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Focal and segmental glomerulosclerosis, or renal scarring, is a debilitating disease. The identification of the molecular mechanisms of its initiation and progression has been limited, thus hampering the development of proper animal models. Dontscho Kerjaschki and his colleagues now report that microRNA-193a is elevated in human cases of the disease and that transgenic expression in mice is sufficient to cause the condition.

The adrenal gland of the oldfield mouse (Peromyscus polionotus) has a recently evolved cell type that promotes monogamous-typical parenting behaviour and is not present in closely related species.

Combining electrophysiology and computational modeling, the authors show that the dendrites of entorhinal cortex stellate and pyramidal cells are electrically excitable and that this improves the robustness of grid cell firing. The results suggest that active dendrites are critical for spatial navigation, a fundamental computation in the brain.

Details of the ontogeny of alveolar macrophages remain unclear. Kopf and colleagues show that fetal monocytes give rise to alveolar macrophages in a manner dependent on the nuclear receptor PPAR-γ and the cytokine GM-CSF.

The p30 isoform of C/EBPα associated with leukemia interacts with WDR5, a component of the SET/MLL histone methyltransferase complex. A small molecule, OICR-9429, disrupted p30-WDR5 interactions, resulting in differentiation of p30-expressing leukemia cells.

A range of techniques are used to investigate the molecular landscape of chronic kidney disease, and the results suggest that distinct populations of pericytes and fibroblasts are the main source of myofibroblasts in kidney fibrosis.

Building retrofits offer enormous potential for energy reduction and must be designed with occupancy in mind. Here, the authors developed a method for estimating building occupancy at urban scale using mobile phone traces and they find that energy saving estimates differ by +1 to −15% for residential buildings and by −4 to −21% for commercial buildings.

Understanding individual variations in the response to seasonal influenza vaccines has broad implications from basic immunology to public health. Here authors show that influenza hemagglutinin-specific T and B cell responses are determined by the pre-vaccination immune phenotype and vaccination history of recipients.

Unmasking the decision making process of machine learning models is essential for implementing diagnostic support systems in clinical practice. Here, the authors demonstrate that adversarially trained models can significantly enhance the usability of pathology detection as compared to their standard counterparts.

The growth of colorectal cancer is reduced by ketogenic diet consumption, the properties of which are mediated by the ketone body β-hydroxybutyrate.

Fluorogenic RNA aptamers such as Chili display strong fluorescence enhancement upon aptamer–ligand complex formation. Here, the authors provide insights into the mechanism of fluorescence activation of Chili by solving the crystal structures of Chili with its bound positively charged ligands DMHBO⁺ and DMHBI⁺, and they reveal that Chili uses an excited state proton transfer mechanism based on time-resolved optical spectroscopy measurements.

DNA-encoded chemistry enables rapid and inexpensive syntheses and screening of vast chemical libraries, and is generating substantial interest and investment in the pharmaceutical industry. Here, Goodnow and colleagues provide an overview of the steps involved in the generation of DNA-encoded libraries, highlighting key applications and future directions for this technology.

Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Bruce Beutler is director of the Center for the Genetics of Host Defense at UT Southwestern in Dallas, Texas. He shared one half of the 2011 Nobel Prize in Physiology or Medicine with Jules Hoffmann for their work on the activation of innate immunity; the other half of the prize was awarded to Ralph Steinman. Here, Beutler talks to Christoph Thaiss about biological puzzles and intuition.

In-depth methylation analysis of formalin-fixed paraffin-embedded glioblastoma samples demonstrates heterogeneity between primary and recurring tumors and enables prediction of composition of the tumor microenvironment and insights into progression.

Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

Johnson and colleagues investigate spiking activity in developing inner hair cells (IHCs), showing that apical IHCs fire spontaneous action potentials in a burst-like pattern, whereas basal IHCs fire randomly. The burst-like firing of apical IHCs depends on acetylcholine. Extracellular ATP affects the resting potential of IHCs by activating SK2 channels.

Miz1 is a binding partner of the transcription factor c-Myc and a regulator of cell cycle progression. Wolf et al. show that inactivation of Miz1 in the mouse central nervous system results in neurodegeneration, and find that Miz1 is essential for the transcriptional regulation of autophagic flux.

A potential therapeutic strategy for spinal cord injury (SCI) is to maintain continuity of damaged axons after contusion, but the viability of such strategies depends on the degree to which initially injured axons can recover. Here the authors use morphological and molecular in vivoimaging after contusion SCI in mice, to show that injured axons persist in a metastable state for hours.

The oncogene STAT5 is involved in cancer cell proliferation. Here, the authors use STAT5 protein to assemble its own small molecule inhibitors via Mannich ligation (three-component-reactions) and show that the resultant ligands can inhibit the proliferation of cancer cells in a mouse model.

Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.

Rhodopsin genes have been identified in some large double-stranded DNA viruses, but the structure and functions of viral rhodopsins remain unknown. Here authors present crystal structure and characterization of an Organic Lake Phycodnavirus rhodopsin II (OLPVRII) which forms a pentamer and is a weak proton pump.

Zebrafish larvae can binocularly detect prey objects in order to strike but lack ipsilateral retinotectal fibers for binocular superposition of visual information. Here the authors describe commissural intertectal neurons and show that they are required for the initiation of capture strikes.

Production of polyphosphate polymers is a ubiquitous trait of bacteria. Here, the authors investigate the role of bacterial long polyphosphates in host immune suppression and show that long polyphosphates produced by E. coli inhibit LPS-mediated inflammation and bacterial clearance in mice.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

The mechanisms that shape the regulatory T cell repertoire in patients with cancer are not completely understood. Here, the authors observe that, in breast cancer patients, tumor-resident regulatory T cells do not show clonal relationship with their circulating counterpart, but share a common origin with intratumoral antigen-experienced conventional T cells.

BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.

Inorganic perovskite tandem solar cells using ligand evolution strategy achieve record efficiencies and durability, maintaining 80% of their initial efficiency under light/heat stresses, guiding the development of high-efficiency, stable inorganic perovskite tandem solar cells.

Predicting disease progression is an important medical problem, but it can be challenging for end-to-end machine learning approaches. Han and colleagues demonstrate that generative models can work together with medical experts to jointly predict the progression of a disease, osteoarthritis.

A single electron quantum dot in bilayer graphene is a candidate for a spin-valley qubit, however its excited state spectrum has not been determined under relevant conditions. Here the authors accomplish this using time-resolved charge detection technique and set the new upper bound on the inter-valley mixing.

By experimentally manipulating atmospheric carbon dioxide concentration, drought, air and soil temperature, and herbivory simultaneously, this study provides evidence that climate change affects interactions between above- and belowground organisms through changes in nutrient availability under field conditions.

In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.

Arabidopsis thaliana UMAMIT uniporters facilitate glucosinolate efflux from biosynthetic cells along the electrochemical gradient into the apoplast, in which the high-affinity H⁺-coupled glucosinolate importers GLUCOSINOLATE TRANSPORTERS (GTRs) load them into the phloem for translocation to the seeds.

Mapping fixed brain samples with extracellular labeling and optical microscopy reveals synaptic connections.

In this pre-specified interim analysis, patients with resected stage IIB/C melanoma who received adjuvant nivolumab had significantly prolonged recurrence-free survival compared to placebo-treated patients, providing another treatment option for this population.

The results of EMPATROPISM-FE, a post hoc analysis of the EMPA-TROPISM trial performed by Angermann et al., suggest that the beneficial effects of empagliflozin treatment in heart failure populations may be related to changes in iron metabolism.

Most proteases have their own endogenous, specific inhibitors which protect living organisms from the deleterious effects of excessive proteolytic activity. Here, authors identify PCPE-2 as a potent and specific inhibitor of BMP-1/tolloid-like proteases.

Lundgren et al. show that in response to transient cold exposure, a distinct subpopulation of brown adipocytes carries out a lipogenic response involving production of acylcarnitines, which enables an improved thermogenic response to secondary cold exposure.

Single-cell screening and sorting is useful for addressing many biological questions. The high-throughput droplet analyzer and sorter described in this protocol has been designed so that it can be constructed without specialist engineering training.

Specificity of inhibitors of voltage-gated ion channels is crucial for their use as therapeutics. Here, the authors show that adamantane derivatives interact with a specific binding site on fenestrations that only become available when accessory subunits are bound to the channel.