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Effective treatments for atopic dermatitis (AD) are highly sought after. Here the authors develop ucenprubart (LY3454738) for treating AD and find, in a randomized, multiple arms, multicenter, placebo controlled, and dose-escalating phase 1 trial (NCT03750643) trial, ucenprubart to be safe and showing preliminary efficacy when compared with placebo at 12 weeks post treatment.

A targeted design to stabilize the respiratory syncytial virus prefusion F trimer enables the generation of a foldon-free immunogen that elicits similar humoral responses to approved vaccines.

The ASAP4 family of genetically encoded voltage indicators allows recording of action potentials and subthreshold activity with either one- or two-photon microscopy over extended periods of time.

CRISPR activators are powerful tools for controlling gene expression, but they suffer from inconsistent efficacy and high toxicity. Here, authors develop a high-throughput method to test thousands of CRISPR activators, revealing distinct principles of activator biology and delivering improved tools.

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

How expectations of reward influence spatial memories remains unclear. Here, the authors reveal a dopamine pathway to the hippocampus that increases activity with proximity to expected rewards, thus stabilizing spatial representations of trajectories that lead to rewards.

This study introduces a genomic typing system for Moraxella catarrhalis, revealing two major lineages with distinct evolution, variability, and virulence traits.

Irisin is shown to mediate beneficial effects on cognitive function associated with exercise and to improve cognitive function in mouse models of Alzheimer’s disease, probably through its direct action in the brain.

It remains poorly understood how the onset of Alzheimer’s disease affects spatial cognition. Here, the authors report that spatial coding in grid cells deteriorates over time in a mouse model of Alzheimer’s disease during the early stages of pathology while place cell and head direction coding remain intact.

Health effects of dietary restriction are uncoupled from longevity.

Natural selection may favor traits underlying aging-related diseases if they benefit the young. Wang et al. find that oxidative activation of CaMKII provides physiological benefits critical to the initial and continued success of vertebrates but at the cost of disease, frailty, and shortened lifespan.

The human brain cycles through a repertoire of brain networks on a 1-second timescale during rest and tasks. This cycling appears to allow periodic engagement of essential cognitive functions, with the speed of cycling linked to genetics and age.

CRISPR-based transcriptional activation (CRISPRa) is a powerful tool for controlling gene expression. Here, Liang et al. show that commonly used CRISPRa systems are surprisingly toxic to cells due to their potent activation domains, informing the application and development of this technology.

MG53 is a protein that regulates the cell membrane repair process, and it’s been suggested that it might play a role in diabetes. Here, the authors demonstrate that circulating MG53 functions as a myokine to facilitate tissue injury-repair and regeneration without impacting glucose handling.

Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.

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

Birds have an excellent ability to learn to discriminate harmless insects from those that they mimic on the basis of subtle differences in appearance.

Two new phosphorylation sites, p-tau₂₆₂ and p-tau₃₅₆, detect the formation of prefibrillar tau aggregates and may serve as early-stage biofluid-based biomarkers of tau neurofibrillary tangle pathology in Alzheimer’s disease.

High contiguity human genomes can be assembled de novo in 6 h using nanopore long-read sequences and the Shasta toolkit.

Collagen VI microfibril cryo-EM structure resolves a cysteine-rich coiled-coil important for heterotrimerization and microfibril assembly, reveals a hotspot of collagen VI muscular dystrophy mutations and provides a template for therapeutic design.

Using a spatial reasoning task in mice, the authors show that retrosplenial cortex encodes spatial hypotheses with well-behaved recurrent dynamics, which can combine these hypotheses with incoming information to resolve ambiguities.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

The authors report an efficacious vaccine for human metapneumovirus based on a prefusion-stabilized fusion protein trimer that does not require a trimerization domain, designed using an AI convolutional classifier trained to predict optimized complex polar interactions.

In mouse models of Parkinson’s disease and dyskinesia, striatal spiny projection neurons of the direct and indirect pathways have abnormal, imbalanced levels of spontaneous and locomotor-related activity, with the two different disease states characterized by opposite abnormalities.

This study reports clusters of ipsilateral eye preferring neurons in layer 4 of mouse visual cortex, extending into layer 2/3 and upper layer 5. This column-like pattern for ocular dominance expands our understanding of the functional organization in neocortex.

tRNA modifications are essential for function, yet their timing relative to processing is unclear. Here, the authors show that queuosine and derivative modifications occur before splicing of pre-tRNA^Tyr, with cryo-EM confirming direct recognition by the QTRT1/2 complex.

Puddu et al. investigate the role of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) as biomarkers for early-stage colorectal cancer (CRC) detection in cell-free DNA (cfDNA). 6-base genome sequencing, using both 5mC and 5hmC biomarkers, increases the detection of stage I CRC.

Genome-wide analyses for 7,266 traits leveraging data from several genetic ancestry groups in UK Biobank identify new associations and enhance resources for interpreting risk variants across diverse populations.

Pyramidal cells are classically thought to comprise the excitatory output of the subiculum. Here, the authors show the existence of “ovoid cells”, excitatory subiculum neurons with specialized gene expression, morphology, projections, and function.

A 1,024-channel microelectrode array is delivered to the brain cortex via a minimally invasive incision in the skull and dura, and allows recording, stimulation and neural decoding across large portions of the brain in porcine models and human neurosurgical patients.

Goltstein et al. investigate the role of mouse visual cortical areas in information-integration category learning. They report widespread changes in neuronal response properties, most prominently in a higher visual area, the postrhinal cortex.

Genomes of nine brown algal species with different sex determination systems show that U/V sex chromosomes evolved 450–224 Ma and show remarkable conservation of genes within the sex-determining region despite independent expansions of the sex locus in each lineage.

Prevailing models have suggested that grid cell firing in the entorhinal cortex for spatial navigation relies on theta rhythmic inputs from head direction cells. Here, the authors show how head direction cells can skip theta cycles in a regular and organized manner in which two head direction cells will alternate theta skipping in opposing cycles. This so-called theta skipping is dependent on the input from the septum, and these results propose a possible mechanism of spatial computation.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Protein citrullination regulates the physiological function of proteins and is linked to various autoimmune disorders. Here, the authors report on the allosteric targeting of PAD1-4 leading to broad inhibition of protein citrullination in neutrophils.

Checkpoint inhibitor (CPI) therapy is modestly effective in Glioblastoma patients, with some patients not benefitting at all. Authors here present the outcomes of single arm prospective clinical trial employing combination CPI therapy in newly diagnosed GBM and identify the pre-treatment genetic, microbiome and immunological factors that might contribute to sensitivity.

Measurements of dopamine, serotonin and norepinephrine in the caudate of conscious humans reveal a neurochemical boundary between patients with essential tremor and Parkinson’s disease based on serotonin release evoked by monetary offers.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

DREDge is a software tool for motion correction of high-density electrophysiology recordings. It can handle action potential or local field potential data and is demonstrated on a variety of acute or chronic recordings from humans, nonhuman primates and mice.

Olfactory deficits occur early in Alzheimer’s disease (AD). Here, the authors identify that loss of locus coeruleus axons in the olfactory bulb underlies impaired olfaction in an AD mouse model and provide translational evidence for similar deficits in humans.

This study explores the genomic and transcriptomic landscapes of triple-negative breast cancer in African American women. The authors show that the mutational profile is broadly similar to that observed in European and East Asian ancestry women while highlighting some interesting differences.

Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.

Cellular imaging reveals that visual cue-evoked activity patterns in visual association cortex are reactivated during subsequent quiet waking. Reactivation rates scale with cue salience and predict next-day changes in functional connectivity and behavior.

This work identified cyclic peptide inhibitors of a mammalian N-terminal cysteine oxidase, ADO, through mRNA display, one of which was used as a scaffold to graft substrate moieties, allowing key interactions to be assessed through structural and biochemical approaches.