 rs2735839_A, ELAC2 rs4792311_A, and TMPRSS2 rs12329760_T in patients with Pca. Rs2735839_A was associated with risk of Pca and rs4792311_A with severity and Gleason score of 7(4 + 3) or greater. There is a need for careful observation of rs2735839 and rs4792311 in association with the prostatic biopsy due to the increased risk of Pca.

Potential Single Nucleotide Polymorphisms markers for radiation dermatitis in head and neck cancer patients: a meta-analysis.

PURPOSE: To identify potential Single Nucleotide Polymorphisms (SNPs) of susceptibility for the development of acute radiation dermatitis in head and neck cancer patients, and also to verify the association between SNPs and the severity of RD. METHODS: This systematic review was reported according to the PRISMA guideline. The proportion meta-analysis was performed to identify the prevalence of genetic markers by geographical region and radiation dermatitis severity. The meta-analysis was performed to verify the association between genetic markers and RD severity. The certainty of the evidence was assessed by GRADE. RESULTS: Thirteen studies were included. The most prevalent SNPs were XRCC3 (rs861639) (36%), TGFß1 (rs1800469) (35%), and RAD51 (rs1801321) (34%). There are prevalence studies in Europe and Asia, with a similar prevalence for all SNPs (29-40%). The prevalence was higher in patients who developed radiation dermatitis ≤2 for any subtype of genes (75-76%). No SNP showed a statistically significant association with very low certainty of evidence. CONCLUSION: The most prevalent SNPs may be predictors of acute RD. The analysis of SNP before starting radiation therapy may be a promising method to predict the risk of developing radiation dermatitis and allow radiosensitive patients to have a customized treatment. This current review provides new research directions.

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Assessment of runs of homozygosity, heterozygosity-rich regions and genomic inbreeding estimates in a subpopulation of Guzerá (Bos indicus) dual-purpose cattle.

For decades, inbreeding in cattle has been evaluated using pedigree information. Nowadays, inbreeding coefficients can be obtained using genomic information such as runs of homozygosity (ROH). The aims of this study were to quantify ROH and heterozygosity-rich regions (HRR) in a subpopulation of Guzerá dual-purpose cattle, to examine ROH and HRR islands, and to compare inbreeding coefficients obtained by ROH with alternative genomic inbreeding coefficients. A subpopulation of 1733 Guzerá animals genotyped for 50k SNPs was used to obtain the ROH and HRR segments. Inbreeding coefficients by ROH (FROH ), by genomic relationship matrix based on VanRaden's method 1 using reference allele frequency in the population (FGRM ), by genomic relationship matrix based on VanRaden's method 1 using allele frequency fixed in 0.5 (FGRM_0.5 ), and by the proportion of homozygous loci (FHOM ) were calculated. A total of 15,660 ROH were identified, and the chromosome with the highest number of ROH was BTA6. A total of 4843 HRRs were identified, and the chromosome with the highest number of HRRs was BTA23. No ROH and HRR islands were identified according to established criteria, but the regions closest to the definition of an island were examined from 64 to 67 Mb of BTA6, from 36 to 37 Mb of BTA2 and from 0.50 to 1.25 Mb of BTA23. The genes identified in ROH islands have previously been associated with dairy and beef traits, while genes identified on HRR islands have previously been associated with reproductive traits and disease resistance. FROH was equal to 0.095 ± 0.084, and its Spearman correlation with FGRM was low (0.44) and moderate-high with FHOM (0.79) and with FGRM_0.5 (0.80). The inbreeding coefficients determined by ROH were higher than other cattle breeds' and higher than pedigree-based inbreeding in the Guzerá breed obtained in previous studies. It is recommended that future studies investigate the effects of inbreeding determined by ROH on the traits under selection in the subpopulation studied.

An integrative approach highlights the discrepancy in the genetic, phenotypic, and presumptive taxonomic structure of Phoxinus (Actinopterygii, Leuciscidae, Phoxininae) in Bulgaria.

The present drainage network of Bulgaria is the result of a complex Neogene and Quaternary evolution. Karst, which has developed on 23% of the territory, further complicates the hydrological pattern. Fresh waters of Bulgaria drain into the Black Sea and the Aegean Sea basins and can be roughly divided into the Danube (Middle and Lower Danube), non-Danube Black Sea, East Aegean, and West Aegean hydrological regions. Phoxinus, a small leuciscid fish, has a mosaic distribution in all four of these regions, inhabiting small mountainous and semi-mountainous streams. Based on morphology, it was identified as three species, Phoxinus phoxinus in the Danube, Phoxinus strandjae in the non-Danube, and Phoxinus strymonicus in West Aegean region. Later, molecular data revealed Phoxinus csikii and Phoxinus lumaireul in the Middle Danube and P. csikii in the Lower Danube. Phoxinus has been the focus of many studies, showing a high molecular and morphological diversity, which is not entirely consistent with previous morphology-only-based taxonomic concepts. In this study, molecular (a mitochondrial marker and a nuclear marker) and morphological data from both historical and recently sampled collections were analysed to assess the applicability of the integrative approach in Phoxinus. The results showed a significant influence of the complex paleo- and recent hydrology on the currently observed genetic structure of the considered populations and species. Furthermore, the study also demonstrated a strong influence of phenotypic plasticity on the morphological analysis of Phoxinus and the lack of a clear differentiation between P. csikii and P. strandjae. A barcoded specimen was designated as neotype to fix the species named P. strandjae in the current taxonomic concept. Finally, a significant discordance between genetically delimited clades and phenotypic groups did not allow a proper delineation of the species distributed in Bulgaria, demonstrating that more molecular markers are needed for further taxonomic study of the Phoxinus complex.

Revealing Genetic Dynamics: scRNA-seq Unravels Modifications in Human PDL Cells across In Vivo and In Vitro Environments.

The periodontal ligament (PDL) is a highly specialized fibrous tissue comprising heterogeneous cell populations of an intricate nature. These complexities, along with challenges due to cell culture, impede a comprehensive understanding of periodontal pathophysiology. This study aims to address this gap, employing single-cell RNA sequencing (scRNA-seq) technology to analyze the genetic intricacies of PDL both in vivo and in vitro. Primary human PDL samples (n = 7) were split for direct in vivo analysis and cell culture under serum-containing and serum-free conditions. Cell hashing and sorting, scRNA-seq library preparation using the 10x Genomics protocol, and Illumina sequencing were conducted. Primary analysis was performed using Cellranger, with downstream analysis via the R packages Seurat and SCORPIUS. Seven distinct PDL cell clusters were identified comprising different cellular subsets, each characterized by unique genetic profiles, with some showing donor-specific patterns in representation and distribution. Formation of these cellular clusters was influenced by culture conditions, particularly serum presence. Furthermore, certain cell populations were found to be inherent to the PDL tissue, while others exhibited variability across donors. This study elucidates specific genes and cell clusters within the PDL, revealing both inherent and context-driven subpopulations. The impact of culture conditions-notably the presence of serum-on cell cluster formation highlights the critical need for refining culture protocols, as comprehending these influences can drive the creation of superior culture systems vital for advancing research in PDL biology and regenerative therapies. These discoveries not only deepen our comprehension of PDL biology but also open avenues for future investigations into uncovering underlying mechanisms.

Development of a real-time PCR protocol for the detection of chicken DNA in meat products.

Food falsification is a pressing issue in today's food industry, with fraudulent substitution of costly ingredients with cheaper alternatives occurring globally. Consequently, developing straightforward and efficient diagnostic systems to detect such fraud is a top priority in scientific research. The aim of the work was to develop a test system and protocol for polymerase chain reaction (PCR) to detect in food products of animal origin the substitution of expensive meat raw materials for by-products of poultry processing. For this, real-time polymerase chain reaction (RT-PCR) was used, which allows determining the qualitative and quantitative substitution in raw and technologically prepared products. Other methods for detecting falsification - enzyme immunoassay (ELISA/ELISA) or express methods in the form of a lateral flow immunoassay are less informative. The extraction of nucleic acids for real-time polymerase chain reaction depends on the source matrix, with higher concentrations obtained from germ cells and parenchymal organs. Extraction from muscle and plant tissues is more challenging, but thorough grinding of these samples improves nucleic acid concentration by 1.5 times using DNA extraction kits. The selection of primers and fluorescent probes through GenBank and PCR Primer Design/DNASTAR software enables efficient amplification and identification of target chicken DNA fragments in various matrices.

Development and validation of blood tumor mutational burden reference standards.

Tumor mutational burden (TMB), measured by exome or panel sequencing of tumor tissue or blood (bTMB), is a potential predictive biomarker for treatment benefit in patients with various cancer types receiving immunotherapy targeting checkpoint pathways. However, significant variability in TMB measurement has been observed. We developed contrived bTMB reference materials using DNA from tumor cell lines and donor-matched lymphoblastoid cell lines to support calibration and alignment across laboratories and platforms. Contrived bTMB reference materials were developed using genomic DNA from lung tumor cell lines blended into donor-matched lymphoblastoid cell lines at 0.5% and 2% tumor content, fragmented and size-selected to mirror the size profile of circulating cell-free tumor DNA with TMB scores of 7, 9, 20, and 26 mut/Mb. Variant allele frequency (VAF) and bTMB scores were assessed using PredicineATLAS and GuardantOMNI next-generation sequencing assays. DNA fragment sizes in the contrived reference samples were similar to those found within patient plasma-derived cell-free DNA, and mutational patterns aligned with those in the parental tumor lines. For the 7, 20, and 26 mut/Mb contrived reference samples with 2% tumor content, bTMB scores estimated using either assay aligned with expected scores from the parental tumor cell lines and showed good reproducibility. A bioinformatic filtration step was required to account for low-VAF artifact variants. We demonstrate the feasibility and challenges of producing and using bTMB reference standards across a range of bTMB levels, and how such standards could support the calibration and validation of bTMB platforms and help harmonization between panels and laboratories.

Psoriasis and Psoriatic Arthritis-Associated Genes, Cytokines, and Human Leukocyte Antigens.

In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines.

A DNA typing panel of 201 genetic markers for degraded samples: development and validation.

With the increasing number of complex forensic cases in recent years, it's more important to combine the different types of genetic markers such as short tandem repeats (STRs), single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (InDels), and microhaplotypes (MHs) to provide more genetic information. In this study, we selected totally 201 genetic markers, including 24 autosomes STRs (A-STRs), 24 Y chromosome STRs (Y-STRs), 110 A-SNPs, 24 Y-SNPs, 9 A-InDels, 1 Y-InDel, 8 MHs, and Amelogenin to establish the HID_AM Panel v1.0, a Next-Generation Sequencing (NGS) detection system. According to the validation guidelines of the Scientific Working Group on DNA Analysis Methods (SWGDAM), the repeatability, accuracy, sensitivity, suitability for degraded samples, species specificity, and inhibitor resistance of this system were assessed. The typing results on 48 STRs and Amelogenin of this system were completely consistent with those obtained using capillary electrophoresis. This system accurately detected 79 SNPs as parallelly confirmed by a FGx sequencer with the ForenSeq™ DNA Signature Prep Kit. Complete allele typing results could be obtained with a DNA input of no less than 200 pg. The detection success rate of this system was significantly higher than that of the GlobalFiler™ kit when the degradation index of mock degraded sample was greater than 15.87. When the concentration of hematin in the amplification system was ≤40 µmol/L, indigo blue was ≤2 mmol/L, or humic acid was ≤15 ng/µL, amplification was not significantly inhibited. The system barely amplified the DNA extract from duck, mouse, cow, rabbit, and chick. The detection rate of STRs on routine samples of this panel is 99.74%, while all the SNPs, InDels, and MHs were successfully detected. In summary, we setup a NGS individual typing panel including 201 genetic markers with the high accuracy, sensitivity, species specificity, and inhibitors resistance, which is applicable for individual identification of degraded samples.

Bioinformatic analysis of the effect of SNPs in the pig TERT gene on the structural and functional characteristics of the enzyme to develop new genetic markers of productivity traits.

BACKGROUND: Telomerase reverse transcriptase (TERT) plays a crucial role in synthesizing telomeric repeats that safeguard chromosomes from damage and fusion, thereby maintaining genome stability. Mutations in the TERT gene can lead to a deviation in gene expression, impaired enzyme activity, and, as a result, abnormal telomere shortening. Genetic markers of productivity traits in livestock can be developed based on the TERT gene polymorphism for use in marker-associated selection (MAS). In this study, a bioinformatic-based approach is proposed to evaluate the effect of missense single-nucleotide polymorphisms (SNPs) in the pig TERT gene on enzyme function and structure, with the prospect of developing genetic markers. RESULTS: A comparative analysis of the coding and amino acid sequences of the pig TERT was performed with corresponding sequences of other species. The distribution of polymorphisms in the pig TERT gene, with respect to the enzyme's structural-functional domains, was established. A three-dimensional model of the pig TERT structure was obtained through homological modeling. The potential impact of each of the 23 missense SNPs in the pig TERT gene on telomerase function and stability was assessed using predictive bioinformatic tools utilizing data on the amino acid sequence and structure of pig TERT. CONCLUSIONS: According to bioinformatic analysis of 23 missense SNPs of the pig TERT gene, a predictive effect of rs789641834 (TEN domain), rs706045634 (TEN domain), rs325294961 (TRBD domain) and rs705602819 (RTD domain) on the structural and functional parameters of the enzyme was established. These SNPs hold the potential to serve as genetic markers of productivity traits. Therefore, the possibility of their application in MAS should be further evaluated in associative analysis studies.

Multimarker omnibus tests by leveraging individual marker summary statistics from large biobanks.

As biobanks become increasingly popular, access to genotypic and phenotypic data continues to increase in the form of precomputed summary statistics (PCSS). Widespread accessibility of PCSS alleviates many issues related to biobank data, including that of data privacy and confidentiality, as well as high computational costs. However, questions remain about how to maximally leverage PCSS for downstream statistical analyses. Here we present a novel method for testing the association of an arbitrary number of single nucleotide variants (SNVs) on a linear combination of phenotypes after adjusting for covariates for common multimarker tests (e.g., SKAT, SKAT-O) without access to individual patient-level data (IPD). We validate exact formulas for each method, and demonstrate their accuracy through simulation studies and an application to fatty acid phenotypic data from the Framingham Heart Study.

Hedgehog signaling-related genomics signature for the accurate progress and prognosis prediction in gastric cancer.

The Hedgehog pathway is thought to be closely associated with the progression of GC; however, a specific link between the Hedgehog pathway on the prognosis and immune infiltration of gastric cancer is still lacking. This study collected Hedgehog pathway-related genes. The Hedgehog pathway-related pattern were identified by consensus cluster analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were used to identify the biological functions which were significantly altered between predefined Cluster1 and Cluster2 in consensus clustering. The risk model of gastric cancer based on Hedgehog signaling pathway was constructed by univariate and multivariate COX regression, and the nomogram was constructed. The results showed that there were significant differences in the expression of Hedgehog pathway-related genes between the two groups. In addition, the constructed risk model was significantly correlated with the clinical prognosis and immune cell infiltration level of patients with gastric cancer. The model effectively predicted the efficacy of chemotherapy in GC patients and the sensitivity of drug treatment between groups. We systematically revealed the mechanism of Hedgehog pathway in gastric cancer and selected biomarkers with biological significance from a new perspective, providing potential direction for the treatment of gastric cancer.

Genetic fingerprint construction and genetic diversity analysis of sweet potato (Ipomoea batatas) germplasm resources.

BACKGROUND: China is the largest producer of sweet potato in the world, accounting for 57.0% of the global output. Germplasm resources are the basis for promoting innovations in the seed industry and ensuring food security. Individual and accurate identification of sweet potato germplasm is an important part of conservation and efficient utilization. RESULTS: In this study, nine pairs of simple sequence repeat molecular markers and 16 morphological markers were used to construct genetic fingerprints for sweet potato individual identification. Combined with basic information, typical phenotypic photographs, genotype peak graphs, and a two-dimensional code for detection and identification were generated. Finally, a genetic fingerprint database containing 1021 sweet potato germplasm resources in the "National Germplasm Guangzhou Sweet Potato Nursery Genebank in China" was constructed. Genetic diversity analysis of the 1021 sweet potato genotypes using the nine pairs of simple sequence repeat markers revealed a narrow genetic variation range of Chinese native sweet potato germplasm resources, and Chinese germplasm was close to that from Japan and the United States, far from that from the Philippines and Thailand, and the furthest from that from Peru. Sweet potato germplasm resources from Peru had the richest genetic diversity, supporting the view that Peru is the center of origin and domestication of sweet potato varieties. CONCLUSIONS: Overall, this study provides scientific guidance for the conservation, identification, and utilization of sweet potato germplasm resources and offers a reference to facilitate the discovery of important genes to boost sweet potato breeding.

The added value of ferritin levels and genetic markers for the prediction of haemoglobin deferral.

BACKGROUND AND OBJECTIVES: On-site haemoglobin deferral for blood donors is sometimes necessary for donor health but demotivating for donors and inefficient for the blood bank. Deferral rates could be reduced by accurately predicting donors' haemoglobin status before they visit the blood bank. Although such predictive models have been published, there is ample room for improvement in predictive performance. We aim to assess the added value of ferritin levels or genetic markers as predictor variables in haemoglobin deferral prediction models. MATERIALS AND METHODS: Support vector machines with and without this information (the full and reduced model, respectively) are compared in Finland and the Netherlands. Genetic markers are available in the Finnish data and ferritin levels in the Dutch data. RESULTS: Although there is a clear association between haemoglobin deferral and both ferritin levels and several genetic markers, predictive performance increases only marginally with their inclusion as predictors. The recall of deferrals increases from 68.6% to 69.9% with genetic markers and from 79.7% to 80.0% with ferritin levels included. Subgroup analyses show that the added value of these predictors is higher in specific subgroups, for example, for donors with minor alleles on single-nucleotide polymorphism 17:58358769, recall of deferral increases from 73.3% to 93.3%. CONCLUSION: Including ferritin levels or genetic markers in haemoglobin deferral prediction models improves predictive performance. The increase in overall performance is small but may be substantial for specific subgroups. We recommend including this information as predictor variables when available, but not to collect it for this purpose only.

Association of apoptosis-related variants to malaria infection and parasite density in individuals from the Brazilian Amazon.

BACKGROUND: In malaria infection, apoptosis acts as an important immunomodulatory mechanism that leads to the elimination of parasitized cells, thus reducing the parasite density and controlling immune cell populations. Here, it was investigated the association of INDEL variants in apoptotic genes-rs10562972 (FAS), rs4197 (FADD), rs3834129 and rs59308963 (CASP8), rs61079693 (CASP9), rs4647655 (CASP3), rs11269260 (BCL-2), and rs17880560 (TP53)-and the influence of genetic ancestry with susceptibility to malaria and parasite density in an admixed population from the Brazilian Amazon. METHODS: Total DNA was extracted from 126 malaria patients and 101 uninfected individuals for investigation of genetic ancestries and genotypic distribution of apoptosis-related variants by Multiplex PCR. Association analyses consisted of multivariate logistic regressions, considering the following comparisons: (i) DEL/DEL genotype vs. INS/DEL + INS/INS; and (ii) INS/INS vs. INS/DEL + DEL/DEL. RESULTS: Individuals infected by Plasmodium falciparum had significantly higher African ancestry proportions in comparison to uninfected controls, Plasmodium vivax, and mixed infections. The INS/INS genotype of rs3834129 (CASP8) seemed to increase the risk for P. falciparum infection (P = 0.038; OR = 1.867; 95% CI 0.736-3.725), while the DEL/DEL genotype presented a significant protective effect against infection by P. falciparum (P = 0.049; OR = 0.446; 95% CI 0.185-0.944) and mixed infection (P = 0.026; OR = 0.545; 95% CI 0.281-0.996), and was associated with lower parasite density in P. falciparum malaria (P = 0.009; OR = 0.383; 95% CI 0.113-1.295). Additionally, the INS/INS genotype of rs10562972 (FAS) was more frequent among individuals infected with P. vivax compared to P. falciparum (P = 0.036; OR = 2.493; 95% CI 1.104-4.551), and the DEL/DEL genotype of rs17880560 (TP53) was significantly more present in patients with mono-infection by P. vivax than in individuals with mixed infection (P = 0.029; OR = 0.667; 95% CI 0.211-1.669). CONCLUSIONS: In conclusion, variants in apoptosis genes are associated with malaria susceptibility and parasite density, indicating the role of apoptosis-related genetic profiles in immune responses against malaria infection.