BACKGROUND:Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequenc...
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BACKGROUND:Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights.
RESULTS:Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest.
CONCLUSIONS:In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://***/SpliceAPP . Source code can be downloaded at https://***/hsinnan75/SpliceAPP .
Southern Thailand's traditional sweet pickled mango, known as Ma-Muang Bao Chae-Im (MBC), holds an important place in the local community. Several immersion processes, including brining and submersion in a hyperto...
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Mutations in tumor suppressor genes and oncogenes are both potentially therapeutically actionable in acute myeloid leukemia (AML). The Wilms' Tumor 1 ( WT1 ) gene is located on 11p13 and encodes a zinc finger tran...
Mutations in tumor suppressor genes and oncogenes are both potentially therapeutically actionable in acute myeloid leukemia (AML). The Wilms' Tumor 1 ( WT1 ) gene is located on 11p13 and encodes a zinc finger transcription factor which has been found to be overexpressed and mutated in AML. In normal development, WT1 is only expressed in a small subset of hematopoietic stem cells. While its overexpression suggests an oncogenic role, the invariable presence of mutations in the cysteine-histidine zinc finger domains indicates a tumor suppressor function, similar to that in WAGR syndrome/11p deletion syndrome in which it was first discovered. Like its unknown function in AML, the clinical significance and genetic associations of WT1 mutations have been also controversial. Although studies of WT1 mutations in AML have been conducted, the lack of solid clinical and molecular characterization of large WT1 -mutant ( WT1 MT ) AML cohort has hampered its definition. In this study, we took advantage of a compendia of genomic results from Cleveland Clinic and publicly available data of 2188 AML patients (primary (p)AML, n= 1636; secondary (s)AML, n= 433; therapy-related (t)AML, n= 119, excluding cases with acute promyelocytic leukemia, MLL- rearrangement, and core-binding factor AML). While several reports only focused on cytogenetic normal AML (CN-AML), which represented 61% of our cohort, we additionally included all other cytogenetic risk groups. In total, WT1 mutations were detected in 5% (114/2188) of patients. WT1 mutations were enriched in pAML (85%) compared to sAML (11%) and tAML (4%). Thirty-nine patients (13%) carried more than 1 WT1 mutation. WT1 MT were younger [59 vs 64 years, P =0.0002] and more often females (55% vs 45%, P =0.03) as compared to WT1 wild type ( WT1 WT ) patients. Univariate analyses of baseline parameters showed that WT1 MT AML had a more proliferative phenotype with a higher WBC [15.1 vs 9.5 x10 9 /L, P =0.03] and bone marrow blast percentages [
Identifying cell type-specific enhancers in the brain is critical to building genetic tools for investigating the mammalian brain. Computational methods for functional enhancer prediction have been proposed and valida...
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Loss of heterochromatin has been implicated as a cause of pre-mature aging and age-associated decline in organ functions in mammals;however,the specific cell types and gene loci affected by this type of epigenetic cha...
Loss of heterochromatin has been implicated as a cause of pre-mature aging and age-associated decline in organ functions in mammals;however,the specific cell types and gene loci affected by this type of epigenetic change have remained *** address this knowledge gap,we probed chromatin accessibility at single-cell resolution in the brains,hearts,skeletal muscles,and bone marrows from young,middle-aged,and old mice,and assessed age-associated changes at 353,126 candidate cis-regulatory elements(cCREs)across 32 major cell ***,we detected increased chromatin accessibility within specific heterochromatin domains in old mouse excitatory *** gain of chromatin accessibility at these genomic loci was accompanied by the cell-type-specific loss of heterochromatin and activation of LINE1 *** further confirmed the loss of the heterochromatin mark H3K9me3 in the excitatory neurons but not in inhibitory neurons or glial *** results reveal the cell-type-specific changes in chromatin landscapes in old mice and shed light on the scope of heterochromatin loss in mammalian aging.
In computational molecular and materials science, determining equilibrium structures is the crucial first step for accurate subsequent property calculations. However, the recent discovery of millions of new crystals a...
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*equal contribution, # co-corresponding authors Although the JAK2V617F mutation is the most common MPN phenotypic driver mutation, the precise consequences of the mutation on the behavior of individual human hematopoi...
*equal contribution, # co-corresponding authors Although the JAK2V617F mutation is the most common MPN phenotypic driver mutation, the precise consequences of the mutation on the behavior of individual human hematopoietic stem cells (HSCs) in vivo remains unknown. We used whole genome sequencing and single-cell profiling of hematopoietic stem and progenitor cells (HSPCs) to quantify the impact of JAK2V617F on the proliferation dynamics of HSCs and the differentiation trajectories of their progenies in individual newly diagnosed MPN patients. We reconstructed the lineage history of individual HSCs obtained from patients with newly diagnosed essential thrombocythemia (ET), using the pattern of spontaneous somatic mutations accrued in their genomes over decades (Figure 1). Intriguingly, our analysis indicates that the JAK2V617F mutation occurred in a single HSC many years before MPN diagnosis - at age 9±2 years in a 34 year-old patient, and at age 19±3 years in a 63 year-old patient. In each patient, we inferred the number of mutated HSCs over the years and computed their fitness. After escaping stochastic extinction, the population of mutated HSCs grew exponentially by 63±15% and 44±13% every year in the two patients respectively. To contrast the differentiation trajectories of the JAK2 -mutant HSCs with those of healthy HSCs, we simultaneously measured the full transcriptome and somatic mutations in single HSPCs in the two ET patients in whom we had performed whole genome sequencing and in one additional ET patient (N=3 total) and also in patients with polycythemia vera (PV) (N=3). We observed, at the time of MPN diagnosis, a consistent lineage bias of JAK2 -mutant HSPCs toward megakaryocyte-erythrocyte fate, across ET and PV patients. Exploiting our ability to discriminate JAK2 -mutant cells from JAK2 wild-type cells within individual MPN patients, we identified genes involved in antigen presentation and inflammation as differentially up-regulated in JAK2 -mutant HS
Dengue virus (DENV) is a significant global health threat, causing millions of cases worldwide each year. Developing antiviral drugs for DENV has been a challenging endeavor. Our previous study identified anti-DENV pr...
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Dengue virus (DENV) is a significant global health threat, causing millions of cases worldwide each year. Developing antiviral drugs for DENV has been a challenging endeavor. Our previous study identified anti-DENV properties of two (-)-cytisine derivatives contained substitutions within the 2-pyridone core from a pool of 19 (-)-cytisine derivatives. This study aimed to expand on the previous research by investigating the antiviral potential of N-methylcytisine thio (mCy thio) derivatives against DENV, understanding the molecular mechanisms of antiviral activity for the active thio derivatives. The inhibitory assays on DENV-2-induced cytopathic effect and infectivity revealed that mCy thio derivatives 3 ((1R,5S)-3-methyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocine-8-thione) and 6 ((1S,5R)-3-methyl-2-thioxo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one) were identified as the active compounds against both DENV-1 and DENV-2. Derivative 6 displayed robust antiviral activity against DENV-2, with EC50 values ranging from 0.002 to 0.005 μM in different cell lines. Derivative 3 also exhibited significant antiviral activity against DENV-2. The study found that these compounds are effective at inhibiting DENV-2 at both the entry stage (including virus attachment) and post-entry stages of the viral life cycle. The study also investigated the inhibition of the DENV-2 NS2B-NS3 protease activity by these compounds. Derivative 6 demonstrated notably stronger inhibition compared to mCy thio 3, revealing its dual antiviral action at both the entry and post-entry stages. Molecular docking simulations indicated that mCy thio derivatives 3 and 6 bind to the domain I and III of the DENV E protein, as well as the active of NS2B-NS3 protease, suggesting their molecular interactions with the virus. The study demonstrates the antiviral efficacy of N-methylcytisine thio derivatives against DENV. It provides valuable insights into the pot
Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models t...
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