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Although polycystic ovary syndrome is the most common cause of female infertility, its etiology remains poorly understood. Here, the authors report a rat model that spontaneously exhibits the clinical heterogeneity of this syndrome and demonstrate that the phenotype is developmentally programmed.

JNJ-9676—a small-molecule inhibitor targeting coronavirus M protein that shows excellent efficacy in Syrian golden hamster models—binds to and stabilizes the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus.

Arany and colleagues integrate metabolomics data, tissue RNA-sequencing data and proteomics data from explanted hearts of patients with end-stage heart failure to provide a comprehensive ‘multi-omic’ evaluation of the metabolic pathways affected by heart failure.

LKB1-mut has been shown as a major genetic driver of primary resistance to immune checkpoint inhibitors. Here this group reports the identification of the LKB1-IAP-JAK dynamic complex as a molecular determinant for immune response of LKB1-mut lung cancer cells.

Abnormal, misfolded tau proteins are found in cognitively normal individuals and Tauopathies, suggesting not all tau species are pathogenic. Here, the authors show tau seeding and post-translational modification profiles were associated with Aβ neuritic plaque density and differentiated two tauopathies.

Recurrent absence seizures aberrantly increase activity-regulated myelination within the seizure network; this maladaptive myelination, in turn, increases network hypersynchrony and seizure burden over time.

Carboxyl terminus of Hsc70-interacting protein (CHIP) is proteostasis regulator. Here the authors show that CHIP-mediated protein turnover is enhanced by PKG-mediated phosphorylation, which results in attenuated cardiac ischemic proteotoxicity.

Two-year interim data from an ongoing phase 1/2 trial of the AAV-based gene therapy bidridistrogene xeboparvovec in six patients with limb-girdle muscular dystrophy show a safe profile and preliminary increased expression of the β-sarcoglycan protein.

Happ et al. uncover an unusual regulatory mechanism in the Hedgehog signaling pathway, which enables a G protein-coupled receptor to physically block the enzymatic activity of a major cellular kinase.

New agonists of the serotonin 5-HT_2A receptor (5-HT_2AR) confer high brain permeability and antidepressant activity and—in contrast to classic 5-HT_2AR agonists—lack psychedelic activity.

HIV vaccine candidates often have limited capacity to induce broadly neutralizing antibodies (nAbs). In this study, the authors show that stabilized Clade C HIV-1 Env protein trimers decorated on CoPoP liposomes induce nAbs against 18 of 20 multiclade tier 2 HIV-1 strains in immunized rabbits.

Intestinal stem cells are responsible for replenishing cells within the high-turnover intestinal epithelium. Here they show that ribosome dynamics affect intestinal stem cell identity through a mechanism that is triggered by changes in nutrient availability.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

An intra-articularly injected depot of nanoparticles targeting collagen and delivering small interfering RNA for matrix metalloproteinase 13 protects cartilage integrity and joint structure in mice with post-traumatic osteoarthritis.

Identification of a hyperstable boronate enables automated lego-like synthesis to access a wider range of three-dimensionally complex small organic molecules rich in Csp³–C bonds. 

Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell analysis of mouse trophoblast stem cells the authors identify Nicol1 as a gatekeeper of the stem cell state and show that CXADR regulates the differentiation dynamics between the two syncytial layers of the mouse placenta.

Cellular, transcriptomic and proteomic analyses of organoids derived from human induced pluripotent stem cells show that mTOR pathway hypoactivation is involved in two genetically distinct lissencephaly spectrum disorders.

Single-cell RNA sequencing analysis identifies cell types and lineages in airway epithelium, including the pulmonary ionocyte, a new cell type predominantly expressing the cystic fibrosis gene CFTR.

The authors used new network-analysis algorithms to examine how distributed networks of brain areas are reorganized as humans learn a new motor skill. Using fMRI, the authors found that learning induced autonomy of sensorimotor systems and that a release of cognitive control hubs predicted individual differences in learning.

Dendritic cell antigen presentation is central to CD8⁺ T cell responses, but surprisingly little is known about the requirement for this functionality in the central nervous system. Here, the authors use three different models of neuroinflammation to show the importance of these cells in the CNS and in response to cerebral malaria, picornavirus infection and experimental glioma.

Data from a variety of sources—including satellite, climate and soil data, as well as field-collected information on plant traits—are pooled and analysed to map the functional diversity of tropical forest canopies globally.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons.

cAMP response element–binding protein (CREB) is a key regulator of the nucleus accumbens shell function in animals' responses to emotional stimuli. The present study demonstrates that passive stress in the form of social isolation induces anhedonia and depression-like symptoms that are mediated by CREB activity and neuronal excitability.

Peripheral macrophages located along motor axons react differently to neurodegeneration compared to CNS microglia in ALS mice. Modifying peripheral macrophages suppresses proinflammatory microglial responses, shifting them toward neuronal support.

In this study Fossati et al. demonstrate how co-fractionation mass spectrometry can be applied to systematically investigate pathogen proteome organization and host interactome plasticity upon Jumbophage infection of Pseudomonas aeruginosa.

Expression of the exercise-induced myokine irisin (FNDC5) is lower in patients with AD. Whereas knockdown of FNDC5/irisin is sufficient to induce learning and memory deficits, restoration of its expression can ameliorate these phenotypes in rodent models.

The authors compare the heat shock response between different cell lines and stimuli and reveal the genome-wide binding of its master transcription factor HSF1 as a platform for context-specific transcription activation.

Employing a widefield cryogenic microscope to parallelize resonant spectroscopy, chip-scale automated optical characterization of solid-state quantum emitters is demonstrated.

Perez-Bermejo et al. performed an in-depth study on a variant in the BAG3 gene that has been previously associated with lowered incidence of heart failure and show that, in induced pluripotent stem cell-derived cardiomyocytes engineered to express such BAG3 variant, the interactome of the corresponding BAG3 protein has changed, rendering the engineered cardiomyocytes more resistant to a well-known cardiotoxic drug.

Lim and colleagues present the UK PROSECO study where they assess humoral and cellular immune responses to one, two and three doses of vaccination against SARS-CoV-2 in patients with B-cell malignancies in a prospective observational study.

The effects of chromosomal translocations involving the mixed-lineage leukemia (MLL) locus on gene expression regulation remain to be explored. Here, the authors find that MLL oncoproteins support lineage-switching events through dynamic chromatin binding.

A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

Selective ablation of Elongator in a conditional knockout mouse model of amyotrophic lateral sclerosis leads to motor neuron degeneration and reduced levels of nuclear and nucleolar TDP-43

Investigators present findings from a double-blind randomized controlled trial of personalized stimulation of the left dorsolateral prefrontal cortex using transcranial magnetic stimulation to increase hypnotizability in a sample of patients with fibromyalgia syndrome.

The authors show that post-transcriptional regulation of the cilia-driven leftward flow target dand5 is central to symmetry breakage in frog, fish and mouse and is mediated by a 139 nt Bicc1 responsive element in the dand5 3′UTR, and they present evidence that Pkd2 regulates this Bicc1/dand5 module.

Dural-associated lymphoid tissues are lymphoid structures around vascular hubs in the dura mater that sample antigens and rapidly support humoral immune responses after local pathogen challenge.

Morphology of metabolosomes affects the encapsulated pathway performance. Here, the authors combine experimental characterizations with structural and kinetic modeling to reveal how the shell protein PduN changes the morphology of 1,2-propanediol utilization (Pdu) metabolosome and how this morphology shift impacts Pdu function.

The PINK1 ubiquitin kinase is shown to recruit the two autophagy receptors NDP52 and OPTN to mitochondria to activate mitophagy directly, independently of the ubiquitin ligase parkin; once recruited to mitochondria, NDP52 and OPTN recruit autophagy initiation components, and parkin may amplify the phospho-ubiquitin signal generated by PINK1, resulting in robust autophagy induction.

Whole-genome sequencing analyses in a cohort of individuals with ataxia-telangiectasia are used to identify genetic variants that might be amenable to treatment with splice-switching antisense oligonucleotides (ASOs), and develop ASOs with therapeutic potential.

FRESH, a multi-lab collaboration, reveals how data quality, analysis pipelines, and researcher expertise influence reproducibility in fNIRS neuroimaging, highlighting key factors driving variability in hypothesis outcomes.

There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

The dysregulation of the m⁶A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m⁶A reader YTHDF2, resulting in the initiation of gliomas.

Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.

Recurrent neural networks (RNNs) can learn to process temporal information, such as speech or movement. New work makes such approaches more powerful and flexible by describing theory and experiments demonstrating that RNNs can learn from a few examples to generalize and predict complex dynamics including chaotic behaviour.

Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.

A study using a mouse solid tumour model suggests that adjusting the dosing frequency of the PI3Kδ inhibitor AMG319 in the treatment of human cancers could decrease tumour growth with fewer adverse effects.

Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.