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The transport and degassing pathways of volatiles through large silicic magmatic systems are central to understanding geothermal fluid compositions, ore deposit genesis, and volcanic eruption dynamics and impacts. Here, we document sulfur (S), chlorine (Cl), and fluorine (F) concentrations in a range of host materials in eruptive deposits from Taupō volcano (New Zealand). Materials analysed are groundmass glass, silicic melt inclusions, and microphenocrystic apatite that equilibrated in shallow melt-dominant magma bodies; silicic melt and apatite inclusions within crystal cores inferred to be sourced from deeper crystal mush; and olivine-hosted basaltic melt inclusions from mafic enclaves that represent the most primitive feedstock magmas. Sulfur and halogen concentrations each follow distinct concentration pathways during magma differentiation in response to changing pressures, temperatures, oxygen fugacities, crystallising mineral phases, the effects of volatile saturation, and the presence of an aqueous fluid phase. Sulfur contents in the basaltic melt inclusions (~ 2000 ppm) are typical for arc-type magmas, but drop to near detection limits by dacitic compositions, reflecting pyrrhotite crystallisation at ~ 60 wt. % SiO2 during the onset of magnetite crystallisation. In contrast, Cl increases from ~ 500 ppm in basalts to ~ 2500 ppm in dacitic compositions, due to incompatibility in the crystallising phases. Fluorine contents are similar between mafic and silicic compositions (< 1200 ppm) and are primarily controlled by the onset of apatite and/or amphibole crystallisation and then destabilisation. Sulfur and Cl partition strongly into an aqueous fluid and/or vapour phase in the shallow silicic system. Sulfur contents in the rhyolite melts are low, yet the Oruanui supereruption is associated with a major sulfate peak in ice core records in Antarctica and Greenland, implying that excess S was derived from a pre-eruptive gas phase, mafic magma recharge, and/or disintegration of a hydrothermal system. We estimate that the 25.5 ka Oruanui eruption ejected > 130 Tg of S (390 Tg sulfate) and up to ~ 1800 Tg of Cl, with potentially global impacts on climate and stratospheric ozone.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth 1 , 2 . Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1 ) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth. Manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

In 2022, the world experienced the deadliest year of armed conflict since the 1994 Rwandan genocide. Much of the intensity and frequency of recent conflicts has drawn more attention to failures in forecasting—that is, a failure to anticipate conflicts. Such capabilities have the potential to greatly reduce the time, motivation, and opportunities peacemakers have to intervene through mediation or peacekeeping operations. In recent years, the growth in the volume of open-source data coupled with the wide-scale advancements in machine learning suggests that it may be possible for computational methods to help the international community forecast intrastate conflict more accurately, and in doing so reduce the rise of conflict. In this commentary, we argue for the promise of conflict forecasting under several technical and policy conditions. From a technical perspective, the success of this work depends on improvements in the quality of conflict-related data and an increased focus on model interpretability. In terms of policy implementation, we suggest that this technology should be used primarily to aid policy analysis heuristically and help identify unexpected conflicts.

Chicken and egg questions The domestication of the chicken over a period of several thousand years and its later specialization into meat producing (broiler) and egg producing (layer) lines is an informative model of domestication and phenotypic evolution. A study using massively parallel sequencing of domestic chicken and its wild ancestor, the red jungle fowl, reveals a number of 'selective sweeps', where benign genetic variations closely linked to a mutation that dramatically enhances survival increase in frequency relative to other alleles. Most striking of these — found in all domestic chickens — is one at a locus encoding thyroid stimulating hormone receptor, which has a key role in metabolism and vertebrate reproductive timing. This sweep may be related to a classic feature of domesticated animals, the absence of the strict regulation of seasonal reproduction found in wild populations. Several of the selective sweeps detected in broilers overlap genes associated with growth, appetite and metabolic regulation. Here, the genomes of birds representing eight populations of domestic chickens are compared with the genome of their wild ancestor, the red jungle fowl. The results reveal selective sweeps of favourable alleles and mutations that may have contributed to domestication. One selective sweep, for instance, occurred at the locus encoding the thyroid stimulating hormone receptor, which is important in metabolism and in the timing of vertebrate reproduction. Domestic animals are excellent models for genetic studies of phenotypic evolution 1 , 2 , 3 . They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens ( Gallus gallus domesticus ) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl ( Gallus gallus ), the major wild ancestor 4 . We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.

Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery. Hahn, van Krieken et al. provide a quantitative account of β-cell mass dynamics and islet longevity in mice treated with Streptozotocin (STZ). They find that STZ-induced hyperglycemia primarily results from β-cell dysfunction rather than its ablation. This study provides insights into how the most widely used preclinical diabetes model works.

We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues. ALD is caused by mutations in the gene encoding a peroxisomal transporter. More than half of males with an mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the -null mouse. We generated a cALD phenotype in 8-week-old, male -null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue. MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, -null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue. This novel mouse model of cALD suggests loss of function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.

Abstract Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd patients. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across patient tumors and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines. By identifying interacting cellular programs, we thus reveal the logic underlying spatially organized immune-malignant cell networks. Competing Interest Statement K.P., M.H., J.C., V.K., A.A., O.R, A.R., and N.H. are co-inventors on US Patent Application No. 16/995,425 relating to methods for predicting outcomes and treating colorectal cancer as described in the manuscript. A.J.A. is a Consultant for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc., and receives research funding from Mirati Therapeutics; Deerfield, Inc.; Novo Ventures. R.B.C. is receiving consulting or speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Fog Pharma, Fount Therapeutics/Kinnate Biopharma, Genentech, Guardant Health, Ipsen, LOXO, Merrimack, Mirati Therapeutics, Natera, N-of-one/Qiagen, Novartis, nRichDx, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Fount Therapeutics/Kinnate Biopharma, nRichDx, and Revolution Medicines; and has received research funding from Asana, AstraZeneca, Lilly, and Sanofi. V.K.K.consults for Pfizer, GSK, Tizona Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Compass Therapeutics, Biocon, Syngene. G.M.B. has sponsored research agreements with Palleon Pharmaceuticals, Olink Proteomics, and Takeda Oncology. She served on scientific advisory boards for Novartis and Nektar Therapeutics. She received honoraria from Novartis. A.C.A. is a paid consultant for iTeos Therapeutics, and is a member of the SAB for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and ImmuneOncia, which have interests in cancer immunotherapy. A.C.A.'s interests were reviewed and managed by the Brigham and Women's Hospital and Partners Healthcare in accordance with their conflict of interest policies. M.G. receives research funding from Bristol Myers-Squibb, Merck and Servier. J.W.R., C.A.F., M.L.H. are employees of and stockholders for NanoString Technologies Inc., D.R.Z. is a former employee of NanoString Technologies Inc. B.I. is a consultant for Merck and Volastra Therapeutic. R.B. is an UptoDate Author. As.R. is an equity holder in Celsius Therapeutics and NucleAI. K.N. has research funding from Janssen, Revolution Medicines, Evergrande Group, Pharmavite; Advisory board: Seattle Genetics, BiomX; Consulting: X-Biotix Therapeutics; Research Funding: Bristol-Myers Squibb, Merck, Servier. B.E.J. is on the SA for Checkpoint Therapeutics. O.R.R. is a named inventor on several patents and patent applications filed by the Broad Institute in the area of single cell genomics. From October, 2020, O.R.R. is an employee of Genentech. A.R. is a founder of and equity holder in Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and was a scientific advisory board member for ThermoFisher Scientific, Syros Pharmaceuticals and Neogene Therapeutics until August 1, 2020. From August 1, 2020, A.R. is an employee of Genentech. A.R. is a named inventor on several patents and patent applications filed by the Broad Institute in the area of single cell and spatial genomics. N.H. holds equity in BioNTech and is an advisor for Related Sciences. Footnotes * ↵22 Lead Contact * Added 1 inch margins to remove copyright notice from figures.