Enhancing sequence alignment of adaptive immune receptors through multi-task deep learning.

Sequence alignment of immunoglobulin (Ig) sequences is central to the computational analysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data, impacting adaptive immunity research and antibody engineering. Traditional Ig sequence aligners often struggle to handle the complexities of V(D)J recombination and somatic hypermutation (SHM), resulting in suboptimal allele assignment accuracy and sequence segmentation. We introduce AlignAIR, a novel deep learning-based aligner that leverages advanced simulation approaches and a multi-task learning framework.

A Broad Survey and Functional Analysis of Immunoglobulin Loci Variation in Rhesus Macaques.

Rhesus macaques (RMs) are a vital model for studying human disease and invaluable to pre-clinical vaccine research, particularly for the study of broadly neutralizing antibody responses. Such studies require robust genetic resources for antibody-encoding genes within the immunoglobulin (IG) loci. The complexity of the IG loci has historically made them challenging to characterize accurately.

Guidelines for reproducible analysis of adaptive immune receptor repertoire sequencing data.

Enhancing the reproducibility and comprehension of adaptive immune receptor repertoire sequencing (AIRR-seq) data analysis is critical for scientific progress. This study presents guidelines for reproducible AIRR-seq data analysis, and a collection of ready-to-use pipelines with comprehensive documentation. To this end, ten common pipelines were implemented using ViaFoundry, a user-friendly interface for pipeline management and automation.

IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data.

In adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step. This process is highly impacted by allele annotations. Aligning sequences, assigning them to specific germline alleles, and inferring individual genotypes are challenging when the repertoire is highly mutated, or sequence reads do not cover the whole V region.

Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity.

Introduction: The success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance.

Methods: We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls.

A somatic hypermutation-based machine learning model stratifies individuals with Crohn's disease and controls.

Crohn's disease (CD) is a chronic relapsing-remitting inflammatory disorder of the gastrointestinal tract that is characterized by altered innate and adaptive immune function. Although massively parallel sequencing studies of the T cell receptor repertoire identified oligoclonal expansion of unique clones, much less is known about the B cell receptor (BCR) repertoire in CD. Here, we present a novel BCR repertoire sequencing data set from ileal biopsies from pediatric patients with CD and controls, and identify CD-specific somatic hypermutation (SHM) patterns, revealed by a machine learning (ML) algorithm trained on BCR repertoire sequences.

Ontogeny of the B Cell Receptor Repertoire and Microbiome in Mice.

The immune system matures throughout childhood to achieve full functionality in protecting our bodies against threats. The immune system has a strong reciprocal symbiosis with the host bacterial population and the two systems co-develop, shaping each other. Despite their fundamental role in health physiology, the ontogeny of these systems is poorly characterized.

T cell receptor beta germline variability is revealed by inference from repertoire data.

Background: T and B cell receptor (TCR, BCR) repertoires constitute the foundation of adaptive immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) is a common approach to study immune system dynamics. Understanding the genetic factors influencing the composition and dynamics of these repertoires is of major scientific and clinical importance.

Immune2vec: Embedding B/T Cell Receptor Sequences in ℝ Using Natural Language Processing.

The adaptive branch of the immune system learns pathogenic patterns and remembers them for future encounters. It does so through dynamic and diverse repertoires of T- and B- cell receptors (TCR and BCRs, respectively). These huge immune repertoires in each individual present investigators with the challenge of extracting meaningful biological information from multi-dimensional data.

Machine Learning Analysis of Naïve B-Cell Receptor Repertoires Stratifies Celiac Disease Patients and Controls.

Celiac disease (CeD) is a common autoimmune disorder caused by an abnormal immune response to dietary gluten proteins. The disease has high heritability. HLA is the major susceptibility factor, and the HLA effect is mediated via presentation of deamidated gluten peptides by disease-associated HLA-DQ variants to CD4+ T cells.

RAbHIT: R Antibody Haplotype Inference Tool.

Summary: Antibody haplotype inference (chromosomal phasing) may have clinical implications for the identification of genetic predispositions to diseases. Yet, our knowledge of the genomic loci encoding for the variable regions of the antibody is only partial, mostly due to the challenge of aligning short reads from genome sequencing to these highly repetitive loci. A powerful approach to infer the content of these loci relies on analyzing repertoires of rearranged V(D)J sequences.

Mosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping.

Analysis of antibody repertoires by high-throughput sequencing is of major importance in understanding adaptive immune responses. Our knowledge of variations in the genomic loci encoding immunoglobulin genes is incomplete, resulting in conflicting VDJ gene assignments and biased genotype and haplotype inference. Haplotypes can be inferred using IGHJ6 heterozygosity, observed in one third of the people.

Antibody Repertoire Analysis of Hepatitis C Virus Infections Identifies Immune Signatures Associated With Spontaneous Clearance.

Hepatitis C virus (HCV) is a major public health concern, with over 70 million people infected worldwide, who are at risk for developing life-threatening liver disease. No vaccine is available, and immunity against the virus is not well-understood. Following the acute stage, HCV usually causes chronic infections.

Selective inactivation of enzymes conjugated to nanoparticles using tuned laser illumination.

We report a novel method for specific deactivation of conjugated enzymes using laser-heated gold nanoparticles. Current methods involve treatment of the entire solution, thereby inactivating all bioactive components. Our method enables inactivation of only a single or subset of targeted enzymes.

Novel role for retinol-binding protein 4 in the regulation of blood pressure.

Elevated levels of serum retinol-binding protein 4 (RBP4) contribute to insulin resistance and correlate with increased prevalence of hypertension and myocardial infarction. We sought to determine whether lowering RBP4 would improve blood pressure (BP) and protect against obesity- or angiotensin (Ang)-II-induced hypertension. Systolic and diastolic BP were lower in the RBP4-knockout (RBP4-KO) mice and higher in the RBP4-overexpressing (RBP4-Tg) mice compared with BP in the wild-type (WT) littermates.

Nanometric agents in the service of neuroscience: Manipulation of neuronal growth and activity using nanoparticles.

Unlabelled: Nerve regeneration and recovery could provide great therapeutic benefits for individuals suffering from nerve damage post trauma or degenerative diseases. However, manipulation of nerves presents a huge challenge for neuroscientists and is not yet clinically feasible. In recent years, nanoparticles have emerged as novel effective agents for control of neuronal growth and behavior.

Gold nanoparticles-based biosensing of single nucleotide DNA mutations.

Detection of DNA mutations is critical for scientific research and diagnostic procedures. Here, we propose a novel interdisciplinary method for rapid and simple detection of DNA mutations. We show that heating a solution containing DNA and gold nanoparticles results in degradation of the DNA.

Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c.

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice.

mTOR complex 2 in adipose tissue negatively controls whole-body growth.

Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood.

mTOR and the control of whole body metabolism.

Mammalian Target of Rapamycin (mTOR) is a highly conserved protein kinase that functions as part of two distinct multiprotein complexes to regulate growth and metabolism. This review describes the most important recent advances in the mTOR signaling field. In addition, we provide an overview on the functions of mTOR in different organs, with a special focus on the role of mTOR in whole body energy metabolism.

Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration.

raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity.