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Astrocytes have important roles in disease. However, modulation of their reactive state is challenging. Here the authors present a phenotypic in vitro screening platform they can leverage to identify chemical compounds able to modulate astrocyte reactivity in vitro and in vivo.

The role of ancestry in target discovery remains to be systematically explored. Here, the authors analyse data from 611 genome scale CRISPR/Cas9 viability experiments in human cell line models as part of The Cancer Dependency Map and identify ancestry-associated genetic dependencies.

Guide RNA folding affects functionality of CRISPR-Cas transcriptional control systems. Here, the authors report computational gRNA design together with creation of synthetic CRISPRa promoters for orthogonal expression control and demonstrate the application in pteridine and human milk oligosaccharide production in E. coli.

Deep learning was used to map the crown sizes of each tree in the West African Sahara, Sahel and sub-humid zone using submetre-resolution satellite imagery, revealing a relatively high density of trees in arid areas.

Systematic assessment of cofactor dependencies of nine transcription factors (TFs) and promoters finds that TFs use unique cofactor combinations to modulate distinct steps in transcription, whereas promoter elements fit into discrete groups where their rate-limiting step for activation influences cofactor compatibility.

The electrostatic potential of the plasma membrane of live mammalian cells is measured with a FRET-based sensor.

An approximately 2-million-year-old male Paranthropus robustus cranium from Drimolen Main Quarry in South Africa refutes influential ideas of sexual dimorphism in this taxon and instead suggests local microevolution within robust australopiths.

Resistance of Neisseria gonorrhoeae to extended spectrum cephalosporins is an increasing concern. Here, the authors conduct whole genome sequencing of isolates from the United States and find that most resistant isolates were associated with a persistent circulating lineage.

In male zebra finches, dopamine responses in Area X are retuned away from self-evaluation of song performance and towards social feedback to song performance when females are present.

The noncoding RNA Xist regulates the accessibility of select chromatin regions on the inactive X chromosome (Xi) by directly inhibiting the chromosome remodeler BRG1 and by expelling it from the Xi.

Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.

Early intermittent feeding of mice with a high-cholesterol Western-type diet accelerates atherosclerosis compared with late continuous exposure to the Western-type diet, despite similar cumulative circulating LDL-C levels.

A variant of MHC class I is protective against severe malaria disease and enriched in affected African populations. Here, Wroblewski et al., characterise the consequences of malaria infection in wild bonobo populations showing that the presence of malaria drives a similar evolution in immune genes.

The development of metal–organic magnets that combine tunable magnetic properties with other desirable physical properties remains challenging despite numerous potential applications. Now, a mixed-valent chromium–triazolate material has been prepared that exhibits itinerant ferromagnetism with a magnetic ordering temperature of 225 K, a high conductivity and large negative magnetoresistance (23%).

The Aegilops tauschii-derived leaf rust resistance gene Lr42 has been widely used for breeding resistance wheat cultivars, but the molecular basis is unknown. Here, the authors show that Lr42 encodes an NLR-type of disease resistance gene by bulked segregant mapping in Ae. tauschii and confirm its function in common wheat.

A suite of human monoclonal antibodies block infection by all human ACE2 binding sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 variants, at subnanomolar concentrations in cell culture and protect mice against severe acute respiratory syndrome coronavirus 2 infection.

Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.

The pathomechanism of succinyl-CoA ligase (SCL) deficiency, a hereditary mitochondrial disease, is not fully understood. Here, the authors show that increased succinyl-CoA levels contribute to SCL pathology by causing global protein hyper-succinylation.

Tumour-associated myeloid cells have been linked to patient outcome and treatment response in multiple cancer types. Here, the authors use deconvolution of single cell RNA-sequencing data to identify myeloid populations which are prognostic across cancer types.

The nucleation mechanisms of biological protein phase separation are poorly understood. Here, the authors perform time-resolved SAXS experiments with the low-complexity domain (LCD) of hnRNPA1 and uncover multiple kinetic regimes on the micro- to millisecond timescale. Initially, individual proteins collapse. Nucleation then occurs via two steps distinguished by their protein cluster size distributions.

Focal adhesions are dynamic structures that link the cell to the extracellular matrix. Here, the authors report that focal adhesions contain tropomyosin-decorated actin filaments, and show evidence that suggests specific functions in adhesion dynamics and cell migration.

Podosomes are actin structures important in multiple cell functions. Here, the authors use iPALM microscopy to reveal an “hourglass” shape of the podosome actin core, a protruding “knob” at the bottom of the core, and two actin networks extending from it.

A new MAP4K4–moesin–talin–β1-integrin pathway regulating endothelial cell motility was discovered through chemical and siRNA screens; loss of Map4k4 or inhibition of MAP4K4 kinase activity altered the sprout morphology of endothelial cells during angiogenesis by blocking moesin phosphorylation, which regulates the disassembly of focal adhesions, demonstrating that this pathway is involved in both normal and pathological angiogenesis.

Genetic variants are grouped into chromosome-spanning haplotypes with the help of chromatin-interaction data.

Here the authors show that BTLA on effector T cells interacts with HVEM on other immunosuppressive cells in the tumor microenvironment. The authors also present evidence that overcoming this checkpoint can ehance CAR T functionality.

Linking proteins secreted from individual cells with other cellular information is challenging. Here, authors report a high-throughput method which uses hydrogel nanovials loaded with single cells to link the secretion profile of individual cells with their surface markers and transcriptomic data.

Intersectional adeno-associated viruses are important for neuroscience research but can be limited by complex and bulky design parameters. Hughes et al. present a unique and space-saving approach that simplifies toolkit development and provides expanded functionality.

People with the metabolic syndrome often develop gallstones. Why these two disorders are linked has not been not clear, but now Kahn and his colleagues have shown that lack of insulin signaling in the liver leads to dysregulation of genes that control the transport and synthesis of bile acids, thus altering the proper profile of bile salts and resulting in the formation of gallstones.

Effective CD8⁺ T cell immunity requires the generation of a long-lived memory pool and the maintenance of a non-exhausted effector T cell pool. The implementation of immune checkpoint blockade can reduced levels of exhaustion but lacks the ability to support memory formation in the effector pool. Here the authors suggest a role for Let-7 in the enhancement of the anti-tumor CD8⁺ T cell response by supporting memory via modulation of metabolic and differentiation state.

Synthetic transcriptional repressors are engineered from natural DNA-binding domains.

Baksh et al. show that oncogenic epidermal stem cells require extracellular serine to initiate squamous cell carcinoma via altering dioxygenases that remove H3K27me3.

The genome is folded in 3-dimensions, though the lack of robust ultra-resolution imaging makes this difficult to visualise. Here, the authors present 3D-EMISH that combines serial block-face scanning electron microscopy with in situ hybridization.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

Results are presented that indicate that alterations to gene regulatory three-dimensional architecture are a critical mechanism that enables structural variant-based oncogene activation in cancer genomes and sheds light on the essential elements for such gene activation events.

Across platforms, nonreciprocity requires time-reversal symmetry to be broken. Interference of an excitation-preserving and a non-preserving interaction realizes unidirectional transport in a time-reversal-symmetric system.

Non-genetic malignant clonal dominance is a cell-intrinsic and heritable property that underpins clonal output and response to therapy in cancer. 

Episodic memory and allocentric spatial navigation are interwoven in the activity of hippocampal neuron ensembles via Hebbian plasticity, which allows rats to encode journey-specific episodes.

The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis.

Climate models project an intensification of extreme precipitation under climate change, but this effect is difficult to detect in the observational record. Here, the authors show that a physically interpretable anthropogenic impact on extreme precipitation is detectable in global observational data sets.

Dynamic mapping of charge motion across multiple length- and timescales is essential for understanding a variety of phenomena. Here, the authors introduce sparse scanning KPFM, which enables fast nanoscale charge mapping at 3 frames per second to track ion migration.

Golub and colleagues identify the phosphate exporter XPR1 as a therapeutic vulnerability in ovarian and uterine cancers, and show that phosphate efflux inhibition reduces tumor cell viability through accumulation of intracellular phosphate.

As an alternative to monetary estimates, this study expresses the costs of climate change in terms of numbers of people left outside the ‘human climate niche’, which reflects the historically highly conserved distribution of human population density relative to mean annual temperature.

Reanalysis of bipedal trackways from Laetoli site A in Tanzania suggest that the footprints were made by a hominin that coexisted with at least one other hominin species.

Circular extrachromosomal DNA in high-risk medulloblastoma contributes to tumor heterogeneity and associates with relapse and survival. Enhancer rewiring events involving known oncogenes are frequent events, affecting transcription and proliferation.

Metabolic changes happening when cells enter quiescence are poorly understood. Here, the authors report that quiescent cells exhibit reduced glycolysis mediated by YAP inhibition and increased mitochondrial activity mediated by pyruvate carrier induced expression.

It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.

Whilst estrogen is known to be tumorigenic in some breast cancer, in some contexts it can be protective against invasion and dissemination. Here, the authors show estrogen can promote generation of Suppressive Cortical Actin Bundles that can inhibit motility dynamics through EVL-mediated actin cytoskeletal remodeling.

Deep proteome sequencing achieves ~80% coverage of the human proteome.