Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.

Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in MYH3 have been identified to cause the dominantly-inherited distal arthrogryposis conditions, Freeman-Sheldon syndrome, Sheldon-Hall syndrome, and multiple pterygium syndrome. In contrast, MYH3 variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra-rare MYH3 variants, c.3445G>A (p.Glu1149Lys) and c.4760T>C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in MYH3 being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in MYH3.

Endogenous fungal endophthalmitis caused by Cladophialophora devriesii: report of a case and literature review.

PURPOSE: To report a case of endogenous endophthalmitis caused by the dematiaceous fungus Cladophialophora devriesii. METHODS: Observational case report and literature review. CASE PRESENTATION: A 73-year-old female with a history of chronic obstructive pulmonary disease presented with a red and painful left eye. Examination revealed anterior segment inflammation and vitritis, indicative of endophthalmitis. She underwent core vitrectomy and intravitreal injection of vancomycin and amphotericin B. The vitreous sample showed inflammatory cells and fungal hyphae, and systemic amphotericin B and itraconazole were commenced for fungal endophthalmitis. Targeted amplification of the sample for bacterial DNA (V2-V3 region of 16 S rDNA) was negative, but fungal DNA targets (ITS1 and ITS2) were present, and their sequences were consistent with Cladophialophora devriesii. Phenotypic characterisation and sequencing of ITS1 and ITS2, carried out on cultured fungus from the sample, also revealed Cladophialophora devriesii. She received repeated intravitreal injections of voriconazole, and based on the antifungal susceptibility results, her systemic medication was changed to posaconazole. After 12 months, the eye showed no signs of inflammation, and posaconazole therapy was discontinued. After 3 months without antifungal medication, the inflammation recurred, and she was restarted on antifungal therapy for an additional 20 months. Another recurrence occurred 3 months after discontinuation of treatment, and a repeat vitreous sample confirmed the presence of Cladophialophora devriesii. She was started on isavuconazole, but developed seclusio pupillae and painful secondary glaucoma. Due to the duration and severity of the infection, the eye was enucleated. Histopathology revealed persistent fungal elements at the ciliary processes and the posterior lens surface. CONCLUSIONS: This second reported case of endogenous endophthalmitis caused by Cladophialophora devriesii illustrates the role of vitreous sampling and molecular methods in diagnosis and treatment of fungal endophthalmitis. Despite early diagnosis and prolonged local and systemic antifungal therapy, it was not possible to achieve long-term control of the fungal infection.

Placental TLR recognition of salivary and subgingival microbiota is associated with pregnancy complications.

BACKGROUND: Pre-term birth, the leading cause of neonatal mortality, has been associated with maternal periodontal disease and the presence of oral pathogens in the placenta. However, the mechanisms that underpin this link are not known. This investigation aimed to identify the origins of placental microbiota and to interrogate the association between parturition complications and immune recognition of placental microbial motifs. Video Abstract METHODS: Saliva, plaque, serum, and placenta were collected during 130 full-term (FT), pre-term (PT), or pre-term complicated by pre-eclampsia (PTPE) deliveries and subjected to whole-genome shotgun sequencing. Real-time quantitative PCR was used to measure toll-like receptors (TLR) 1-10 expression in placental samples. Source tracking was employed to trace the origins of the placental microbiota. RESULTS: We discovered 10,007 functionally annotated genes representing 420 taxa in the placenta that could not be attributed to contamination. Placental microbial composition was the biggest discriminator of pregnancy complications, outweighing hypertension, BMI, smoking, and maternal age. A machine-learning algorithm trained on this microbial dataset predicted PTPE and PT with error rates of 4.05% and 8.6% (taxonomy) and 6.21% and 7.38% (function). Logistic regression revealed 32% higher odds of parturition complication (95% CI 2.8%, 81%) for every IQR increase in the Shannon diversity index after adjusting for maternal smoking status, maternal age, and gravida. We also discovered distinct expression patterns of TLRs that detect RNA- and DNA-containing antigens in the three groups, with significant upregulation of TLR9, and concomitant downregulation of TLR7 in PTPE and PT groups, and dense correlation networks between microbial genes and these TLRs. 70-82% of placental microbiota were traced to serum and thence to the salivary and subgingival microbiomes. The oral and serum microbiomes of PTPE and PT groups displayed significant enrichment of genes encoding iron transport, exosome, adhesion, quorum sensing, lipopolysaccharide, biofilm, and steroid degradation. CONCLUSIONS: Within the limits of cross-sectional analysis, we find evidence to suggest that oral bacteria might translocate to the placenta via serum and trigger immune signaling pathways capable of inducing placental vascular pathology. This might explain, in part, the higher incidence of obstetric syndromes in women with periodontal disease.

Staphylococcus aureus small colony variants: A potentially underestimated microbiological challenge in peritoneal dialysis.

INTRODUCTION: Peritonitis remains the major infectious complication in the setting of peritoneal dialysis (PD). Despite known only moderate pathogenicity, the most frequently detected pathogens in PD-related peritonitis are surprisingly coagulase-negative staphylococci. However, this could be explained, at least in part, by Staphylococcus aureus small colony variants (SCVs) induced by PD fluids (PDFs) and misidentified by routinely used microbiological methods. MATERIAL AND METHODS: Bacteria were exposed to commonly used PDFs in various regimens designed to simulate daily use as closely as possible. Wild-type isolates and SCVs were subsequently used to determine minimum inhibitory concentrations (MICs), in vitro biofilm formation capacities, and auxotrophies. Underlying genetic alterations were investigated using whole-genome sequencing, and various microbial identification methods were tested to determine their performance for wild-types and SCVs. RESULTS: Stable SCVs could be isolated most successfully after exposure to glucose-containing PDFs alone. The reading of MICs was significantly affected by the reduced growth of SCVs, resulting in lower MIC values in 44% of all tests. Nonsynonymous mutations were found in all but one SCV, while only two isolates showed typical auxotrophic responses. While MALDI-TOF, PCR and Pastorex Staph-Plus correctly identified all S. aureus SCVs, API-Staph and VITEK-2 yielded identification rates of only 40% and 10%, respectively. CONCLUSIONS: Overall, the present study has shown that commercially available PDFs induce S. aureus SCVs in vitro, which are difficult to identify and test for antimicrobial susceptibility and can potentially lead to recurrent or persistent infections. Thus, they represent a potentially underappreciated challenge not only for microbiologists, but also for clinicians.

Impact of surface characteristics on the peri-implant microbiome in health and disease.

BACKGROUND: Because little is known about the impact of implant surface modifications on the peri-implant microbiome, we aimed to examine peri-implant communities in various surface types in order to better understand the impact of these surfaces on the development of peri-implantitis (PI). METHODS: One hundred and six systemically healthy individuals with anodized (AN), hydroxyapatite-coated (HA), or sandblasted acid-etched (SLA) implants that were >6 months in function were recruited and categorized into health (H) or PI. Peri-implant biofilm was analyzed using 16S rRNA gene sequencing and compared between health/disease and HA/SLA/AN using community-level and taxa-level metrics. RESULTS: Healthy implants did not demonstrate significant differences in clustering, alpha- or beta-diversity based on surface modification. AN and HA surfaces displayed significant differences between health and PI (p < 0.05); however, such a clustering was not evident with SLA (p > 0.05). AN and HA surfaces also differed in the magnitude and diversity of differences between health and PI. Six species belonging to the genera Shuttleworthia, Scardovia, and Prevotella demonstrated lower abundances in AN implants with PI, and 18 species belonging to the genera Fretibacterium, Tannerella, Treponema, and Fusobacterium were elevated, while in HA implants with PI, 20 species belonging to the genera Streptococcus, Lactobacillus, Veillonella, Rothia, and family Ruminococcaceae were depleted and Peptostreptococcaceae, Atopobiaceae, Veillonellaceae, Porphyromonadaceae, Desulfobulbaceae, and order Synergistales were enriched. CONCLUSIONS: Within the limitations of this study, we demonstrate that implant surface can differentially modify the disease-associated microbiome, suggesting that surface topography must be considered in the multi-factorial etiology of peri-implant diseases.

Antifungal Susceptibility and Biological Characteristics of Fonsecaea monophora Causing Cerebral Phaeohyphomycosis in Jinhua, China.

Background: The management of cerebral abscesses caused by dark-pigmented Fonsecaea monophora in healthy individuals continues to be challenging due to no consensus on the therapeutic regimen. Due to the absence of an accurate identification method, Fonsecaea species are often misidentified due to indistinct morphology features. Materials and Methods: An F. monophora strain from an immunocompetent host with cerebral abscess was collected and identified by ITS rDNA molecular sequencing. The ITS sequences of the isolate were compared with that of the other ten Chinese F. monophora isolates obtained from GenBank for difference comparison and phylogenetic analysis. Fluorescence, Gram stains, and medan lactate were used to observe the colonial morphology. Antifungal susceptibility testing was implemented to demonstrate the antibiotic susceptibility profile. Galleria mellonella larvae were used as a model to study virulence of F. monophora. Medical records and clinical data of the patient were collected and analyzed. Results: Antifungal susceptibility testing indicated that triazole antifungal drugs possess remarkable antifungal effect against F. monophora, and satisfactory antifungal effect of itraconazole was corresponding to the drug susceptibility results. Compared with the GM test, the serum G test was found to be more sensitive. The virulence and melanization in G. mellonella models for F. monophora were observed, and the death rates of infected larvae were positively related to injected concentrations of fungus. The phylogenetic tree was constructed from the ITS sequences of the clinical isolate along with ten Chinese F. monophora isolates, revealing that there is high relatedness in F. monophora strains collected from China. Conclusion: F. monophora is an important neurotropic dematiaceous fungus and increasingly causing disease in immunocompetent individuals by means of noninvasive ways. Fungal culture, stainings, and molecular methods could be utilized to identify the etiologic agent. Triazole antifungal drugs can be applied as empiric therapeutic agents for phaeohyphomycosis.

Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms.

BACKGROUND: Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients. RESULTS: Of the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants - H1778R - was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC. CONCLUSIONS: IPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India.

Comparison of Two Variant Analysis Programs for Next-Generation Sequencing Data of Whole Mitochondrial Genome.

BACKGROUND: With advance of next-generation sequencing (NGS) techniques, the need for mitochondrial DNA analysis is increasing not only in the forensic area, but also in medical fields. METHODS: Two commercial programs, Converge Software (CS) and Torrent Variant Caller for variant calling of NGS data, were compared with a considerable amount of sequence data of 50 samples with a homogeneous ethnicity. RESULTS: About 2,300 variants were identified and the two programs showed about 90% of consistency. CS, a dedicated analysis program for mitochondrial DNA, showed some advantages for forensic use. By additional visual inspection, several causes of discrepancy in variant calling results were identified. Application of different notation rules for mitochondrial sequence and the minor allele frequency close to detection threshold were the two most significant reasons. CONCLUSION: With prospective improvement of each program, researchers and practitioners should be aware of characteristics of the analysis program they use and prepare their own strategies to determine variants.

Predictive factors of genetic diagnosis and real-life impact of next-generation sequencing for children with epilepsy.

OBJECTIVE: Identify the predictive variables of genetic pathogenic results and the impact of test results on epilepsy diagnosis and management. METHODS: Analytical observational design evaluated 130 patients with epilepsy that had performed genetic testing over January 2017 to July 2022. RESULTS: There was a gradual increase in the number of exams performed over the years. The frequency of pathogenic results was 34% (n = 44/130), 8 altered genes with 54% (n = 24/44) of the results. The tests were more positive in patients with developmental delay and/or regression (p = .01). None of the other factors analyzed were associated with higher diagnostic yield. The age at onset of epilepsy brought diagnostic yield to the test (p = .041). Patients with negative genetic test had a reduction in the number of electroencephalograms performed before and after the test (respectively, 3.80 ± 6.37 and .84 ± 1.67; p < .001). SIGNIFICANCE: Facing a large proportion of patients with unexplained epilepsy have a genetic cause a genetic test has the potential to reduce the use of unnecessary diagnostic tests, improve patient outcomes by identifying targeted treatments, and provide families with genetic counseling and risk assessment. But an early genetic testing can be crucial to reach these goals. Even in cases where the genetic test is negative, the study suggests that it still has important implications for patient care and management.

Allele frequency of SLC4A3 (PRA1), TTC8 (PRA2), and PRA-prcd mutations in golden retrievers in Brazil.

Progressive retinal atrophy (PRA) is a term used in veterinary medicine to describe inherited and progressive retinal diseases characterized by progressive retinal degeneration and loss of vision. In the Golden Retriever (GR) breed, the mutations associated with PRA have an autosomal recessive inheritance pattern. This study aimed to verify the allele frequencies of PRA1, PRA2, and PRA-prcd in the GR breed in Brazil. A total of 121 GR DNA samples (n = 66 females and n = 55 males) were analyzed. All animals assessed in this study were identified as wild-type (121/121 animals; 100%) for PRA1 and PRA2 mutations; therefore, no carrier or homozygous animals were identified in this population. For the PRA-prcd mutation, 118 animals (118/121 animals; 97.52%) were wild-type. Three animals were genotyped as heterozygous for PRA-prcd (3/121 animals; 2.47%), demonstrating that this mutation is still present in some bloodlines and animals in Brazil, even with a rare prevalence. Five animals (5/121 animals, 4.2%) had a previous eye disease, which was diagnosed by a veterinarian as entropion (2 animals), keratoconjunctivitis sicca (1 animal), corneal ulcer (1 animal), and bilateral blindness (1 animal). This dog with bilateral blindness was identified as wild type homozygous for three mutations assessed in this study; therefore, blindness was not associated with the investigated mutations. In addition, the vast majority (98.3%) of Brazilian breeders assessed in this study were unaware of these mutations as a cause of blindness in the Golden Retriever. Therefore, the present study will serve to disseminate knowledge about PRA and its genetic etiologies, as well as to support future studies with other Brazilian GR populations.

Identification of a novel missense mutation in non-syndromic familial multiple supernumerary teeth.

OBJECTIVE: This study intended to evaluate the involvement of genetic factors in the etiology of non-syndromic multiple supernumerary teeth. DESIGN: We filtered the single nucleotide polymorphisms (SNPs) of the proband and his mother with similar phenotypes through whole-genome sequencing (WGS). By integrating multiple databases related to human genome mutations and disease information for mutation annotation, we excluded the SNPs of people without supernumerary teeth. Subsequently, the bioinformatics analysis tools (Sorting Intolerant From Tolerant (SIFT) < 0.05, Polymorphism Phenotyping (PolyPhen) > 0.90) were used to screen out the most correlated SNPs of the disease, besides, Gene Ontology (GO) analysis (P<0.05, FDR<0.05) and Sanger sequencing was applied to further verify the candidate pathogenic mutation point. RESULTS: A novel heterozygous variant in fer-1 like family member 6 (FER1L6) gene likely denoted pathogenicity in non-syndromic familial multiple supernumerary teeth. We identified a cohort of 3499 non-synonymous SNPs (nsSNPs), and only 142 nsSNPs with the score of SIFT < 0.05 and PolyPhen > 0.90 were retained. Then we got 54 nsSNPs from 31 candidate genes through GO analysis. Sanger sequencing revealed a missense variant in exon 31 of the FER1L6 gene, causing a transition from guanine to adenine in position 1447 of protein kinase C conserved region 2. CONCLUSIONS: We identified a novel heterozygous chromosome 8q24.13 mutation of FER1L6, which was a new mutation site identified in non-syndromic familial multiple supernumerary teeth through genetic analysis of a Chinese family.

Comparison of two commercial methods for smooth-shelled mussels (Mytilus spp.) species identification.

Seafood international trade has increased the labeling requirements in standards and regulations to include product information that enable traders and consumers to make informed choices. The European Union (EU) Regulation No. 1379/2013 imposes the declaration of an official commercial designation and scientific names for all the fishery and aquaculture products to be offered for sale to the final consumers. DNA analyses are used to enforce this regulation and to test authenticity in processed foods. We compared the performance of two mono-locus approaches for species identification (SI) in 61 Mytilus mussels: the high-resolution melting analysis of the polyphenolic adhesive protein gene and the partial sequencing of the histone H1C gene. The H1C sequences were analyzed with five different methods. Both approaches show discrepancies in the identification of putative hybrids (0.0 < κ < 0.687 and 0.0 < MCC < 0.724). Excluding putative hybrids, methods show substantial to perfect agreement (0.772 < κ < 1.0 and 0.783 < MCC < 1.0). This study highlights the need to use standardized molecular tools, as well as to use multi-locus methods for SI of Mytilus mussels in testing laboratories.

Genetic Diversity of Amylomyces rouxii from Ragi tapai in Java Island Based on Ribosomal Regions ITS1/ITS2 and D1/D2.

Amylomyces rouxii is commonly found as amylolytic fungi in tapai fermentation. However, its diversity is rarely reported despite being often used for food production in Southeast Asia. This research aims to analyze the genetic diversity and the distribution pattern of A. rouxii from Ragi tapai in Java Island, Indonesia. We isolated the fungus from samples obtained from Ragi tapai producing centers in Bandung, Sumedang, Muntilan, Blora, Yogyakarta, and Bondowoso. The obtained isolates were molecularly identified based on the ribosomal regions ITS1/ITS2 and D1/D2, then analyzed for phylogenetic tree reconstruction, genetic distance, genetic variation, and haplotype networking. Six isolates showed specific morphological traits of A. rouxii. However, phylogenetic tree reconstruction on the ribosomal genes showed that the isolates were grouped into two different clades related to two species. Clade A included BDG, SMD, and MTL isolates related to A. rouxii, whereas clade B included YOG, BLR, and BDS isolates related to Mucor indicus. The genetic distances between clades for ITS1/ITS2 and D1/D2 were 0.6145 and 0.1556, respectively. In conclusion, we confirmed the genetic diversity of molds from Ragi tapai in Java Island and showed that the isolates are not only related to A. rouxii as reported before.

Next-Generation Sequencing to Characterize Mitochondrial Genomic DNA Heteroplasmy.

Mitochondria play a very important role in many crucial cellular functions. Each eukaryotic cell contains hundreds of mitochondria with hundreds of mitochondrial genomes. Mutant and wild-type mitochondrial DNA (mtDNA) may co-exist as heteroplasmy and cause human disease. The purpose of the protocols in this article is to simultaneously determine the mtDNA sequence and quantify the heteroplasmy level using parallel sequencing. The protocols include mitochondrial genomic DNA PCR amplification of two full-length products using two distinct sets of PCR primers. The PCR products are mixed at an equimolar ratio, and the samples are then barcoded and sequenced with high-throughput next-generation sequencing technology. This technology is highly sensitive, specific, and accurate in determining mtDNA mutations and the degree/level of heteroplasmy. © 2022 Wiley Periodicals LLC. Basic Protocol 1: PCR amplification of mitochondrial DNA Basic Protocol 2: Analysis of next-generation sequencing of mitochondrial DNA Basic Protocol 3: Mutect2 pipeline for automated sample processing and large-scale data analysis.

Corrigendum: Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation.

[This corrects the article DOI: 10.3389/fgene.2021.744068.].

abc4pwm: affinity based clustering for position weight matrices in applications of DNA sequence analysis.

BACKGROUND: Transcription factor (TF) binding motifs are identified by high throughput sequencing technologies as means to capture Protein-DNA interactions. These motifs are often represented by consensus sequences in form of position weight matrices (PWMs). With ever-increasing pool of TF binding motifs from multiple sources, redundancy issues are difficult to avoid, especially when every source maintains its own database for collection. One solution can be to cluster biologically relevant or similar PWMs, whether coming from experimental detection or in silico predictions. However, there is a lack of efficient tools to cluster PWMs. Assessing quality of PWM clusters is yet another challenge. Therefore, new methods and tools are required to efficiently cluster PWMs and assess quality of clusters. RESULTS: A new Python package Affinity Based Clustering for Position Weight Matrices (abc4pwm) was developed. It efficiently clustered PWMs from multiple sources with or without using DNA-Binding Domain (DBD) information, generated a representative motif for each cluster, evaluated the clustering quality automatically, and filtered out incorrectly clustered PWMs. Additionally, it was able to update human DBD family database automatically, classified known human TF PWMs to the respective DBD family, and performed TF motif searching and motif discovery by a new ensemble learning approach. CONCLUSION: This work demonstrates applications of abc4pwm in the DNA sequence analysis for various high throughput sequencing data using ~ 1770 human TF PWMs. It recovered known TF motifs at gene promoters based on gene expression profiles (RNA-seq) and identified true TF binding targets for motifs predicted from ChIP-seq experiments. Abc4pwm is a useful tool for TF motif searching, clustering, quality assessment and integration in multiple types of sequence data analysis including RNA-seq, ChIP-seq and ATAC-seq.

Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. METHODS: A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. RESULTS: A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). CONCLUSION: In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.

Deep transformers and convolutional neural network in identifying DNA N6-methyladenine sites in cross-species genomes.

As one of the most common post-transcriptional epigenetic modifications, N6-methyladenine (6 mA), plays an essential role in various cellular processes and disease pathogenesis. Therefore, accurately identifying 6 mA modifications is necessary for a deep understanding of cellular processes and other possible functional mechanisms. Although a few computational methods have been proposed, their respective models were developed with small training datasets. Hence, their practical application is quite limited in genome-wide detection. To overcome the existing limitations, we present a novel model based on transformer architecture and deep learning to identify DNA 6 mA sites from the cross-species genome. The model is constructed on a benchmark dataset and explored a feature derived from pre-trained transformer word embedding approaches. Subsequently, a convolutional neural network was employed to learn the generated features and generate the prediction outcomes. As a result, our predictor achieved excellent performance during independent test with the accuracy and Matthews correlation coefficient (MCC) of 79.3% and 0.58, respectively. Overall, its performance achieved better accuracy than the baseline models and significantly outperformed the existing predictors, demonstrating the effectiveness of our proposed hybrid framework. Furthermore, our model is expected to assist biologists in accurately identifying 6mAs and formulate the novel testable biological hypothesis. We also release source codes and datasets freely at https://github.com/khanhlee/bert-dna for front-end users.