Animals have developed many different solutions to survive, and these abilities are inspiring technological innovations in a wide range of fields including robotics1-3. However, biologically inspired robots, especially those mimicking octopus locomotion4,5, are based on limited in situ behavioural data owing to the complexity of collecting quantitative observations. Here we describe deployments of a remotely operated vehicle, equipped with a suite of imaging systems, to study the mechanics of locomotion in the octopus Muusoctopus robustus at the recently discovered 3,000-m deep Octopus Garden. Using a recently developed light-field imaging system called EyeRIS and an ultra-high-definition science camera, we were able to capture wide and zoomed-in views to characterize whole-animal gaits in a completely unconstrained environment across multiple individuals. Furthermore, the real-time volumetric data captured using EyeRIS yielded quantitative kinematics measurements of individual octopus arms during crawling, showing regions of high curvature and strain concentrated at distinct arm locations. Our results indicate that M. robustus crawling patterns showed several elements of simplified control, with implications for the design of future octopus-inspired robots. Further developments and deployments of technologies such as EyeRIS, coupled with capable robotic vehicles, will enable mining of the deep ocean for biological inspiration.

Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)1. However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.

Action potentials are generated by opening of voltage-activated sodium (Nav) and potassium (Kv) channels1, which can rapidly inactivate to shape the nerve impulse and contribute to synaptic facilitation and short-term memory1-4. The mechanism of fast inactivation was proposed to involve an intracellular domain that blocks the internal pore in both Nav5,6 and Kv7-9 channels; however, recent studies in Nav10,11 and Kv12,13 channels support a mechanism in which the internal pore closes during inactivation. Here we investigate the mechanism of fast inactivation in the Shaker Kv channel using cryo-electron microscopy, mass spectrometry and electrophysiology. We resolved structures of a fully inactivated state in which the non-polar end of the N terminus plugs the internal pore in an extended conformation. The N-terminal methionine is deleted, leaving an alanine that is acetylated and interacts with a pore-lining isoleucine residue where RNA editing regulates fast inactivation14. Opening of the internal activation gate is required for fast inactivation because it enables the plug domain to block the pore and repositions gate residues to interact with and stabilize that domain. We also show that external K+ destabilizes the inactivated state by altering the conformation of the ion selectivity filter rather than by electrostatic repulsion. These findings establish the mechanism of fast inactivation in Kv channels, revealing how it is regulated by RNA editing and N-terminal acetylation, and providing a framework for understanding related mechanisms in other voltage-activated channels.

Parent-of-origin effects (POEs) occur when the effect of a genetic variant depends on its parental origin1. Traditionally linked to genomic imprinting, POEs are believed to occur due to parental conflict over resource allocation to offspring, resulting in opposing parental influences2. Despite their importance, POEs remain underexplored in complex traits, owing to the lack of parental genomes. Here we present an approach to infer the parent of origin of alleles without parental genomes, leveraging interchromosomal phasing, mitochondrial and X chromosome data, and sex-specific crossover in siblings. Applied to the UK Biobank, this enabled parent-of-origin inference for up to 109,385 individuals. Genome-wide association study scans for 59 complex traits and over 14,000 protein quantitative trait loci contrasting maternal and paternal effects identified over 30 POEs and confirmed more than 50% of known associations. More than one third of these showed opposite parental influences, especially for traits related to growth (for example, IGF1 and height) and metabolism (for example, type 2 diabetes and triglyceride levels). Replication in up to 85,050 individuals from the Estonian Biobank and 42,346 offspring from the Norwegian Mother, Father and Child Cohort Study (MoBa) validated 87% of testable associations. Overall, our findings highlight the contribution of POEs to complex traits and support the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon.

Extrachromosomal DNA amplification is associated with poor cancer prognoses1. Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination2,3. However, current dogma states that ESCs are progressively lost through cell division4. Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase-ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes.

GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans1. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand-receptor pair underlying microglia-progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.

The dispersal of archaic hominins beyond mainland Southeast Asia (Sunda)1 represents the earliest evidence for humans crossing ocean barriers to reach isolated landmasses2-4. Previously, the oldest indication of hominins in Wallacea, the oceanic island zone east of Sunda, comprised flaked stone artefacts deposited at least 1.02 ± 0.02 million years ago (Ma) at Wolo Sege on Flores5. Early hominins were also established on the oceanic island of Luzon (Philippines), as indicated by both stone artefacts and cut marks on faunal remains dating to between 777 and 631 thousand years ago (ka) at Kalinga6. Moreover, fossils of extinct, small-bodied hominins occur on Flores (Homo floresiensis)7-12 and Luzon (Homo luzonensis)13. On Sulawesi, the largest Wallacean island, previous excavations revealed stone artefacts with a minimum age of 194 ka at the open site of Talepu in the Walanae Depression14, long preceding the earliest known presence of modern humans (Homo sapiens) in the region (73-63 ka in Sunda)15. Here we show that stone artefacts also occur at the nearby site of Calio in fossiliferous layers dated to at least 1.04 Ma and possibly up to 1.48 Ma, using palaeomagnetic dating of sedimentary rocks and coupled Uranium-series (U-series) and electron-spin resonance (US-ESR) dating of fossil teeth. The discovery of Early Pleistocene artefacts at Calio suggests that Sulawesi was populated by hominins at around the same time as Flores, if not earlier.

Whole-genome sequencing provides an unbiased and complete view of the human genome and enables the discovery of genetic variation without the technical limitations of other genotyping technologies. Here we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping effort1. This advance deepens our understanding of how genetics associates with disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations and identified novel genetic and clinical insights. Although most associations with disease traits were primarily observed in individuals of European ancestries, strong or novel signals were also identified in individuals of African and Asian ancestries. With the improved ability to accurately genotype structural variants and exonic variation in both coding and UTR sequences, we strengthened and revealed novel insights relative to whole-exome sequencing2,3 analyses. This dataset, representing a large collection of whole-genome sequencing data that is available to the UK Biobank research community, will enable advances of our understanding of the human genome, facilitate the discovery of diagnostics and therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood1-5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3-5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in difficult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.

The aridity index is widely used to indicate water availability on land. Balancing climatic water supply (precipitation, P) against demand (potential evapotranspiration, PET), it is often expressed as the P/PET ratio1 or humidity index. Water also flows laterally by rivers and groundwater, from hills to valleys and from mountains to plains, subsidizing the receiving lowlands2. Here, we show that this lateral subsidy reduces aridity in the receiving lowlands. We first estimate monthly subsidies (Qlat) by surface and groundwater at 30″ global grids with a global hydrology model. We then calculate the conventional global humidity index (GHI) as P/PET and a new GHI including Qlat as (P + Qlat)/PET. Termed GHI_topo, the latter reflects land topography, higher in hydrologically convergent lowlands. It also exhibits a delayed and dampened seasonality (relative to P) owing to delayed and diffused Qlat arrival at the receiving lowlands. Such spatiotemporal features of Qlat, arising from both the climate and the terrain, make GHI_topo a more realistic indicator of local water availability in downgradient societies and ecosystems, enabling life in arid locations and times. Global land area with GHI_topo ≥ 1 (supply meets or exceeds demand) is 33% greater than GHI ≥ 1 and far higher in arid and season-arid climates.

The standard scenario for the origin of jawed vertebrates depicts a transition from benthic grazers to nektonic predators1-3, facilitated by a suite of anatomical innovations, including elaborate sensory systems, a high-flow heart and the integration of jaw-opening muscles with the craniothoracic hinge4-7. However, the lamprey-like internal anatomy8-13 reconstructed for osteostracans, the sister group of jawed vertebrates, seem to lack these gnathostome traits, implying a morphological gap despite phylogenetic proximity. Here, using synchrotron-based X-ray microtomography on the model osteostracan Norselaspis glacialis, we reveal derived gnathostome traits straddling a uniquely ossified head-trunk interface in this jawless fish. The inner ear of Norselaspis shows sensory elaborations (enlarged pars inferior and sinus superior) acquired well before the origin of jaws. As in crown gnathostomes, paired venous drainage channels blood into a high-volume cardiac tract. We also confirm a feature not yet demonstrated in any other vertebrate, to our knowledge: the most anterior trunk nerve extends its single trunk to the pectoral fin. In this respect, our reconstruction challenges the hypotheses14-16 that the gnathostome shoulder evolved from the gill apparatus. Our observations highlight Norselaspis as a prelude to the intercalation of the muscular neck and throat that would power the early jaw apparatus. Therefore, the vertebrate jaw-often considered the functional driver for 'gnathostome' innovations1-3-evolved instead as a follower to the sensory enhancement, increased cardiac output and greater locomotory control now inferred in the jawless sister group.

Migration of transplanted allogeneic myeloid cells into the brain following systemic haematopoietic stem and progenitor cell transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases1-3. However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects, limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Contrary to previous assumptions, we found that haematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment, and Sca1- committed progenitor cells were highly efficient in replacing microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment, thus eliminating complications such as graft-versus-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescued the mouse model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human embryonic stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.

As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses2. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.

The value of population screening for suicide risk remains unclear. The U.S. Army's annual medical examination, the Periodic Health Assessment (PHA), screens for suicidality and other mental and physical health problems. This 2014-2019 cohort study used PHA and Army administrative data (n=1,042,796 PHAs from 452,473 soldiers) to develop a model to predict 6-month nonfatal and fatal suicide attempts (SAs). The model was designed to establish eligibility for a planned high-risk SA prevention intervention. The PHA suicide risk screening questions had limited value, as 95% of SAs occurred among soldiers who denied suicidality. However, a simple lasso penalized regression model that included a wide range of administrative predictors had good test sample discrimination (0.794 [SE=0.009] area under the receiver operating characteristic curve) and calibration (0.0001 integrated calibration index). The 25% of soldiers at highest predicted risk accounted for 69.5% of 6-month SAs, supporting use of the model to target preventive interventions.