Search

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins. Here, the authors develop a high-throughput workflow combining cell-free gene expression with AlphaLISA to rapidly characterize and engineer PTMs on both proteins and peptides.

A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.

The authors identify defective viral particles, in people with non-suppressible HIV-1, that can replicate through superinfection and interfere with the wild-type virus. However, they show no evidence of these preventing disease progression in the individuals studied.

Synthetic receptors are a powerful approach for engineering cell-based therapies that can sense and respond to their environment. Here cytokine receptor domains have been repurposed to develop engineered T cells that can sense and respond to cues associated with cancer or immune dysfunction.

The broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, the authors established a generalizable re-engineering framework to narrow the activity windows of diverse base editors, streamlining the development of therapeutic base editing.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

The discovery that DNA methylation of different CpG sites can serve as digital barcodes of clonal identity led to the development of EPI-Clone, an algorithm that enables single-cell lineage tracing through cellular differentiation at scale.

Utilizing a selenium-dependent enzyme, gut bacteria degrade uric acid via a previously unrecognized anaerobic pathway which gives them a competitive advantage in the gut.

Here the authors show thatMETTL9 enzyme sustains neural development in vertebrates by maintaining the secretory pathway, mainly independently of METTL9 catalytic activity. METTL9 loss in cells leads to Golgi fragmentation.

Genome-wide CRISPR/Cas9 screening reveals novel modulators of heparan sulfate proteoglycans that regulate cellular uptake of α-synuclein fibrils, including in human dopaminergic neurons.

Glycosylation of human IgG antibodies in bacterial hosts has proven challenging. Here, the authors identify a bacterial enzyme enabling E. coli to glycosylate IgGs at native sites, thereby advancing therapeutic antibody development in this host.

ESCAPE-seq (enhanced single-chain antigen presentation sequencing) is a massively parallel platform for screening of class I HLA–peptide combinations for antigen presentation. The authors assess more than 75,000 peptide–HLA combinations, revealing presented epitopes from oncogenic driver mutations and fusions across diverse HLA-A, HLA-B and HLA-C alleles.

Antibody discovery is bottlenecked by the individual expression and evaluation of antigen specific hits. Here, the authors build an antibody screening workflow leveraging cell-free protein synthesis that enables expression and evaluation of hundreds of antibody fragments in less than 24 h.

Engineering mammalian cellular functions requires a toolkit of orthogonal and well-characterized genetic components. Here the authors develop COMET: an ensemble of transcription factors, promoters, and accompanying models for the design and construction of genetic programs.

Activation of an LTR retrotransposon inserted upstream of the Fgf8 gene produces viral-like particles in the mouse developing limb, triggering apoptosis and causing limb malformation. This phenotype can be rescued by mutations in the retrotransposon coding sequence.

Lowry et al. use embryonic motor neuron selector transcription factors to partially rejuvenate the gene expression profile of mature neurons, making them more resistant to an ALS model without compromising their normal function.

Bacterial CRISPR–Cas loci acquire short phage sequences called spacers that integrate between DNA repeats and how these viral sequences are chosen was unknown; in these studies of the type II CRISPR–Cas system of Streptococcus pyogenes, the Cas9 nuclease known to inactivate invading viral DNA was found to be required for the selection of functional spacers during CRISPR immunity.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

A PICALM allele associated with increased risk of late-onset Alzheimer’s disease has a microglial-specific role in lipid droplet accumulation.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

A study reports that the structural maturation of the matrix domain of the Gag protein of HIV-1 is induced by the proteolytic release and binding of the spacer peptide SP2.

Cell cycle control depends on phosphorylation of many proteins by the kinase Cdk1. Here, the authors show that phosphorylation of Cdk1 substrates is influenced by a phosphate-binding pocket on the surface of the cyclin regulatory subunit.

Biochemical reconstitution and functional analysis reveal how newly synthesized multipass membrane proteins dynamically remodel the translocon to facilitate their successful biogenesis.

T cell receptors are identified in large-scale screening of T cell repertoires cloned from primary human T cells.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

Neutrophils actively induce tumour necrosis, driving vascular occlusion, pleomorphic necrosis and metastasis.

Traditional genetic perturbation tools such as siRNA and CRISPR knockout operate on timescales that render them unsuitable for exploring dynamic processes or studying essential genes, where chronic depletion can lead to cell death. Here, the authors present AID 2.1, a degron technology with minimal basal degradation and rapid and effective target protein depletion.

Sarcomas are a group of mesenchymal malignancies which are molecularly heterogeneous. Here, the authors develop an in vivo muscle electroporation system for gene delivery to generate distinct subtypes of orthotopic genetically engineered mouse models of sarcoma, as well as syngeneic allograft models with scalability for preclinical assessment of therapeutics.

The cellular RNA polymerase II C-terminal domain is known to support transcription of influenza virus mRNAs. Here, Krischuns et al. use cell-based and in vitro approaches to demonstrate that it also plays a role in replication of the viral genome.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

Gene expression is imaged in deep tissues in mice using ultrasound.

Here, Schwartz, Bravo, and Ahsan et al. show how multi-subunit fusion proteins are arranged around a crRNA in a type III CRISPR-Cas effector to cleave target RNA. Structures and molecular dynamics of this complex show three distinct active sites that can be used for programmable RNA cleavage.

Quiescent populations are a likely key source of treatment resistance in glioblastoma. Here, the authors characterize KAT5 as a critical mediator of quiescence and adoption of progenitor-like states.

The GlycoSCORES method, which involves cell-free protein expression and substrate-site profiling of glycosyltransferase enzymes by SAMDI–MS, enables the identification of glycosylation tags for glycoengineering efforts.

Functional mutations identified in patients with androgen insensitivity syndrome, in the formin and actin nucleator DAAM2, uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

The APC/C ubiquitylates histones to regulate gene expression in pluripotent cells. Here, the authors pair cryo-EM and biochemical and biophysical assays to show that instead of modifying nucleosome-incorporated histones, the APC/C ubiquitylates extranucleosomal histone complexes through a mechanism that bypasses canonical substrate degrons.

Characterizing infection, pathogenesis and transmission of BANAL-52 and BANAL-236 in primary respiratory cells, mice and hamsters shows how viruses closely related to SARS-CoV-2 present a threat for spillover.