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Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.

Fatigue influences our choices to engage in physical activity. Here, the authors investigate the underlying cognitive and neuronal mechanisms by which fatigue influences decisions to exert, and show that information about motor cortical state modulates decisions to engage in physical activity.

Single-cell RNAseq can struggle to capture cellular heterogeneity due to the relatively low expression of biologically meaningful transcripts. Here the authors present an approach called scCLEAN, which uses CRISPR/Cas9 to target and remove certain ubiquitous transcripts, thereby enhancing the detection of low-abundance transcripts.

Learning is ubiquitous in everyday life, yet it is unclear how neurons change their activity together during learning. Golub and colleagues show that short-term learning relies on a fixed neural repertoire, which limits behavioral improvement.

Genome-wide association analyses identify 11 loci associated with native myocardial T1 time, a marker of interstitial fibrosis, providing insights into the pathways involved in myocardial fibrosis and myofibroblast cell state acquisition.

The epigenetic mechanisms underlying phenotypic diversity across different metastatic sites in castration-resistant prostate cancer (CRPC) remain to be characterised. Here, multi-omic profiling across metastatic lesions identifies regulatory networks driving tumour lineage programs and potential therapeutic targets.

EGFR regulates cellular processes across the animal kingdom. Here, the authors show that transmembrane conformational coupling is the first step in EGFR signaling, providing evidence for the existence of transmembrane intramolecular conformational changes in a single pass membrane protein.

Here, via applying metagenomics and metabolomics analyses, the authors show that fecal microbiota composition and microbiota-derived metabolites predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection, suggesting the gut-lung axis to play an important role in the recovery from COVID-19.

A digital twin represents a real world object using available data. Here, the authors develop a digital twin for mandaring orchards in Jeju island showing the value of individualized agriculture to predict fruit quality at tree level.

Qudits can encode a richer class of topologically ordered states, which are promising for quantum information, but experimental realizations have been limited to qubits. Here, the authors report a study of a qutrit toric code on a trapped-ion quantum computer.

Genome-wide analyses of cardiac magnetic resonance imaging data identify loci associated with right heart structure and function. A polygenic predictor of right ventricular ejection fraction is associated with dilated cardiomyopathy risk.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Topological photonic structures can be understood by solving the eigenvalue problem of Maxwell’s equations in the static case. Here, the authors study Floquet topological phases in nonlinear photonic crystals under external drive and show how non-reciprocal transport can be achieved in a Floquet Chern insulator.

Terahertz frequency combs are highly desired for applications in precision measurements, sensing, spectroscopy and metrology. Here the authors demonstrate the room-temperature chip-based THz frequency comb using nonlinear frequency generation from a mid-infrared quantum cascade laser comb.

Most research on alleviating acute hypoxic stress has focused on managing consequences of hypoxia instead of addressing cellular adaptation to low-oxygen environments. Here, the authors present a “phenopushing” screening platform to identify compounds and targets that fast-track cells from stressed to adapted states.

KSRP is involved in mRNA instability, a role that is repressed upon AKT kinase–mediated phosphorylation, which promotes 14-3-3 interaction. This modification site is now shown to be exposed upon AKT phosphorylation through unfolding of the KH1 domain of KSRP, an event that allows 14-3-3 interaction, which in turn affects nuclear cytoplasmic partitioning.

Cells rely on limited numbers of transmembrane receptors to process signals from dynamic microenvironments. Using microfluidics and endogenous reporters, the authors track single cells to reveal how temporal dosing rewires chromatin, leading to a model of signalling with near single-cell accuracy.

Crystallographic analysis and spectroscopic studies employing the nitrile moiety of bosutinib as an IR-active probe reveal that structured water molecules, organized by the gatekeeper residues of kinases, mediate the selectivity profile of kinase inhibitor binding.

Gao and colleagues explore soluble biomarkers, immune cell subsets, viral antibody responses and plasma proteomics to better define and understand long COVID in two independent cohorts.

FRET can be used to study conformational changes and protein-protein interactions. Here the authors report Binary-FRET for monitoring two FRET reactions, one encoded in the fluorescence lifetime of the donor, another encoded in its anisotropy, and monitor the dynamics of CaMKII and its interaction with NR2B.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Rare mutations in the high requirement temperature protein A1 (HTRA1) cause cerebral vasculopathy. Here, authors establish mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the assembly and protease function of HTRA1.

When reading, we extract information about upcoming words before we saccade to them. Here the authors provide insights on the neural mechanisms supporting this previewing process using MEG data, and show an association between previewing effects and reading speed.

Forecasting ecology can support proactive decision-making in the face of uncertain environmental conditions. Using case studies on whale entanglement and sea turtle bycatch, this study showcases the capacity for existing management tools to transition to a forecast configuration and provide skilful forecasts up to 12 months in advance.

How do humans learn complex rules from small available data? Rule et al introduce metaprogram learning as a model that fits human behaviour in complex learning situations. Unlike previous approaches, this model is based on programs revising programs, making it more efficient.

The beamsplitter operation is a key component for quantum information processing, but implementations in superconducting circuit-QED usually introduce additional decoherence. Here, the authors exploit the symmetry within a SQUID, driven in a purely differential manner, to realise clean BS operations between two SC cavity modes.

Here, using human liver chimeric mice, the authors describe perturbation of the diurnal transcriptome and epigenome of human hepatocytes during hepatitis C virus infection, affecting pathways mediating metabolic alterations, fibrosis, and cancer, and further show that the pathways remain affected in patients with advanced liver disease.

Interneuron circuits in the retina allow structurally similar retinal ganglion cells to show different responses. Here the authors use an intersectional genetics approach to identify an object motion sensitive amacrine cell subtype in the mouse retina.

Serological tests are important diagnostic and disease surveillance tools for addressing the COVID-19 pandemic. Here, the authors present a tri-part Nanoluciferase based assay to detect antibodies against SARS-CoV-2.

Septoria tritici blotch (STB) is a devastating foliar disease affecting worldwide wheat production. Here, the authors report a cysteine-rich receptor-like kinase that can confer resistance to Zymoseptoria tritici, the pathogen that causes STB, and slow penetration and intercellular growth of the pathogen.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

CD4⁺ T cells promote immunity to tuberculosis infection via macrophages. Here the authors show upregulation of SLAMF1/CD150 on infected macrophages after interaction with CD4⁺ T cells and that the presence of SLAMF1 promotes ROS production by macrophages and the absence of Slamf1 in macrophages results in higher mycobacterial loads in infected mice.

The identification of HLA peptides by mass spectrometry is non-trivial. Here, the authors extended and used the wealth of data from the ProteomeTools project to improve the prediction of non-tryptic peptides using deep learning, and show their approach enables a variety of immunological discoveries.

Human leukocyte antigen loss of heterozygosity (HLA LOH) is an important mechanism of immune escape in patients with cancer. Here the authors design and validate a machine learning algorithm with subclonal sensitivity for the identification of HLA LOH from paired tumor-normal sequencing data.

Complete RNA isoforms are captured by a new single-nuclei sequencing method.

Sedimentary osmium isotopes from the Gulf of Mexico indicate that after the Cretaceous-Paleogene impact, nutrients were supplied by hydrothermal activity for 700 kyr and may have contributed to the post-extinction recovery of the marine ecosystem

HIV reservoir decay is less well studied in acute infection. Here, the authors show that reservoir decay rates are biphasic and 5x faster in people initiating antiretroviral therapy during acute HIV than prior estimates for chronic HIV. Higher initial CD4+ counts and lower viral loads predicted faster decay.

The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs.

Quantifying intact proviruses is key to understanding decreases in HIV reservoirs but results can differ depending on the method. To balance sensitivity and specificity of two assays, the authors use mathematical models and measurements of intact and defective proviruses to assess how misclassification can impact estimates of natural and therapeutic reservoir reduction.