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Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

Using avian trait data and genomic data, the authors infer whether changes in net effective population size over time in response to climate change are correlated with multiple morphological and life history traits; they find that larger-bodied, slower-reproducing species with limited dispersal capacity are most sensitive to changes in warming and cooling climates.

Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.

In patients with sporadic Alzheimer’s disease part of the Asp23 residues are isomerized to L-isoaspartate (L-isoAsp23). Here the authors present the MicroED structures of wild-type and L-isoAsp23 Aβ 20–34 amyloid fibrils that both form tightly packed cores and self-associate through two distinct interfaces with one of these interfaces being strengthened by the isoaspartyl modification.

Literature produced inconsistent findings regarding the links between extreme weather events and climate policy support across regions, populations and events. This global study offers a holistic assessment of these relationships and highlights the role of subjective attribution.

U-shaped glacial valleys dominate >10 ka since the last major glaciation and the transitions from glacier-dominated to fluvial regimes are poorly understood. Here, the authors use digital topographic data to show that glacial topography is rapidly replaced by fluvial topography where rock uplift rates are high.

Segments from TDP-43 LCD form irreversible steric zippers typical of amyloid fibrils and labile interactions found in reversible assemblies. Familial ALS mutations or a phosphorylation event can convert reversible to irreversible aggregates.

The cause of the increase in atmospheric methane from 375 p.p.b.v. during the last ice age to 680 p.p.b.v. at the onset of Industrialization remains uncertain. Here, using an Earth system model, the authors show that we cannot reconcile this rise based on our current understanding of natural methane sources.

In cancer, the impact on cellular fitness of copy-number gains affecting collaterally-amplified genes remains poorly understood compared to oncogenes. Here, the authors integrate genomic data from tumours and cell lines and identify a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes, with potential therapeutic applications.

A short segment of α-synuclein called NACore (residues 68–78) is responsible for the formation of amyloid aggregates responsible for cytotoxicity in Parkinson disease; here the nanocrystal structure of this invisible-to-optical-microscopy segment is determined using micro-electron diffraction, offering insight into its function and simultaneously demonstrating the first use of micro-electron diffraction to solve a previously unknown protein structure.

TOI-500 hosts at least four planets, the innermost of which is an Earth-sized ultra-short-period body with a density similar to Earth. The architecture of the TOI-500 system can be explained by a slow, secular, low-eccentricity migration scenario.

A clinically viable speech neuroprosthesis could restore natural speech to individuals with vocal-tract paralysis. In this Review, Silva et al. discuss rapid progress in neural interfaces and computational algorithms for decoding speech from cortical activity and propose evaluation metrics to help standardize speech neuroprostheses.

Altering cellular responses to double-strand breaks in DNA could rebalance CRISPRediting outcomes. Here, the authors use a pooled CRISPR screen to identify inhibition of CDC7 as a strategy to improve HDR outcomes.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

A molecular mechanism for brain-specific angiogenesis operates under the control of Wnt7a/b ligands.

Plasma extracellular vesicles contain quantifiable amounts of TDP-43 and full-length tau, allowing the accurate assessment of pathology in frontotemporal dementia, frontotemporal dementia spectrum disorders and amyotrophic lateral sclerosis.

Iris Heid, Gonçalo Abecasis, Sudha Iyengar and colleagues report the results of a large genome-wide association meta-analysis of macular degeneration based on over 43,000 subjects. They identify 16 new risk loci, including some very rare coding variants.

Whole-genome analysis of oestrogen-receptor-positive tumours in patients treated with aromatase inhibitors show that distinct phenotypes are associated with specific patterns of somatic mutations; however, most recurrent mutations are relatively infrequent so prospective clinical trials will require comprehensive sequencing and large study populations.

The helicase Ded1p associates with the pre-initiation complex and influences translation from near-cognate initiation codons by controlling the levels of mRNA secondary structure in 5′ untranslated regions.

Structural analyses of fibrils formed by segments from human TDP-43 RRM2 reveal extensive packing and positional polymorphism.

This study searched for putative regulatory mutations specific to the human lineage by looking for sequences that are highly conserved between chimpanzees and other species, but are not present in the human genome. The 500-odd human-specific deletions tend to lie in non-coding DNA stretches and near genes involved in steroid hormone signalling and neural function. This is illustrated with two examples, one of which affects penile anatomy whereas the other affects brain size.

Terence Capellini, David Kingsley and colleagues use transgenic mice to show that a Gdf5 enhancer (termed GROW1) is required for normal bone length. They suggest that a common variant at the human GROW1 enhancer was under selection in human populations and also contributes to arthritis susceptibility.

The ATLAS experiment at the Large Hadron Collider reports a search for charged-lepton-flavour violation in decays of Z bosons into a τ lepton and an electron or muon of opposite charge.

The ATLAS Collaboration reports the observation of the electroweak production of two jets and a Z-boson pair. This process is related to vector-boson scattering and allows the nature of electroweak symmetry breaking to be probed.

The ATLAS Collaboration reports a measurement of the ratio of the decay rates of W bosons to τ leptons and muons, in agreement with universal lepton couplings as postulated in the standard model of particle physics.

Quantum electrodynamics predicts a rare process in which light is scattered by light. The ATLAS Collaboration reports signs of this elusive effect in the collisions of ultra-relativistic lead ions.

David Kingsley and colleagues functionally investigate a previously identified GWAS region in an enhancer of the KITLG gene (encoding KIT ligand) that is significantly associated with blond hair color in northern European populations. They show that a single regulatory SNP, located 350,000 bp upstream of the human gene, reduces the activity of a tissue-specific hair follicle enhancer and is sufficient to alter hair color in mice.

Syllables play a central role in speech production and perception. In this Review, Poeppel and Assaneo outline how a simple biophysical model of the speech production system as an oscillator explains the remarkably stable rhythmic structure of spoken language.

A class of enzymes known as alkyltransferase-like proteins (ATLs) can protect against alkylation damage to DNA. To gain insight into how this occurs, the structure of a yeast ATL has been solved in the presence and absence of damaged DNA, revealing that ATL flips the alkylated base out of the DNA helix, leaving the lesion to be acted on by proteins of the nucleotide excision repair pathway.

An automated tool (EPP) identifies distinct cell phenotypes in flow cytometry data through optimized 2D gating as shown in 4 published datasets. EPP’ C++ code integrates with any software, as demonstrated in MATLAB with FlowJo.

The structures of amyloid fibres are currently primarily studied through solid state NMR and cryo-EM. Here the authors present a free-standing graphene support device that allows diffraction imaging of non-crystalline amyloid fibrils with single X-ray pulses from an X-ray free-electron laser.

Crystal structures of the neuropeptide Y₁ receptor in complex with two distinct antagonists combined with NMR, molecular docking and mutagenesis studies inform a proposed model for receptor–agonist binding.

Fatal Ebola virus disease is characterized by a high proportion of CD4⁺ and CD8⁺ T cells expressing the inhibitory molecules CTLA-4 and PD-1, correlating with high virus load; individuals who survive the infection exhibit lower expression of these inhibitory molecules and generate Ebola-specific CD8⁺ T cells, suggesting that dysregulation of the T cell response is a key component of Ebola virus disease pathophysiology.

Tetrahydrobiopterin (BH4) is an enzyme co-factor that is involved in the nervous system; it is shown here to also function in T cell activation and proliferation, with roles in autoimmunity, allergic inflammation and cancer.

Monoterpene emissions from vegetation are more sensitive to temperature than previously thought and are primarily governed by plant functional type with warmer ecosystems appearing to be more sensitive, according to a meta-analysis of monoterpene emission data published between 1980 and 2020.

Pvt1 overexpression in mice contributes to high Myc levels due to 8q24.21 gain and to MYC-driven tumorigenesis.

A novel high-throughput sequencing kinetics approach is used to measure functional binding of the apparently nonspecific RNA-binding protein C5 to all possible sequence variants in its substrate binding site; C5 binds different substrate variants with affinities varying widely, and with a similar affinity distribution to that of highly specific nucleic-acid-binding proteins, but it does not bind its physiological RNA targets with the highest affinity.

Gonçalo Abecasis and colleagues report a large-scale meta-analysis of genome-wide association studies for age-related macular degeneration (AMD), including over 17,100 advanced cases and 60,000 controls. They identify seven loci newly associated with AMD and report pathway analysis that shows enrichment in the complement system and atherosclerosis signaling.

The use of land, energy and water can contribute to climate change, which, in turn, affects the systems that provide those resources. Efficient resource management can limit climate impacts and support adaption practices. An approach integrating resource assessments and policy-making is proposed to manage land, energy and water effectively.

Stephen Meehan, Gleb A. Kolyagin et al. present a fully automated subset identification and characterization pipeline for robust cluster matching and data visualization of high-dimensional flow/mass cytometry data. They show that the method can be applied to single- or multi-dimensional data.