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Mathematical prodigy Stephen Wolfram has laboured for a decade on what he claims is a revolutionary book. Jim Giles meets a supremely confident scientific loner, but finds expert opinion on the work's merits divided.

Warming ocean water plays a significant role in accelerating Arctic sea ice melt. Here the authors present detailed observations of warm water of Pacific origin entering and diving beneath the Arctic ocean surface, and explore the dynamical processes governing its evolution.

Understanding the genetic influences on human aging requires a large number of subjects for a study of sufficient power. Here, Jim Wilson and colleagues use information on parental ages at death to show that common variants near the genes for apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 are associated with longer lifespan.

The use of mitomycin C inductions to determine the fraction of lysogenic cells in mixed natural communities is highly variable and insensitive to bacterial host density, suggesting that other methods should be developed and used to measure lysogeny.

2023 CX1 is the only L-chondrite-like asteroid analysed from space to ground. It catastrophically fragmented in the atmosphere, depositing 98% of its energy in one burst—an unusual, high-risk fragmentation mode with implications for planetary defence.

Researchers have measured the equation of state of hydrocarbon in a high-density regime, which is necessary for accurate modelling of the oscillations of white dwarf stars.

Swapping the Xist/Tsix transcriptional units and placing their promoters in each other’s topologically associating domain shows that the topological partitioning of the X-inactivation center is critical to ensure proper X inactivation during development.

In this study, Kagan et al. highlight the relevance of adequate cardiolipin homeostasis by offering mechanistic insight into the pathogenesis of Barth syndrome. The study shows how altered accumulation of mono-lyso-cardiolipin, one of the derivatives of the mitochondrial lipid cardiolipin, forms an anomalous peroxidase complex with cytochrome c, thus leading to increased oxidation of polyunsaturated phospholipids.

SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.

Systemic autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS) are rare and often involve genes related to the inflammasome. Here, the authors report a syndrome characterised by systemic inflammation and cold-induced urticarial rash associated with a Factor XII-activating mutation.

With the yearly exodus from labs and lecture theatres imminent, Nature's regular reviewers and editors share some tempting holiday reads.

The BAM complex is assisted by periplasmic chaperones, such as SurA, in its folding and insertion of proteins into the bacterial outer membrane. Here, the authors use disulphide bond engineering to trap transient protein complexes and solve their cryoEM structures to shed light on the cycle of SurA arrival, OMP delivery, and handover to BAM.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Streptococcus pneumoniae, the causative agent of pneumococcal disease, has become increasingly resistant to fluoroquinolones. Through CRISPRi-seq, the authors identify the role of the LiaFSR operon in resensitizing S. pneumoniae to fluoroquinolones.

Effective delivery of signals from the cell surface to the nucleus is a key to activate gene transcription. Here, the authors show how endosomes containing EphA2 are transported and captured at the nuclear surface, triggering depletion of G-actin from the nucleus and activating MRTF signalling.

Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

The relationship between regulatory elements, chromatin interactions and gene expression during development remains poorly understood. Here the authors present Tiled-C, a low-input 3C approach to study genome architecture at high resolution, and apply it to mouse erythroid differentiation in vivo, finding that enhancer-promoter interactions are formed gradually during differentiation, concomitant with progressive upregulation of gene activity.

V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.

Forests are a key component of the Paris Agreement, providing about a quarter of planned emission reductions. Realizing this ambition, however, requires greater confidence in forest estimates, presenting a challenge and an opportunity for science.

A physics-based training pipeline is developed to help tackle the challenges of data scarcity. The framework aligns large language models to a physically consistent initial state that is fine-tuned for learning polymer properties.

Histone 3 lysine 79 is mono (me1), di (me2), or tri (me3) methylated by the methyltransferase DOT1L. Here the authors reveal a group of enhancers defined by H3K79me2/3 which regulates enhancer-promoter interactions and other key enhancer features in MLL-AF4 leukemia cells.

Neocortical circuits exhibit diverse cell types that can be difficult to build into computational models. Here the authors employ a genetic algorithm-based parameter optimization to generate multi-compartment Hodgkin-Huxley models for diverse cell types in the Allen Cell Types Database.

Simplified neuron models, such as generalized leaky integrate-and-fire (GLIF) models, are extensively used in network modeling. Here the authors systematically generate and compare GLIF models of varying complexity for their ability to classify cell types in the Allen Cell Types Database and faithfully reproduce spike trains.

Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

The authors examine the role of medial entorhinal cortex (MEC) in learning complex timing behavior. MEC inactivation disrupts task learning, and MEC time cells display context-dependent dynamics that evolve over learning and predict timing behavior.

The impacts of power plant water shortage during drought on electricity prices are understudied. Here the authors show that on extreme days, almost 50% (7 GWe) of the freshwater thermal capacity is unavailable in the Great Britain and annualized cumulative costs on electricity prices are in the range of £29-95m per year.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Fruit acidity is an important factor affecting fleshy fruit taste. Here, the authors identify the PHgene that regulates fruit acidity in a number of species and report a mutation that is responsible for the diversification and evolution of the sweet melon.

Advanced LIGO has detected gravitational waves from two binary black hole mergers, plus a merger candidate. Here the authors use the COMPAS code to show that all three events can be explained by a single evolutionary channel via a common envelope phase, and characterize the progenitor metallicity and masses.

The coordination of interactions between multiple regulatory elements and genes within a chromatin domain remains poorly understood. Here, the authors use a method to detect multi-way chromatin interactions in a mouse model in which the α-globin domain is extended to include several additional genes, finding that the promoters do not form mutually exclusive interactions with the enhancers, but all interact simultaneously in a single complex.

Intraspecies response to climate change is expected to align with genetic affinity. Using the American pika as a case study suggests that divisions of species distributions best explain intraspecific heterogeneity in climate relationships.

Whole-genome sequencing of chronic lymphocytic leukemia from 485 patients identifies putative coding and noncoding drivers of disease. Genomically defined subgroups show distinct clinical and biological characteristics.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

A technique for the site-directed conjugation of antibodies via the small-protein ubiquitin allows for the efficient multivalent conjugation of antibodies and nanobodies to fusions of ubiquitin with molecular or proteinic moieties.

How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.

Photocurrent microscopy on suspended vanadium dioxide nanobeams reveals the thermal origin of the photoresponse in materials with strong electron–electron and electron–phonon correlations.

Self-interacting chromatin domains encompass genes and their cis-regulatory elements. Here the authors use high-resolution chromosome conformation capture and super-resolution imaging to study a 70 kb domain that includes the mouse α-globin regulatory locus and find that a tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.

The microbial composition of metagenomes is identified in seconds by profiling against large databases.

Here, the authors identify in the 3′ untranslated region of the genome of Usutu virus, an emerging mosquito-borne flavivirus, a sequence that confers a unique capacity to resist degradation by the ISG20 exonuclease.