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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.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.

Isolating and studying haematopoietic stem cells in young and aged mice demonstrates evolutionary processes related to blood production and provides a framework for interpreting future work using laboratory mice to study stem cell ageing.

PET–CT allows simultaneous capture and co-registration of functional and anatomical data. Here, Australian-based authors outline the current clinical status of this 'functional imaging' in renal cell carcinoma. New radiotracers and approaches—including radiolabeled monoclonal antibodies and imaging of tumor hypoxia—are touched on, and areas of future research discussed.

Granulomatous/sarcoid-like lesions have been reported in patients treated with immune checkpoint inhibitors (ICIs). Here the authors report the occurrence of “nodal immune flare”, an apparent radiological cancer progression in the nodes characterized by the absence of cancer and the presence of non-caseating granulomas, in patients with non-small cell lung cancer following neoadjuvant ICI treatment.

Down syndrome causes extensive Alzheimer’s disease pathology in all individuals and has been instrumental in development of the amyloid hypothesis in AD. Here, the authors use proteomics on Down syndrome spinal fluid and brain tissues to illustrate the common and unique changes in DSAD compared to other genetic forms of AD and the more common late-onset form of the disease.

The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.

Remotely sensed NDVI data and contemporary field data from 84 grasslands on 6 continents show increasing divergence in aboveground plant biomass between sites in different bioclimatic regions.

Lipid particles loaded with RNA coding for tumour-unspecific antigens can enhance early responses of type-I interferons, mediating the success of immune checkpoint inhibitors as well as epitope spreading.

This Review discusses multiomic approaches for the characterization and biological understanding of cellular senescence, including detailed case studies on skeletal muscle and adipose tissue that highlight current outstanding issues in the field.

Functional and metabolic properties of innate-like T cells — namely, iNKT cells, MAIT cells and some γδ T cells — differ from those of conventional T cells. This Review describes how metabolic pathways support innate-like T cell properties such as acquisition of effector capability in the thymus, rapid responsiveness, tissue persistence, antigen adaptation and functional flexibility.

Stereotactic radiosurgery (SRS) has been established as a key therapeutic modality for the management of brain metastases. In this Review, an international group of experts discuss the expanding opportunities for SRS, including application for larger brain metastases and cumulative intracranial tumour volumes, fractionated delivery, neoadjuvant use and combinatorial approaches with modern systemic therapy, as well as associated challenges and remaining questions.

A genomic barcoding scheme called two-layer DNA seqFISH+ enables the simultaneous mapping of more than 100,000 loci and has been used to identify cell-type-specific subnuclear compartments in the mouse brain.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

Peter Fraser and colleagues report a genome-wide analysis of transcription interactions involving the globin genes in mouse erythroid cells. They demonstrate that the transcription factor Klf1 mediates preferential co-associations between genes it regulates.

A method that quantifies signal reductions in proton magnetic resonance spectroscopy resulting from the replacement of ¹H with ²H after the administration of a deuterated substrate can be used to monitor the turnover of cellular metabolites in vivo.

Real-time joint motion feedback during exercise interventions can enhance hand and wrist rehabilitation. Here, the authors introduce electrogoniometry systems that accurately monitor target joint angles in fingers and wrists in real-time for use in medical and physical activity settings.

Analysis of data from forest plants worldwide shows that margins between threshold xylem pressures at which plants suffer damage and the lowest xylem pressures experienced are small, with no difference between dry and wet forests, providing insight into why drought-induced forest decline is occurring in both arid and wet forests.

Terrestrial ecosystem productivity is widely accepted to be nutrient limited. A series of standardized nutrient addition experiments, carried out on grasslands on five continents, suggests aboveground grassland productivity is commonly limited by multiple nutrients, including potassium and micronutrients.

Parkinson’s diseases and other synucleinopathies are on the verge of a major paradigm shift toward being defined and staged by their biology, rather than symptoms; this Perspective offers context on progress, needs and opportunities toward this goal.

Myeloid-derived growth factor (MYDGF) is an endoplasmic reticulum protein of therapeutic interest because it promotes tissue repair in a murine model of myocardial infarction. Here the authors present the NMR structure of human MYDGF and attribute function to a set of residues conserved in MYDGFs but not the vanin base domain, which has a similar fold.

The discovery of a male-specific sex hormone in the mosquito <em>Anopheles gambiae</em> may allow new strategies for the control of this notorious disease vector.

Non‐compressible wounds are a major source of high mortality in trauma victims. Here the authors report on the creation of xerogels impregnated with liquid adhesives which can rapidly absorb fluids promoting blood clotting while forming adhesions to tissue and demonstrate the xerogel in ex vivo and in vivo models.

Although continuous monitoring of tissue oxygenation is critically important after tissue/organ graft procedures, current technologies have key limitations. Here, the authors develop a miniaturized, minimally invasive, self-anchoring optical probe and demonstrate continuous monitoring of oxygenation in porcine flap and organ models.

Mercey et al. demonstrate that without deuterosomes, multiciliated cells still develop the proper number of centrioles with normal step-wise kinetics, independent of the growing platform.

A protein condensate formed by multivalent interactions between the long non-coding RNA Xist and specific RNA-binding proteins drives the compartmentalization required to perpetuate gene silencing on the inactive X chromosome.

Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.

The neuroendocrine tumor pheochromocytoma is usually detected via measurement of levels of catecholamines and their metabolites in plasma and urine. In patients with Parkinson disease, however, the results of these tests can be confounded by dopaminergic medications. Mehtaet al. present the case of a 59-year-old man with Parkinson disease in whom a diagnosis of pheochromocytoma was confirmed by means of structural and functional imaging.

Antibiotics to treat carbapenem-resistant Acinetobacter baumannii infection are an urgent need. The cerastecins are potent, bactericidal and efficacious in animal models of infection, and may enable new treatment modalities targeting LOS transport.

Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

Current contrast-enhanced magnetic resonance angiography approaches are sub-optimal. Here the authors present a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd), enabling sophisticated micro-vessel angiography of cardiac-cerebrovascular diseases with ultrahigh resolution.

A number of disease-causing human transthyretin (TTR) mutations are known to lead to amyloid formation. Here the authors combine neutron crystallography, native mass spectrometry and modelling studies to characterize the T119M and S52P-TTR mutants, providing mechanistic insights into TTR amyloidosis.

Here, the authors perform repurposing screens of the ReFRAME drug library in two cell lines and identify inhibitors of SARS-CoV-2 infection. Antiviral activity of prodrug MK-4482 is confirmed in hamsters.

ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson’s disease models.

Collagen lysyl hydroxylases promote cancer progression. Here the authors present the crystal structure of the lysyl hydroxylase domain of L230 from Acanthamoeba polyphaga mimivirus, which is of interest for LH inhibitor development, and show that ectopic expression of L230 in tumors promotes collagen cross-linking and metastasis.

Retroviral Integration into the host DNA is a rare event with evidence suggesting that it relies on DNA topology and sequence. Here the authors present single molecule evidence that shows the retroviral integration machinery vigorously scans the target DNA by 1D-diffusion but infrequently integrates.

Accumulation of zinc in muscle cells resulting from transcriptional upregulation of metal transporter ZIP14 causes muscle atrophy and promotes cachexia in metastatic cancer.

The 4D Nucleome Network aims to map the spatial and dynamic organization of the human and mouse genomes to gain insight into the structure and biological functions of the nucleus.

Annexin A2 (ANXA2) is identified as the target of a pharmacological YAP activator and as a druggable component of the Hippo pathway.

Multiplexed imaging of 3,660 chromosomal loci in individual mouse embryonic stem cells by DNA seqFISH+ with immunofluorescence of 17 chromatin marks and subnuclear structures reveals invariant organization of loci within individual cells, and heterogeneous and long-lived distinct combinatorial chromatin states in cellular subpopulations.

Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.