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Abstract Augmenting the portfolio of therapeutics for type 2-driven diseases is crucial to address unmet clinical needs and to design personalized treatment schemes. An attractive therapy for such diseases would consist in targeting the recruitment of T helper 2 (Th2) lymphocytes to inflammatory sites. Herein, we show the degradation of filamins (FLN) a and b by the ASB2α E3 ubiquitin ligase as a mechanism sustaining Th2 lymphocyte functions. Low levels of FLNa and FLNb confer an elongated shape to Th2 lymphocytes associated with efficient αVβ3 integrin-dependent cell migration. Genes encoding the αVβ3 integrin and ASB2α belong to the core of Th2-specific genes. Using genetically modified mice, we find that increasing the levels of FLNa and FLNb in Th2 lymphocytes reduces airway inflammation through diminished Th2 lymphocyte recruitment in inflamed lungs. Collectively, our results highlight ASB2α and its substrates FLNa and FLNb to alter Th2 lymphocyte-mediated responses.

Inhibiting TGF-β1 to increase immune responses against tumors bears the risk of tumor-promoting toxicity. Here the authors show that selectively blocking TGF-β1 produced by immunosuppressive cells is feasible with anti-GARP:TGF-β1 antibodies and improves the efficacy of PD-1 blockade immunotherapy.

Augmenting the portfolio of therapeutics for type 2-driven diseases is crucial to address unmet clinical needs and to design personalized treatment schemes. An attractive therapy for such diseases would consist in targeting the recruitment of T helper 2 (Th2) lymphocytes to inflammatory sites. Herein, we show the degradation of filamins (FLN) a and b by the ASB2α E3 ubiquitin ligase as a mechanism sustaining Th2 lymphocyte functions. Low levels of FLNa and FLNb confer an elongated shape to Th2 lymphocytes associated with efficient αVβ3 integrin-dependent cell migration. Genes encoding the αVβ3 integrin and ASB2α belong to the core of Th2-specific genes. Using genetically modified mice, we find that increasing the levels of FLNa and FLNb in Th2 lymphocytes reduces airway inflammation through diminished Th2 lymphocyte recruitment in inflamed lungs. Collectively, our results highlight ASB2α and its substrates FLNa and FLNb to alter Th2 lymphocyte-mediated responses. Filamin proteins are degraded by ASB2α E3 ubiquitin ligase and may affect T cell function. Here the authors show that increased levels of Filamin A and Filamin B in Th2 cells reduces allergic inflammation in mouse models through reduced Th2 cell recruitment into inflamed lungs. [ABSTRACT FROM AUTHOR]

Abstract Toxins of toxin-antitoxin systems use diverse mechanisms to inhibit bacterial growth. In this study, we characterize the translation inhibitor toxin MenT3 of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis in humans. We show that MenT3 is a robust cytidine specific tRNA nucleotidyltransferase in vitro, capable of modifying the aminoacyl acceptor ends of most tRNA but with a marked preference for tRNASer, to which long stretches of cytidines are added. Furthermore, transcriptomic-wide analysis of MenT3 targets in M. tuberculosis identifies tRNASer as the sole target of MenT3 and reveals significant detoxification attempts by the essential CCA-adding enzyme PcnA in response to MenT3. Finally, under physiological conditions, only in the presence the native menAT3 operon, an active pool of endogenous MenT3 targeting tRNASer in M. tuberculosis is detected, likely reflecting the importance of MenT3 during infection.

Abstract Plants growing at high densities can detect competitors through changes in the composition of light reflected by neighbours. In response to this far-red-enriched light, plants elicit adaptive shade avoidance responses for light capture, but these need to be balanced against other input signals, such as nutrient availability. Here, we investigated how Arabidopsis integrates shade and nitrate signalling. We unveiled that nitrate modulates shade avoidance via a previously unknown shade response pathway that involves root-derived trans-zeatin (tZ) signal and the BEE1 transcription factor as an integrator of light and cytokinin signalling. Under nitrate-sufficient conditions, tZ promotes hypocotyl elongation specifically in the presence of supplemental far-red light. This occurs via PIF transcription factors-dependent inhibition of type-A ARRs cytokinin response inhibitors. Our data thus reveal how plants co-regulate responses to shade cues with root-derived information about nutrient availability, and how they restrict responses to this information to specific light conditions in the shoot.

Abstract Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.

Abstract Fauna is highly abundant and diverse in soils worldwide, but surprisingly little is known about how it affects soil organic matter stabilization. Here, we review how the ecological strategies of a multitude of soil faunal taxa can affect the formation and persistence of labile (particulate organic matter, POM) and stabilized soil organic matter (mineral-associated organic matter, MAOM). We propose three major mechanisms - transformation, translocation, and grazing on microorganisms - by which soil fauna alters factors deemed essential in the formation of POM and MAOM, including the quantity and decomposability of organic matter, soil mineralogy, and the abundance, location, and composition of the microbial community. Determining the relevance of these mechanisms to POM and MAOM formation in cross-disciplinary studies that cover individual taxa and more complex faunal communities, and employ physical fractionation, isotopic, and microbiological approaches is essential to advance concepts, models, and policies focused on soil organic matter and effectively manage soils as carbon sinks, nutrient stores, and providers of food.

Abstract During extensive periods without rain, known as dry-downs, decreasing soil moisture (SM) induces plant water stress at the point when it limits evapotranspiration, defining a critical SM threshold (θcrit). Better quantification of θcrit is needed for improving future projections of climate and water resources, food production, and ecosystem vulnerability. Here, we combine systematic satellite observations of the diurnal amplitude of land surface temperature (dLST) and SM during dry-downs, corroborated by in-situ data from flux towers, to generate the observation-based global map of θcrit. We find an average global θcrit of 0.19 m3/m3, varying from 0.12 m3/m3 in arid ecosystems to 0.26 m3/m3 in humid ecosystems. θcrit simulated by Earth System Models is overestimated in dry areas and underestimated in wet areas. The global observed pattern of θcrit reflects plant adaptation to soil available water and atmospheric demand. Using explainable machine learning, we show that aridity index, leaf area and soil texture are the most influential drivers. Moreover, we show that the annual fraction of days with water stress, when SM stays below θcrit, has increased in the past four decades. Our results have important implications for understanding the inception of water stress in models and identifying SM tipping points.

Abstract Euchelicerata is a clade of arthropods comprising horseshoe crabs, scorpions, spiders, mites and ticks, as well as the extinct eurypterids (sea scorpions) and chasmataspidids. The understanding of the ground plans and relationships between these crown-group euchelicerates has benefited from the discovery of numerous fossils. However, little is known regarding the origin and early evolution of the euchelicerate body plan because the relationships between their Cambrian sister taxa and synziphosurines, a group of Silurian to Carboniferous stem euchelicerates with chelicerae and an unfused opisthosoma, remain poorly understood owing to the scarce fossil record of appendages. Here we describe a synziphosurine from the Lower Ordovician (ca. 478 Ma) Fezouata Shale of Morocco. This species possesses five biramous appendages with stenopodous exopods bearing setae in the prosoma and a fully expressed first tergite in the opisthosoma illuminating the ancestral anatomy of the group. Phylogenetic analyses recover this fossil as a member of the stem euchelicerate family Offacolidae, which is characterized by biramous prosomal appendages. Moreover, it also shares anatomical features with the Cambrian euarthropod Habelia optata, filling the anatomical gap between euchelicerates and Cambrian stem taxa, while also contributing to our understanding of the evolution of euchelicerate uniramous prosomal appendages and tagmosis.

Abstract Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

Abstract Droughts or floods are usually attributed to precipitation deficits or surpluses, both of which may become more frequent and severe under continued global warming. Concurring large-scale droughts in the Southwest and flooding in the Southeast of China in recent decades have attracted considerable attention, but their causes and interrelations are not well understood. Here, we examine spatiotemporal changes in hydrometeorological variables and investigate the mechanism underlying contrasting soil dryness/wetness patterns over a 54-year period (1965–2018) across a representative mega-watershed in South China—the West River Basin. We demonstrate that increasing rainfall intensity leads to severe drying upstream with decreases in soil water storage, water yield, and baseflow, versus increases therein downstream. Our study highlights a simultaneous occurrence of increased drought and flooding risks due to contrasting interactions between rainfall intensification and topography across the river basin, implying increasingly vulnerable water and food security under continued climate change.

Abstract Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.

Abstract The response of vegetation physiology to drought at large spatial scales is poorly understood due to a lack of direct observations. Here, we study vegetation drought responses related to photosynthesis, evaporation, and vegetation water content using remotely sensed data, and we isolate physiological responses using a machine learning technique. We find that vegetation functional decreases are largely driven by the downregulation of vegetation physiology such as stomatal conductance and light use efficiency, with the strongest downregulation in water-limited regions. Vegetation physiological decreases in wet regions also result in a discrepancy between functional and structural changes under severe drought. We find similar patterns of physiological drought response using simulations from a soil–plant–atmosphere continuum model coupled with a radiative transfer model. Observation-derived vegetation physiological responses to drought across space are mainly controlled by aridity and additionally modulated by abnormal hydro-meteorological conditions and vegetation types. Hence, isolating and quantifying vegetation physiological responses to drought enables a better understanding of ecosystem biogeochemical and biophysical feedback in modulating climate change.

Abstract Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity.

Abstract Increasing atmospheric moisture content is expected to intensify precipitation extremes under climate warming. However, extreme precipitation sensitivity (EPS) to temperature is complicated by the presence of reduced or hook-shaped scaling, and the underlying physical mechanisms remain unclear. Here, by using atmospheric reanalysis and climate model projections, we propose a physical decomposition of EPS into thermodynamic and dynamic components (i.e., the effects of atmospheric moisture and vertical ascent velocity) at a global scale in both historical and future climates. Unlike previous expectations, we find that thermodynamics do not always contribute to precipitation intensification, with the lapse rate effect and the pressure component partly offsetting positive EPS. Large anomalies in future EPS projections (with lower and upper quartiles of −1.9%/°C and 8.0%/°C) are caused by changes in updraft strength (i.e., the dynamic component), with a contrast of positive anomalies over oceans and negative anomalies over land areas. These findings reveal counteracting effects of atmospheric thermodynamics and dynamics on EPS, and underscore the importance of understanding precipitation extremes by decomposing thermodynamic effects into more detailed terms.

Khufu’s Pyramid is one of the largest archaeological monuments in the world, and still contains unexplored voids. Here, the authors use cosmic-ray muon radiography in multiple positions to precisely characterize one of these inner structures called the North Face Corridor.

To refold client proteins, HSP90 chaperone undergoes large structural rearrangements. Here the authors use NMR and molecular simulation and reveal structure and dynamics of a key functionally relevant metastable state of human HSP90α N-terminal domain.

Canopy rainfall interception (E i ) is a key component of global water cycle. Here, the authors quantify E i using flux tower data and machine learning, and find that rainfall gets less partitioned into E i as it gets more intense and less frequent.

Aryl hydrocarbon receptor (AHR) is a sensor of the chemical environment including pollutants, diet components and metabolites. Here, authors determine the structure of the indirubin-bound AHR cytosolic complex providing mechanistic insights into ligand-binding promiscuity and selectivity.

Hypothyroidism is a common condition that cannot always be satisfactorily treated through continued hormone replacement. Here the authors report the generation of transplantable thyroid organoids derived from human embryonic stem cells that can restore plasma thyroid hormone in athyreotic mice.

Abstract Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

The magnitude of the tropical low cloud feedback, which contributes considerably to uncertainty in estimates of climate sensitivity, is closely linked to tropical deep convection and its effects on the tropical atmospheric overturning circulation.

Here, the authors find increased dry–season and decreased wet–season water availability over subtropical regions and the Amazon. This is caused by seasonally varying soil moisture–atmosphere feedbacks under global warming.

Changes in vegetation responses to precipitation may be hydroclimate dependent. Here the authors reveal contrasting trends of vegetation sensitivity to precipitation in drylands vs. wetter ecosystems over the last 4 decades and identify increased CO2 as a major contributing factor.

The seasonal greening of Northern Hemisphere ecosystems due to extended growing periods and enhanced photosynthetic activity is, via experiments, shown to modify near-surface warming by perturbing land-atmosphere energy exchanges.

The dominant driver of variations in global land carbon sink remains unclear. Here the authors show that the seasonal compensation of temperature effects on land carbon sink in the Northern Hemisphere could induce a global water dominance.

It remains unclear how predictions of future threat affect memory recall, specifically in the case of post-traumatic stress disorder (PTSD). Here, the authors combined computational modeling and brain connectivity analyses to show that individuals with PTSD have exaggerated predictive control and reduced reactive control in a memory suppression task.

Integrated kinetic and structural investigations reveal that the ubiquitous co-chaperonin prefoldin interacts with its coiled-coil helices on the islet amyloid polypeptide fibril surface and fibril ends to inhibit fibril elongation and secondary nucleation.

Toxin-antitoxin systems are widespread in bacteria. Here the authors present structures of M. tuberculosis HigBTAC alone and bound to the ribosome in the presence of native cspA mRNA, shedding light on its mechanism of translation inhibition.

The drug AT-527 targets the SARS-CoV-2 replication machinery. Here the authors use Cryo-EM to show how AT-527 inhibits SARS-CoV-2 polymerase by acting as an immediate RNA chain terminator and stably binding in a NiRAN active-site pocket; impeding an essential nucleotide-transfer activity.

Using global flux tower observations, the authors show that atmospheric dryness always reduces photosynthesis, whereas soil dryness can increase photosynthesis if soil water stores are sufficient.

The centriole exhibits an evolutionarily conserved 9-fold radial symmetry that stems from a cartwheel containing vertically stacked ring polymers that harbor 9 homodimers of the protein SAS-6. Here the authors show how dual properties inherent to surface-guided SAS-6 self-assembly possess spatial information that dictates correct scaffolding of centriole architecture.

To provide in depth characterization of HIV reservoir cells, the authors here develop a single-cell approach to simultaneously sequence TCR, integration sites and proviral genomes, called STIP-Seq, and show that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5’-end of the genome.

Centriole biogenesis begins with self-assembly of SAS-6 proteins into 9-fold symmetrical ring polymers, which then stack into a cartwheel that scaffolds organelle formation. Here, the authors develop monobodies against Chlamydomonas reinhardtii SAS-6 and use X-ray crystallography, atomic force microscopy and cryo-electron microscopy to reveal insights into ring assembly and stacking.

Acquisition of dying tumor cell-associated antigens is an essential step for the initiation of anti-tumor immune response by conventional type 1 dendritic cells (cDC1). Here the authors show that the loss of TIM4 expression in lung tumor associated cDC1 is associated with less efficient uptake of cell associated antigens and reduction of CD8 + T cell activation in advanced lung tumors.

The cause of clonal expansions in the HIV reservoir remains unclear. Here, Gantner et al. perform single-cell TCR sequencing on longitudinal samples from eight individuals on antiretroviral therapy and find that antigens inducing clonal expansions of memory cells are major contributors to the HIV reservoir.

T cell receptors (TCR) are internalized when activated by their ligands. Here the authors show that the internalized TCRs are localized to endosomes expressing IRAP and Syntaxin 6 to maintain intracellular signalling capacity, whose importance is shown by the absence of efficient polyclonal anti-tumour response in mice with T-specific conditional deletion of IRAP.

CLE and CEP peptides regulate rhizobial symbiosis in legumes to balance the benefits of nitrogen fixation with the metabolic costs of nodule production. Here Laffont et al. show that cytokinin and bacterial Nod factors induce Medicago CEP7 which acts antagonistically to CLE13 to fine-tune nodulation.

Classical human dendritic cells (cDCs) are rare sentinel cells specialized in regulating adaptive immunity. Here, the authors show that expression of membrane bound FLT3L, along with stem cell factor (SCF) and CXCL12 in stromal cells induces specification of pre/AS-DCs, type 1 and type2 cDC from haematopoietic stem cells.

Correct spindle positioning is critical for cell division but the full set of proteins regulating this is unclear. Here, with a live imaging siRNA-based screen in human cells, the authors identify 16 candidates required for this process, 11 of which were previously unassociated with such a function, including TYRO3 and GAK.

Large protein machines are tightly regulated through allosteric communication channels. Here authors use single-molecule FRET and demonstrate the involvement of ultrafast conformational dynamics in the allosteric regulation of ClpB, a hexameric AAA+ machine that rescues aggregated proteins.

SecB homologs can be associated with stress-responsive type II toxin–antitoxin (TA) systems and form tripartite toxin-antitoxin-chaperone systems (TAC). Here the authors provide structural insights into TACs by presenting the crystal structure of the M. tuberculosis TA-associated SecB chaperone in complex with the C-terminal ChAD (chaperone addiction) extension of the antitoxin HigA1.

Storm runoff extremes dominate flash flood formation and generation, posing a grand threat to ecosystems and communities across the world. Here the authors show that current projected response of these storm runoff extremes to climate and anthropogenic changes are underestimated.

The identification of new drug targets is highly challenging, particularly for diseases of the brain. This study describes a general computational gene regulatory framework called CRAFT for drug target discovery, and the authors use CRAFT to identify the microglial membrane receptor Csf1R as a potential therapeutic target for epilepsy.

Many bacterial proteins exhibit spatially defined localization important for function. Here the authors show that the polar localization of Shigella IpaC type III secretion substrate is mediated by its interaction with the DnaK chaperone and occlusion by the bacterial nucleoid.

Land use and land cover change has led to more frequent hot, dry summers in parts of the mid-latitudes. Here the authors use an Earth system model to show that regions converted to crops and pastures experience hot, dry summers 2 to 4 times more frequently than they would if native forests had remained.

Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.