REAL-TIME VISUALIZATION OF SPLICEOSOME ASSEMBLY REVEALS BASIC PRINCIPLES OF SPLICE SITE SELECTION.

The spliceosome is a megadalton protein-RNA complex which removes introns from pre-mRNA, yet the dynamic early assembly steps have not been structurally resolved. Specifically, how the spliceosome selects the correct 3' splice site (3'SS) amongst highly similar non-functional sites is not known. Here, we develop a kinetic model of splice site selection based on single-molecule U2AF heterodimer imaging and .

Latent Dirichlet allocation mixture models for nucleotide sequence analysis.

Strings of nucleotides carrying biological information are typically described as sequence motifs represented by weight matrices or consensus sequences. However, many signals in DNA or RNA are recognized by multiple factors in temporal sequence, consist of distinct alternative motifs, or are best described by base composition. Here we apply the latent Dirichlet allocation (LDA) mixture model to nucleotide sequences.

Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia.

Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells ( = 98 CLL patients) and healthy volunteers ( = 9).

A Large Postmortem Database of COVID-19 Patients Can Inform Disease Research and Public Policy Decision Making.

Context.—: Autopsies performed on COVID-19 patients have provided critical information about SARS-CoV-2's tropism, mechanisms of tissue injury, and spectrum of disease.

Objective.

Predicting the impact of rare variants on RNA splicing in CAGI6.

Variants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant's impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact.

Rosaceae fruit transcriptome database (ROFT)-a useful genomic resource for comparing fruits of apple, peach, strawberry, and raspberry.

Rosaceae is a large plant family consisting of many economically important fruit crops including peach, apple, pear, strawberry, raspberry, plum, and others. Investigations into their growth and development will promote both basic understanding and progress toward increasing fruit yield and quality. With the ever-increasing high-throughput sequencing data of Rosaceae, comparative studies are hindered by inconsistency of sample collection with regard to tissue, stage, growth conditions, and by vastly different handling of the data.

Single-cell methylation sequencing data reveal succinct metastatic migration histories and tumor progression models.

Recent studies exploring the impact of methylation in tumor evolution suggest that although the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Because changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and for jointly identifying lineage-informative CpG sites that harbor changes in methylation status that are retained along the lineage.

Sex Biases in Cancer and Autoimmune Disease Incidence Are Strongly Positively Correlated with Mitochondrial Gene Expression across Human Tissues.

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues.

Development and Validation of Decision Rules Models to Stratify Coronary Artery Disease, Diabetes, and Hypertension Risk in Preventive Care: Cohort Study of Returning UK Biobank Participants.

Many predictive models exist that predict risk of common cardiometabolic conditions. However, a vast majority of these models do not include genetic risk scores and do not distinguish between clinical risk requiring medical or pharmacological interventions and pre-clinical risk, where lifestyle interventions could be first-choice therapy. In this study, we developed, validated, and compared the performance of three decision rule algorithms including biomarkers, physical measurements, and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension against commonly used clinical risk scores in 60,782 UK Biobank participants.

Comparative transcriptomic analysis of apple and peach fruits: insights into fruit type specification.

Fruits represent key evolutionary innovations in angiosperms and exhibit diverse types adapted for seed dissemination. However, the mechanisms that underlie fruit type diversity are not understood. The Rosaceae family comprises many different fruit types, including 'pome' and 'drupe' fruits, and hence is an excellent family for investigating the genetic basis of fruit type specification.

Working memory training efficacy in COPD: the randomised, double-blind, placebo-controlled Cogtrain trial.

Background: Cognitive impairment is highly prevalent in COPD and is associated with a sedentary lifestyle, unhealthy diet and increased cognitive stress susceptibility. Enhancement of cognitive performance by working memory training (WMT) may reverse these effects. Therefore, this study aimed to investigate the efficacy of WMT in COPD on cognitive performance, healthy lifestyle behaviours and cognitive stress susceptibility.

Expanding plant genome-editing scope by an engineered iSpyMacCas9 system that targets A-rich PAM sequences.

The most popular CRISPR-SpCas9 system recognizes canonical NGG protospacer adjacent motifs (PAMs). Previously engineered SpCas9 variants, such as Cas9-NG, favor G-rich PAMs in genome editing. In this manuscript, we describe a new plant genome-editing system based on a hybrid iSpyMacCas9 platform that allows for targeted mutagenesis, C to T base editing, and A to G base editing at A-rich PAMs.

An Atlas of Genomic Resources for Studying Rosaceae Fruits and Ornamentals.

Rosaceae, a large plant family of more than 3,000 species, consists of many economically important fruit and ornamental crops, including peach, apple, strawberry, raspberry, cherry, and rose. These horticultural crops are not only important economic drivers in many regions of the world, but also major sources of human nutrition. Additionally, due to the diversity of fruit types in Rosaceae, this plant family offers excellent opportunities for investigations into fleshy fruit diversity, evolution, and development.

Undiagnosed Malignancy and Therapeutic Complications in Oncology Patients.

Context.—: Despite technologic and medical advancements, autopsies are essential to uncover clinically unsuspected diagnoses, to advance our understanding of disease processes, and to help reduce medical errors.

Objective.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

Context.—: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting.

Human Adenovirus 7-Associated Hemophagocytic Lymphohistiocytosis-like Illness: Clinical and Virological Characteristics in a Cluster of Five Pediatric Cases.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation. Children often suffer from primary genetic forms of HLH, which can be triggered by infection. Others suffer from secondary HLH as a complication of infection, malignancy, or rheumatologic disease.

Insights into pathogenesis of fatal COVID-19 pneumonia from histopathology with immunohistochemical and viral RNA studies.

Introduction: We describe post-mortem pulmonary histopathologic findings of COVID-19 pneumonia in patients with a spectrum of disease course, from rapid demise to prolonged hospitalisation.

Methods And Results: Histopathologic findings in post-mortem lung tissue from eight patients who died from COVID-19 pneumonia were reviewed. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed to detect virus.