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Arrayed CRISPR libraries with each plasmid encoding an array of four non-overlapping single-guide RNAs allow for the efficient genome-wide ablation, activation and epigenetic silencing of human protein-coding genes.

This study maps out the diversity and evolution of the bacterial order Caulobacterales, including the model organism C. crescentus, which reveals widespread phototrophy and illuminates the evolution of bacterial cell shapes and lifecycle complexity.

A combination of engineering a fluorine-selective trans-acyltransferase and manipulation of the fluorinated extender unit pool in Escherichia coli enables the production of site-selectively fluorinated erythromycin precursors in vitro in vitroin vitro and in vivo.

Duan and Kaushik et al. reveal the structural basis of how Escherichia coli and Thermus thermophilus RNA polymerases initiate transcription from Np₄A alarmones producing Np₄-capped transcripts. The caps form various interactions with a polymerase during initial steps, influencing capping efficiency.

The jumbo phage ΦKZ constructs a proteinaceous nucleus-like compartment around its genome that protects phage DNA from degradation by DNA-targeting immune effectors of the host, including CRISPR–Cas and restriction enzymes.

The de novo design and synthesis of the Sc 2.0 chromosome XIII enable in-depth investigations into biology. Here the authors construct the 884 Kb synXIII of Saccharomyces cerevisiae to investigate replicative aging.

The apoptosome is known as a protein complex that initiates cell death. Here Borgeaud et al. reveal that in living cells, the apoptosome protein components assemble into dynamic meshwork-like structures that dissociate in cells surviving apoptosis.

Nanoparticles are a promising approach to increase immunogenicity of protein antigens for vaccines. Here, Brouwer et al. design self-assembling, two-component protein NPs that present native-like SOSIP trimers of HIV envelope protein and determine immunogenicity in a small animal model.

BiP–glucose-regulated protein 94 chaperones are critical to the proper folding of secretory and transmembrane proteins. Brenner et al. provide biochemical and structural insight into a conserved mechanism of chaperone cooperation underlying this quality control process.

Active and passive demethylation pathways have been implicated in the genome-wide erasure of 5mC accompanying mammalian preimplantation development. Here the authors reveal a recently evolved, mammalian-specific pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation.

Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

The lysine methyltransferase SMYD5 and its newly identified substrate ribosomal protein L40 are implicated in the progression of gastric adenocarcinoma, and ablation of SMYD5 prevents metastatic disease in mouse models of this cancer.

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.

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.

The dynein motor complex has a variety of important functions in both dividing and non-dividing cells. Here, Gallisà et al. describe a mode of regulation of dynein based on the phosphorylation of its adaptor BICD2 by the kinase PLK1, and how this is central for the regulation of centrosome position in G2 and M.

A phage genetic engineering platform will enable a better understanding of phage biology and engineering of phage therapies.

Hailong, an anti-phage defence system, synthesizes an oligodeoxyadenylate signal that blocks effector activity in the absence of phage infection but is degraded by phage-encoded DNA exonucleases, leading to protective growth arrest of infected cells.

Whole-genome siRNA screens to identify regulators of human LINE-1 retrotransposition reveal that BRCA1 and Fanconi anemia DNA repair factors inhibit retrotransposition at stalled replication fork targets created and exploited by L1.

This work repurposes the Type I-C Cascade–Cas3 system from Pseudomonas aeruginosa to achieve large deletions in bacterial genomes.

Using a novel assay, Ellis et al. show that stem cell-derived neurons from individuals with autism carrying SHANK2 mutations are hyperconnected, have impaired activity-dependent dendrite extension, and have perturbed transcription of ASD gene modules.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

The protein complexes associated with specific chromatin marks in living cells are identified using engineered binding proteins.

Tryptophan C-mannosyltransferase (CMT) enzymes append a mannose to the first tryptophan of select sequences, which is important for the trafficking, folding and function of secretory and transmembrane proteins involved in cellular communication processes. A study reveals the structure, mode of peptide recognition and catalytic mechanism for the eukaryotic C-mannosyltransferase DPY19.

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.

Apoptosis often requires mitochondrial outer membrane permeabilization, a process targeted by Bcl-2-binding BH3 mimetics. Here the authors describe and apply 'mito-priming', a method that allows triggering mitochondrial apoptosis in a synchronous manner, facilitating the investigation of mitochondrial apoptosis and its regulation by Bcl-2 proteins.

Advanced ecological modelling reveals how Sahul (Australia and New Guinea) was first peopled, suggesting the most probable routes and surprisingly rapid early settlement of this continent by anatomically modern humans starting 50,000 to 75,000 years ago.

SIVmac239 infection of macaques is a favored model of human HIV infection, but antibody-mediated protection for SIVmac239 is insufficiently understood. Here, Zhao and Berndsen et al isolated nAbs and confirmed protection against SIVmac239 infection in passive transfer studies in macaques. The nAb was used to provide the first high-resolution structure of a rhesus SIV trimer by CryoEM. Analysis of the glycosylation pattern of this SIV trimer suggests a denser glycan shield on Env for rhesus SIV compared to chimpanzee SIV or HIV-1, which partially explains the poor nAb response of rhesus macaques to SIVmac239 infection.

The plasma membrane of eukaryotic cells can fold inwards to create reservoirs that store or release excess membrane. Zhu et al. show that Salmonella-secreted effectors modulate these reservoirs to facilitate host cell invasion.

Getting synthetic biology circuit-based sensors into field applications is still a challenge. Here the authors combine a circuit sensor with a glucose meter for small analyte and nucleic acid detection.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Telomere crisis has been shown to induce chromothripsis and breakage fusion bridge (BFB) cycles in vitro. Here, the authors show that telomere crisis generates a much broader spectrum of structural variations, implying that cancers without chromothripsis and BFB cycles could have emerged from telomere crisis.

Epithelial-to-mesenchymal transition is a key process in tumorigenesis but little is known about the molecular mechanism regulating such process at the translational level. Here, the authors identify a subset of mRNAs important for this process that are specifically modulated by the RNA-binding protein CELF1.

A combination of a sensitive blue light–gated channelrhodopsin actuator and red-shifted Arch-based voltage sensors allows all-optical electrophysiology without cross-talk in cultured neurons or brain slices.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

The establishment of a drug-discovery screening pipeline for cryptosporidiosis, and identification of pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.

The mHsp60-mHsp10 chaperonin system forms alternating single and double ring complexes to assist protein folding, but the molecular details of this cycle are not fully understood. Here, the authors present cryoEM and crystal structures of key intermediates of the mHsp60-mHsp10 reaction cycle.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.