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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.

To study pathways that lead to aneuploidy during aging, the authors provide a system that enables cohesion protein depletion in mouse oocytes, mimicking effects that occur during aging. They uncover a threshold for cohesion loss driving chromosome errors and show that actin and centromere defects amplify aneuploidy.

Parkinson’s disease is managed through co-treatment with levodopa and tolcapone, with tolcapone altering the microbiome to increase its capacity to metabolize levodopa, implicating the gut microbiome in drug–drug interaction.

The fluorescence-based protein assembly platform GEMINI is able to record the history of individual cells by leveraging a computationally designed protein assembly as an intracellular memory device.

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

Limited experimental platforms exist for assessing quantitative sequence-function relationships for multiple antibodies. Here, authors develop a deep-sequencing based technology called MAGMA-seq, that determines the quantitative properties of antibody libraries.

A synthetic genetic circuit made up of recombinase-based cell-fate branching devices enables precise control over the ratios of cell types in an offspring population derived from one founder strain, and could be used to build user-defined multicellular aggregates.

Saturation genome editing of a cancer mutation hotspot in CTNNB1, the gene encoding β-catenin, reveals a gradient of effects of missense mutations on Wnt signaling.

A toolbox for rapidly creating synthetic circuits that respond to past and present inputs opens new doors for cellular engineering.

Precise and scalable regulation of gene expression in mammalian cells is challenging. Here, the authors created a highly tunable CRISPR-based synthetic transcription system for programmable control of mammalian gene expression and cellular activity.

A multi-model intercomparison using six global agro-economic models explores how ozone reductions arising from climate change mitigation could impact crop yields. Yield changes are projected to 2050, linking reduced ozone to food security and the alleviation of hunger.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

DNA recognition and cleavage control in type II topoisomerases are poorly understood processes. Here, the authors determine cleaved and uncleaved structures of supercoiled DNA-bound topoisomerase VI that reveal how the enzyme activates its cleavage state and prefers to act at deformable substrates.

Insights into regulatory T cell biology are accelerating therapeutic innovation in cancer immunotherapy, autoimmune diseases and transplant rejection.

Nitazenes are potent synthetic opioids that are difficult to detect. Here, authors computationally redesign a plant receptor to create sensitive sensors capable of detecting diverse nitazenes and their metabolites in biological samples.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Expression of genetically encoded antibodies for cell labelling is often limited by folding issues. Here, the authors engineer an anti-HA scFv antibody that works in the cellular environment and use it to track mRNA translation dynamics in living cells and to label proteins in live zebrafish embryos.

A protocol describing how to construct a platform for two-input Boolean logic functions with concomitant DNA-based memory that enables the straightforward assembly of integrated logic-and-memory circuits that implement desired behaviors within a couple of weeks.

Here, the authors show that reticulocytes derived from immortalized erythroblasts support invasion and development of Plasmodium falciparum and use CRISPR-mediated gene knockout and complementation of an invasion receptor to demonstrate utility of this model system for research in malaria invasion.

Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

Bacteriophage single-stranded DNA annealing proteins (SSAPs) interact with the C termini of single-stranded binding proteins in host bacteria, a finding that enables engineering of enhanced SSAP portability and DNA recombineering activities.

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.

iGluSnFR variants with improved signal-to-noise ratios and targeting to postsynaptic sites have been developed, enabling the analysis of glutamatergic neurotransmission in vivo as illustrated in the mouse visual and somatosensory cortex.

Autonomous hypermutation yeast surface display (AHEAD) mimics the process of somatic hypermutation in animals to enable the rapid in vitro evolution of antibodies, including nanobodies targeting the RBD of SARS-CoV-2.

Synthetic methylotrophic organisms provide potential for valorization of greenhouse gas-derived methanol. Here an Escherichia coli strain is generated that reaches a similar growth rate on methanol to many natural methylotrophs and is capable of producing chemicals from this carbon source.

Arrayed and pooled high-throughput screening is crucial for drug discovery and CRISPR functional genomics. Here, the authors present dFLASH; a dual FLuorescent transcription factor Activity Sensor for Histone-integrated live-cell reporting for high performance screening applications across numerous pathways and screening contexts.

Stack pressure controls porosity during Li alloying/dealloying. A threshold pressure is needed for the densification and stable cycling of Li alloys in batteries, leading to the design of Li alloy anodes with densified interfacial layers for cycling at low pressures in solid-state batteries.

M-CREATE is an in vivo screening strategy for identifying recombinant AAVs with desired tropism. The approach involves both positive and negative selection and yields vectors with diversified cell-type tropism that can cross the blood–brain barrier in adult mice across strains when delivered intravenously.

Massively parallel genetic screening reveals synergies between miRNAs regulating cancer cell proliferation and drug resistance.

Regulatory elements for specific human genes are rapidly identified with CRISPR epigenome editing.

Polycystic ovary syndrome (PCOS) is a common disorder, the causes of which remain incompletely understood. Here the authors report the discovery of gene regulatory mechanisms that help to explain genetic associations with PCOS in the GATA4, FSHB and DENND1A loci.

Design of a bicistronic biosensor allows simultaneous quantification of cap- and IRES-mediated translation under normal and stress conditions in living mammalian cells.

Epithelial organoids are grown without Matrigel using a single-chain antibody.

The design of genetic networks in mammalian cells is still slow and often fails. Here the authors show that miRNA-based incoherent feedforward loop circuits can be used to alleviate cellular burden.

Strong underwater adhesive fibres are self-assembled by fusing mussel foot proteins with an amyloid-based protein.

Kava (Piper methysticum), an ethnomedicinal shrub native to the Polynesian islands, produces psychoactive kavalactones and anticancer flavokavains. Structures of key enzymes in their biosynthetic network may enable heterologous production.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

Single cell analysis of histologic variant bladder tumors detects a shared CA125+ tumor cell state associated with aggressive clinical features and reveals enriched expression of TM4SF1, a membrane protein that can be targeted with CAR T cells.

Wood and colleagues report that the XPO1 inhibitor selinexor activates PI3Ky-dependent AKT signaling in AML via upregulation of P2RY2 and demonstrate a synergistic effect of combining selinexor with inhibition of prosurvival AKT signaling.

This study presents a multiomic Gene–Metabolite Association Prediction (GeneMAP) platform for discovery of metabolic gene function and identifies SLC25A48 as a mediator of mitochondrial choline import.

Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

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.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

A dual-layer encapsulation approach provides physical containment of genetically modified bacteria (especially when combined with chemical containment) while also protecting them from environmental stressors and maintaining their sensing functions.