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Here, the authors provide molecular insight into the remarkable ability of Tardigrades to withstand high levels of radiation by demonstrating that their Dsup protein interacts with multiple surfaces of the nucleosome to protect the genome from oxidative DNA damage.

This work presents Perturb-tracing, integrating CRISPR screening with barcode readout and chromatin tracing for loss-of-function screens, enabling the identification of chromatin folding regulators at various length scales.

A large-scale mouse study reveals that while existing epigenomic data detect many developmental enhancers, a substantial fraction is missed - highlighting the need for expanded resources to fully annotate enhancers genome-wide.

Thermal lepton pairs are ideal probes for the temperature of quark-gluon plasma. Here, the STAR Collaboration uses thermal electron-positron pair production to measure quark-gluon plasma average temperature at different stages of the evolution.

A self-transmissible CRISPR-associated transposase system encodes a nanobody payload to treat Shiga toxin infections.

Gutierrez and Tyler investigate the limits of replicative lifespan in yeast. The authors show that nucleolar expansion during aging is a mortality timer. Enlargement of nucleoli beyond a defined size alters their biophysical properties; normally excluded DNA repair protein enter, causing aberrant rDNA recombination, genome instability and death.

Prime-editing mouse models enable the study of specific cancer mutations in vivo.

A signal amplification circuit based on recycling nucleic acid inputs with RNA polymerase off-target transcription improves the sensitivity of transcription factor-based cell-free biosensors, achieving 10-fold decreases in limits of detection.

Medium- and branched-chain diols and amino alcohols are important industrial feedstocks, but they are biosynthetically challenging to produce. Here the authors introduce a modular polyketide synthase platform for the efficient production of these compounds.

The authors report that a change to lysosome morphology, from vesicular to tubular form, supports lifespan extension upon dietary restriction and promotes heightened autophagy and healthy aging when stimulated artificially in well-fed animals.

Unlike that in plants, fungi, and marine animals, bacteria are vastly underrepresented in the production of terpenoids. Here, the authors report a systematic screening of terpene synthases from bacteria and identify three new skeletons that are not found in other organisms.

The Global Flourishing Study provides a comprehensive view of the distribution and determinants of well-being by assessing domains such as health, happiness, meaning, character, relationships and financial security. Initial findings reveal significant variations in flourishing across countries and demographic groups, with factors such as age, marital status and religious service attendance showing strong associations with well-being.

Bialowolski et al. analyse financial well-being across 22 countries using data from the Global Flourishing Study. They find that demographic factors (for example, age) and early-life conditions (for example, childhood finances) correlate with financial outcomes.

Molecular tools enabling precise DNA mutations and targeted modulation of gene expression have significant potential in medicine and biology. Here, the authors develop a compact system for simultaneous and independent gene editing, activation, and repression in mammalian cells.

Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.

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.

Engineered polyketide synthases (PKSs) have great potential as biocatalysts for the synthesis of chemically challenging molecules. Here the authors show a retrobiosynthesis approach to design and construct PKSs to produce a series of valerolactams for biopolymer production.

TDP43 proteinopathies are a devastating group of neurodegenerative disorders. Here the authors show that RNA-targeting CRISPR effector proteins can be used to mitigate TDP-43 pathology when targeting ataxin-2, a modifier of TDP-43-associated toxicity, and apply this to a mouse model.

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

A cell free or synthetic biochemistry approach offers a way to circumvent the many constraints of living cells. Here, the authors demonstrate, via enzyme and process enhancements, the production of isobutanol with the metrics exceeding highly developed ethanol fermentation.

Electrical excitability in neuroendocrine SCLC cells promotes tumour progression through action potential firing, increasing ATP demand and oxidative phosphorylation dependency, whereas non-neuroendocrine cells provide metabolic support, driving a tumour-autonomous cycle that enhances tumorigenesis and metastasis.

Producing individual cannabinoids by metabolically engineered microbes has proven challenging. Here, the authors develop a cell-free enzymatic prenylating system to generate isoprenyl pyrophosphate substrates directly from glucose and produce both common and rare cannabinoids at >1 g/L.

Mouse models of lung and colorectal cancer with sporadic DNA mismatch repair deficiency clarify that the intratumor heterogeneity and clonal architecture rather than tumor mutational burden are powerful determinants of immunotherapy response.

Evolution of the SARS-CoV-2 spike protein is likely driven by many factors, including immune escape and receptor binding. Here, by measuring the binding affinity of more than 30,000 variants of the SARS-CoV-2 RBD to its receptor ACE2, Moulana et al. show that the evolution of the Omicron BA.1 variant was driven by interactions between mutations.

Current bacterial sgRNA activity models struggle with accurate predictions and generalizations. Here the authors report crisprHAL, a machine learning architecture that can be trained on existing datasets, and shows good sgRNA activity prediction accuracy can generalize predictions to different bacteria.

A. aegypti is the principal vector for arboviruses that impact on human health and wellbeing. Here the authors use precision guided sterile insect technique—pgSIT—to suppress or eliminate mosquito populations in multigeneration cage experiments.

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.

A synthetic receptor platform that enables mammalian cells to respond to soluble factors allows specific signalling networks to be precisely controlled, with a variety of therapeutic applications.

By investigating key transcription factors in Drosophila, the authors show that pioneering activity is not an intrinsic, binary property. Instead, it is heavily influenced by the level of chromatin occupancy of the transcription factors, which is controlled by multiple protein domains and protein-extrinsic features.

A druggable genome CRISPR-Cas9 screen followed by functional validation in preclinical lung cancer models uncovers Slc33a1 as a Keap1-mutant-specific targetable dependency.

The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice—an important proof-of-principle for the engineering of gut microbial pathways.

ACE2 binding is an ancestral, widespread trait of sarbecovirus receptor-binding domains, and many single mutations enable binding to different ACE2 receptors.

Multivalent nanobodies against SARS-CoV-2 from mice engineered to produce camelid nanobodies recognize conserved epitopes that are inaccessible to human antibodies and show promise as a strategy for dealing with viral escape mutations.

Amaryllidaceae alkaloids, such as the Alzheimer’s medication galantamine, are currently extracted from low-yielding daffodils. Here, authors pair biosensor-assisted screening with machine learning-guided protein design to rapidly engineer an improved Amaryllidaceae enzyme in a microbial host.

Recent studies proposed that m⁶A modification in mammalian mRNAs increases their recruitment to stress granule. However, here the authors observed that m⁶A modification has a limited effect on mRNA entry into stress granules.

A programmable transposase integrates donor DNA at user-defined genomic target sites with high fidelity, revealing a new approach for genetic engineering that obviates the need for DNA double-strand breaks and homologous recombination. 

Coordination of cell wall assembly is critical for bacterial morphology and survival. Here, the authors show that activation of cell wall synthesis by the Rod complex is regulated by the structural dynamics of RodA-PBP2.

Hydroxyglutarate synthase (HglS) converts 2-oxoadipate to D-2- hydroxyglutarate during lysine catabolism in bacteria. Here the authors use structural and biochemical approaches to show that HglS acts via successive decarboxylation and intramolecular hydroxylation and that homologous enzymes catalyze the final step of lysine catabolism in plants.

Large DNA sequences are integrated into human cells using RNA-guided CRISPR-associated transposases.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Terpenes are bioactive natural products derived from plants with several commercial applications. Here, the authors engineer a cell-free system composed of 27 enzymes that convert glucose into terpenes, highlighting the potential of synthetic biochemistry approaches for biocompounds production.

The development of a high-throughput tagging platform to screen kinases of the parasite Toxoplasma gondii led to the identification of a kinase regulating invasion of and egress from host cells.

By using a supporting cell promoter, the authors show that transient expression of Atoh1 drives regeneration and maturation of hair cells in the mature mouse vestibular organs, with transcriptomes similar to maturing type II hair cells.

Efficiency of transversion base editing is increased by matching a set of base editors to target sequences.

A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit.

A cell-free system for cannabinoid production uses only low-cost inputs with 12 enzymes and can operate either aerobically or anaerobically, in addition to reducing ATP requirements by use of an engineered system for malonate-CoA biosynthesis.

In a mouse tumour model, immunotherapy-induced rejection of tumour cells requires presentation of both MHC class I and MHC class II antigens, which activate CD4⁺ and CD8⁺ T cells, respectively.