Search

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

CRISPR/Cas9 screens have identified genetic contributions to many phenotypes. However, studying combinations of genes or regulatory elements remains challenging. Here, the authors use CRISPR/Cas12a to overcome those challenges and enable new approaches to study combinatorial genetic mechanisms.

Here, the authors present the cryoEM structure of the sodium-translocating methyltransferase (Mtr) complex from Methanosarcina mazei. Along with providing catalytic insights, they identify MtrI, an unannotated small protein, bound to the Mtr complex in a redox-dependent manner.

Gram-negative bacteria use diverse virulence factors to infect eukaryotic cells. Here, the authors perform structure-function analyses on the S. negevensis deSUMOylase SnCE1 and provide mechanistic insights how lysine acetylation reprograms virulence adjusting it to the host cells’ metabolic state.

Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

Karposi’s Sarcoma-associated herpesvirus (KSHV) infection is associated with malignancy in older infected humans. Here the authors characterise antigen presentation using a KSHV-specific CD4⁺ T cell-derived TCR in a mouse model and show that although KSHV-specific CD4⁺ T cells are difficult to detect in humans, antigen presentation is effective in vivo suggesting persistence and accumulation of these cells through antigen recognition.

Regulatory DNA screens often lack nucleotide-level resolution. Here, authors present an end-to-end CRISPR base-editing and sequencing framework that maps regulatory variants at single-nucleotide resolution, revealing enhancer mutations that alter CD19 expression and enable CAR-T therapy resistance.

Structural and biochemical studies of influenza virus RNA-dependent RNA polymerase (FluPol) in complex with transcribing host RNA polymerase II reveal the molecular mechanisms of RNA cap snatching by FluPol.

Capsular polysaccharides are bacterial virulence factors, yet their transport mechanism remains unclear. Here, the authors reveal the structure and dynamics of the Wza–Wzc complex, uncovering how a trans-envelope channel assembles to guide capsular polysaccharide synthesis and export.

Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic oligoadenylates that activate effectors such as Csm6 ribonucleases. Here, Garcia-Doval et al. show that Enteroccocus italicus Csm6 degrades its cyclic hexa-AMP activator, and report the crystal structure of the protein bound to an activator mimic.

Smargon et al. show that small nuclear RNAs can improve the cellular safety and efficacy of endogenous protein-mediated RNA base editing, enhancing nuclear RNA editing and the rescue of premature termination codon disease.

SpbK protects Bacillus subtilis from phage infection by depleting NAD⁺. In this study, the authors uncover the molecular mechanisms underlying SpbK’s self association-dependent NADase activity and its activation by the SPβ phage portal protein YonE.

A combined cryo-electron tomography and cryo-electron microscopy pipeline was developed to inflict axonal damage and monitor the cellular response induced by epothilone B, revealing that microtubule polymerization at and beyond the lesion site promote axon regeneration.

A synthetic biology system called SMART has been developed that uses conditional protein splicing for the programmable ligation of functional proteins from previously defined molecular combinations on cell surfaces.

ARGONAUTE (AGO) is the core protein component of small RNA-guided silencing complexes. Free, but not RNA-bound, AGO turns over rapidly. The authors identify a structural AGO switch whose accessibility only in the free state confers rapid degradation.

Durable, multi-antigen CAR T responses in B-cell malignancies are in need. The authors here demonstrate that AI-guided CAR designs combined with targeted pathway modulation enhance persistence, prevent antigen escape, and improve anti-tumor efficacy.

Targeted-directed genome mining identified a widespread family of bacterial ClpP-associated clusters whose active products previously eluded detection. One of these clusters from Streptomyces cattleya produces clipibicyclene that selectively inactivates ClpP and may play a role in bacterial competition.

TREM2 is an important AD risk factor playing essential roles in the microglial response to amyloid pathology. Here, authors show using a TREM2 reporter mouse that TREM2 levels are critical for efficacy of TREM2 agonism informing current clinical efforts.

In this work, authors develop a live vaccine candidate against Pseudomonas aeruginosa using an unnatural amino acid-based auxotrophic strategy. They provide insight on the vaccine’s in vivo safety profile and protection of mice against lethal P. aeruginosa challenge.

Lysosome positioning is essential for cell metabolism and stress responses. Here, the authors show that the TMEM55B-associated protein TBC1D9B controls lysosome positioning, autophagy, and starvation-induced degradation by serving as a GTPase activating protein of ARL8B

The nanoscale organization of the antigen-antibody complexes influences the therapeutic action of monoclonal antibodies. Here, the authors present a multi-target 3D RESI imaging assay for the nanometer spatial analysis of CD20 in complex with therapeutic monoclonal antibodies within intact cells, to analyse the interdependency between the mode of antibody binding and the therapeutic function.

The bacterial flagellum is a complex macromolecular structure that requires a highly regulated assembly of building blocks. Here, Halte et al. show that a protein controls assembly of the flagellum’s periplasmic rod and prevents misformation of flagella in the periplasm.

A screen utilizing an environmental DNA library in Escherichia coli is used to identify Brig1, a previously unknown anti-phage defence system with homologues across distinct clades of bacteria.

CRISPR-associated protein Csm6 is activated by a cyclic oligoadenylate second messenger generated by Cas10 activity in the CRISPR type III interference complex, representing a novel mechanism of CRISPR interference.

Single molecule real-time DNA sequencing allows genome-wide identification of DNA methylation patterns. Here, Jensen et al. present a high-throughput method that allows rapid coupling of DNA methylation patterns with their corresponding methyltransferase genes in bacteria.

CRISPR enzymes require a defined protospacer adjacent motif (PAM) which can be limiting for editing applications. Here the authors recombine the PAM-interacting domain of SpRY with the N-terminus of Sc + + to generate a chimeric enzyme with highly flexible PAM preference: SpRYc.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Single-cell comparison of developing bat and mouse limbs reveals conservation of cell populations and gene expression patterns, and suggests repurposing of genes involved in proximal limb development for wing evolution.

The multipass membrane transporter MFSD6 localizes to the plasma membrane and acts as a host entry factor for enterovirus D68 (EV-D68) by binding directly to EV-D68 particles through its extracellular, third loop, offering a potential target to combat infections by this emerging pathogen.

RETICULATA1 is a plastid membrane transporter in Arabidopsis that enables basic amino acid exchange across the plastid inner envelope. Loss-of-function mutants reveal its essential role in amino acid homeostasis, plant development and seed production.

The multistep incorporation process of the catalytic NiFe(CN)₂(CO) cofactor into [NiFe]-hydrogenase was deciphered by isolating key maturation intermediates, which were characterized by biochemical and a variety of spectroscopic techniques.

CRISPR activation/interference screens identify transcriptional regulators of human CD8⁺ T cells, including BATF3. BATF3 overexpression counteracts T cell exhaustion and enhances cancer immunotherapy in in vivo models.

Some antibiotic resistance genes found in pathogenic bacteria might derive from antibiotic-producing actinobacteria. Here, Jianget al. provide bioinformatic and experimental evidence supporting this hypothesis, and propose a specific mechanism for the transfer of these genes between bacterial phyla.

The type I interferon response is suppressed during early development, making embryos susceptible to pathogens. Here, the authors show that this suppression contributes to normal development by preventing an aberrant immune response against endogenous double stranded RNAs.

Toxicity and limited solubility inhibits the biological production of many organic compounds. Here the authors metabolically engineer sulfate uptake and activation in order to produce sulfate esters of phenolic compounds, such as zosteric acid, thereby addressing these issues.

The Legionella effector DrrA AMPylates the host protein Rab1 during infection, but the mechanism is still under debate. Here, the authors provide structural insights into the low-affinity DrrA:Rab1 interaction, showing that Rab1 allosterically activates DrrA through a non-conventional binding mechanism.

Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.

Cryo-EM shows SSNA-1 forms anti-parallel coiled-coils with a triple-helical junction for microtubule binding. Disrupting self-assembly or deleting SSNA-1 reduces C. elegans embryonic viability and disrupts spindles, revealing its role in cell division.

Protein folding is facilitated by cellular machinery, but studying folding in the cellular context is challenging. Here, the authors developed Arrest Peptide Profiling to map co-translational folding and chaperone interactions in living cells.

Witte et al show that previously acquired substitutions in the SARS-CoV-2 spike protein enable the acquisition of new antibody escape substitutions. New and old substitutions interact to enable escape from broadly neutralizing antibodies.

The Omicron variant is partially attenuated, likely because it fails to efficiently infect lung cells. Here, Hoffmann et. al. show that this defect can be lost during Omicron evolution as demonstrated for the subvariant BA.5 that robustly infects lung cells in vitro and in vivo.

Mitophagy activation is mediated by mitochondrial depolarization. Here, the authors show that mitochondrial protein misfolding can activate mitophagy in a depolarization-independent manner mediated by a protein import reduction.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

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.

pOXA-48 plasmids have emerged as key vectors of carbapenem resistance within Enterobacteriaceae. In this study, the authors use a transposon sequencing (Tn-seq) approach to identify genetic determinants critical for plasmid stability and conjugative transfer.

Mechanisms coupling Hox genes to neural crest are largely unknown. Here, the authors use cross species regulatory comparisons between the Hox2 genes of jawed vertebrates and lamprey, a jawless vertebrate, finding a conserved ancestral mechanism for Hox2 neural crest regulation.

Therapeutic application of RNA viruses requires tight control over viral activity. Here the authors design a regulatory switch that enables control over activity with clinically approved HIV protease inhibitors.

BindCraft, an open-source, automated pipeline for de novo protein binder design with experimental success rates of 10–100%, leverages AlphaFold2 weights to generate binders with nanomolar affinity without the need for high-throughput screening.