PLANNER: a multi-scale deep language model for the origins of replication site prediction.

Origins of replication sites (ORIs) are crucial genomic regions where DNA replication initiation takes place, playing pivotal roles in fundamental biological processes like cell division, gene expression regulation, and DNA integrity. Accurate identification of ORIs is essential for comprehending cell replication, gene expression, and mutation-related diseases. However, experimental approaches for ORI identification are often expensive and time-consuming, leading to the growing popularity of computational methods.

Digerati - A multipath parallel hybrid deep learning framework for the identification of mycobacterial PE/PPE proteins.

The genome of Mycobacterium tuberculosis contains a relatively high percentage (10%) of genes that are poorly characterised because of their highly repetitive nature and high GC content. Some of these genes encode proteins of the PE/PPE family, which are thought to be involved in host-pathogen interactions, virulence, and disease pathogenicity. Members of this family are genetically divergent and challenging to both identify and classify using conventional computational tools.

Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls.

Signatures of TSPAN8 variants associated with human metabolic regulation and diseases.

Here, with the example of common copy number variation (CNV) in the gene, we present an important piece of work in the field of CNV detection, that is, CNV association with complex human traits such as H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report exon 11 (ENSE00003720745) as a pleiotropic locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D) and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define metabolomic signatures for variants in .

Nanopore sequencing as a scalable, cost-effective platform for analyzing polyclonal vector integration sites following clinical T cell therapy.

Background: Analysis of vector integration sites in gene-modified cells can provide critical information on clonality and potential biological impact on nearby genes. Current short-read next-generation sequencing methods require specialized instruments and large batch runs.

Methods: We used nanopore sequencing to analyze the vector integration sites of T cells transduced by the gammaretroviral vector, SFG.

Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions.

During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of the mechanisms of disease and protection. We sought to model the contributions of the parasite multiplication rate and host response to observed parasite load in individual subjects infected with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates.

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells.

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells.

Purpose: Inducible caspase 9 () is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of -transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.

Patients And Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.

Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria.

The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In malaria, host and parasite processes can be assessed by dual RNA sequencing of blood from infected patients. We performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria.

Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host-Pathogen Interactions.

Transcriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analyses of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, the simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions.

Mycobacterium tuberculosis Exploits a Molecular Off Switch of the Immune System for Intracellular Survival.

Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood.

Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.

The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM).

Scaffolding and completing genome assemblies in real-time with nanopore sequencing.

Third generation sequencing technologies provide the opportunity to improve genome assemblies by generating long reads spanning most repeat sequences. However, current analysis methods require substantial amounts of sequence data and computational resources to overcome the high error rates. Furthermore, they can only perform analysis after sequencing has completed, resulting in either over-sequencing, or in a low quality assembly due to under-sequencing.

Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities.

Background: Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility.

Methods And Results: To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set.

Streaming algorithms for identification of pathogens and antibiotic resistance potential from real-time MinION(TM) sequencing.

The recently introduced Oxford Nanopore MinION platform generates DNA sequence data in real-time. This has great potential to shorten the sample-to-results time and is likely to have benefits such as rapid diagnosis of bacterial infection and identification of drug resistance. However, there are few tools available for streaming analysis of real-time sequencing data.

Realtime analysis and visualization of MinION sequencing data with npReader.

Motivation: The recently released Oxford Nanopore MinION sequencing platform presents many innovative features opening up potential for a range of applications not previously possible. Among these features, the ability to sequence in real-time provides a unique opportunity for many time-critical applications. While many software packages have been developed to analyze its data, there is still a lack of toolkits that support the streaming and real-time analysis of MinION sequencing data.

cnvCapSeq: detecting copy number variation in long-range targeted resequencing data.

Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets.

cnvOffSeq: detecting intergenic copy number variation using off-target exome sequencing data.

Motivation: Exome sequencing technologies have transformed the field of Mendelian genetics and allowed for efficient detection of genomic variants in protein-coding regions. The target enrichment process that is intrinsic to exome sequencing is inherently imperfect, generating large amounts of unintended off-target sequence. Off-target data are characterized by very low and highly heterogeneous coverage and are usually discarded by exome analysis pipelines.

Diagnosis of childhood tuberculosis and host RNA expression in Africa.

Background: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).

Methods: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children).

YHap: a population model for probabilistic assignment of Y haplogroups from re-sequencing data.

Background: Y haplogroup analyses are an important component of genealogical reconstruction, population genetic analyses, medical genetics and forensics. These fields are increasingly moving towards use of low-coverage, high throughput sequencing. While there have been methods recently proposed for assignment of Y haplogroups on the basis of high-coverage sequence data, assignment on the basis of low-coverage data remains challenging.

Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study.

Background: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.

Methods And Findings: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.

Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.

Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens.

Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity.