Reading the repertoire: Progress in adaptive immune receptor analysis using machine learning.

The adaptive immune system holds invaluable information on past and present immune responses in the form of B and T cell receptor sequences, but we are limited in our ability to decode this information. Machine learning approaches are under active investigation for a range of tasks relevant to understanding and manipulating the adaptive immune receptor repertoire, including matching receptors to the antigens they bind, generating antibodies or T cell receptors for use as therapeutics, and diagnosing disease based on patient repertoires. Progress on these tasks has the potential to substantially improve the development of vaccines, therapeutics, and diagnostics, as well as advance our understanding of fundamental immunological principles.

Chromosome-level reference genome for the Jonah crab, Cancer borealis.

The Jonah crab, Cancer borealis, is integral to marine ecosystems and supports a rapidly growing commercial fishery in the northwest Atlantic Ocean. This species also has a long history as a model for neuroscience that has expanded our understanding of central pattern generators, neuromodulation, synaptic plasticity, and the connectivity of neural circuits. Here we present a highly contiguous reference genome for the Jonah crab that will provide an essential resource to advance fisheries, conservation, and biomedical research.

T cell epitope mapping reveals immunodominance of evolutionarily conserved regions within SARS-CoV-2 proteome.

As SARS-CoV-2 variants continue to emerge capable of evading neutralizing antibodies, it has become increasingly important to fully understand the breadth and functional profile of T cell responses to determine their impact on the immune surveillance of variant strains. Here, sampling healthy individuals, we profiled the kinetics and polyfunctionality of T cell immunity elicited by mRNA vaccination. Modeling of anti-spike T cell responses against ancestral and variant strains of SARS-CoV-2 suggested that epitope immunodominance and cross-reactivity are major predictive determinants of T cell immunity.

OpenFold: retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization.

AlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (1) tackle new tasks, like protein-ligand complex structure prediction, (2) investigate the process by which the model learns and (3) assess the model's capacity to generalize to unseen regions of fold space.

The Plausibility of Sampling as an Algorithmic Theory of Sentence Processing.

Words that are more surprising given context take longer to process. However, no incremental parsing algorithm has been shown to directly predict this phenomenon. In this work, we focus on a class of algorithms whose runtime does naturally scale in surprisal-those that involve repeatedly sampling from the prior.

Identification, Heterologous Expression, and Characterization of the Tolypodiol Biosynthetic Gene Cluster through an Integrated Approach.

Cyanobacteria are tremendous producers of biologically active natural products, including the potent anti-inflammatory compound tolypodiol. However, linking biosynthetic gene clusters with compound production in cyanobacteria has lagged behind that in other bacterial genera. Tolypodiol is a meroterpenoid originally isolated from the cyanobacterium HT-58-2.

Anti-inflammatory Quinoline Alkaloids from the Roots of .

Sixteen new quinoline alkaloids (-, , , , -, , and ) and 10 known analogs (, , , , -, and -), along with three known cyclopeptide alkaloids (-), were isolated from the roots of . The structures of the new compounds were elucidated by detailed NMR and circular dichroism with computational support and mass spectrometry data interpretation. Anti-inflammatory potential of isolates was evaluated based on inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production and tumor necrosis factor-alpha (TNF-α)-induced nuclear factor kappa B (NF-κB) activity with cell culture models.

On TCR binding predictors failing to generalize to unseen peptides.

Several recent studies investigate TCR-peptide/-pMHC binding prediction using machine learning or deep learning approaches. Many of these methods achieve impressive results on test sets, which include peptide sequences that are also included in the training set. In this work, we investigate how state-of-the-art deep learning models for TCR-peptide/-pMHC binding prediction generalize to unseen peptides.

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8 T cells. In bladder tumors, NKG2A is acquired on CD8 T cells later than PD-1 as well as other well-established immune checkpoints.

Synthesizing theories of human language with Bayesian program induction.

Automated, data-driven construction and evaluation of scientific models and theories is a long-standing challenge in artificial intelligence. We present a framework for algorithmically synthesizing models of a basic part of human language: morpho-phonology, the system that builds word forms from sounds. We integrate Bayesian inference with program synthesis and representations inspired by linguistic theory and cognitive models of learning and discovery.

Coumarinolignans with Reactive Oxygen Species (ROS) and NF-κB Inhibitory Activities from the Roots of .

Seven new coumarinolignans, walthindicins A-F (, , -, ), along with five known analogs (, -), were isolated from the roots of . The structures of the new compounds are determined by detailed nuclear magnetic resonance (NMR), circular dichroism (CD) with extensive computational support, and mass spectroscopic data interpretation. Compounds were tested for their antioxidant activity in Human Cervical Cancer cells (HeLa cells).

Spirovetivane- and Eudesmane-Type Sesquiterpenoids Isolated from the Culture Media of Two Cyanobacterial Strains.

As part of a study examining polar metabolites produced by cyanobacterial strains, we examined media extracts of a sp. (strain R-3-1) and a sp. (strain U-3-3).

Low-coverage whole-genome sequencing reveals molecular markers for spawning season and sex identification in Gulf of Maine Atlantic cod (, Linnaeus 1758).

Atlantic cod (, Linnaeus 1758) in the western Gulf of Maine are managed as a single stock despite several lines of evidence supporting two spawning groups (spring and winter) that overlap spatially, while exhibiting seasonal spawning isolation. Low-coverage whole-genome sequencing was used to evaluate the genomic population structure of Atlantic cod spawning groups in the western Gulf of Maine and Georges Bank using 222 individuals collected over multiple years. Results indicated low total genomic differentiation, while also showing strong differentiation between spring and winter-spawning groups at specific regions of the genome.

TGM4: an immunogenic prostate-restricted antigen.

Background: Prostate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the Food and Drug Administration-approved vaccine sipuleucel-T, which targets prostatic acid phosphatase (PAP), extends survival for 2-4 months, the identification of new immunogenic tumor-associated antigens (TAAs) continues to be an unmet need.

Methods: We evaluated the differential expression profile of castration-resistant prostate epithelial cells that give rise to CRPC from mice following an androgen deprivation/repletion cycle.

Landscape and selection of vaccine epitopes in SARS-CoV-2.

Background: Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4 T cell, and CD8 T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE).

Methods: We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage.

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) has complex and dynamic interactions with the human host, and subpopulations of Mtb that emerge during infection can influence disease outcomes. This study implicates zinc ion (Zn2+) availability as a likely driver of bacterial phenotypic heterogeneity in vivo. Zn2+ sequestration is part of "nutritional immunity", where the immune system limits micronutrients to control pathogen growth, but this defense mechanism seems to be ineffective in controlling Mtb infection.

P-Alkynyl functionalized benzazaphospholes as transmetalating agents.

Exposure of 10π-electron benzazaphosphole 1 to HCl, followed by nucleophilic substitution with the Grignard reagent BrMgCCPh afforded alkynyl functionalized 3 featuring an exocyclic -C[triple bond, length as m-dash]C-Ph group with an elongated P-C bond (1.7932(19) Å). Stoichiometric experiments revealed that treatment of trans-Pd(PEt3)2(Ar)(i) (Ar = p-Me (C) or p-F (D)) with 3 generated trans-Pd(PEt3)2(Ar)(CCPh) (Ar = p-Me (E) or p-F (F)), 5, which is the result of ligand exchange between P-I byproduct 4 and C/D, and the reductively eliminated product (Ar-C[triple bond, length as m-dash]C-Ph).

Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors.

Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts.

A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti-Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients.

Introduction: Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited.

Methods: We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non-immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls.

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases.

MHCflurry 2.0: Improved Pan-Allele Prediction of MHC Class I-Presented Peptides by Incorporating Antigen Processing.

Computational prediction of the peptides presented on major histocompatibility complex (MHC) class I proteins is an important tool for studying T cell immunity. The data available to develop such predictors have expanded with the use of mass spectrometry to identify naturally presented MHC ligands. In addition to elucidating binding motifs, the identified ligands also reflect the antigen processing steps that occur prior to MHC binding.

Production and excretion of astaxanthin by engineered Yarrowia lipolytica using plant oil as both the carbon source and the biocompatible extractant.

This study aimed to develop a bioprocess using plant oil as the carbon source for lipid-assimilating yeast to produce high-value astaxanthin. Using high-oleic safflower oil as a model, efficient cell growth and astaxanthin production by the engineered Yarrowia lipolytica strain ST7403 was demonstrated, and a considerable portion of astaxanthin was found excreted into the spent oil. Astaxanthin was the predominant carotenoid in the extracellular oil phase that allowed facile in situ recovery of astaxanthin without cell lysis.