Browse Articles

Programmable radio-frequency calculations in electromagnetic-wave domain

Calcitriol–PKM2 axis drives transcriptional and metabolic reprogramming of ILCPs into intestinal dual-cytokine-producing ILC3s

Vitamin D deficiency is associated with dysregulated alloimmune responses, but the mechanisms by which its active metabolite calcitriol shapes innate lymphoid cell (ILC) development and function remain incompletely understood. Here, we elucidate how calcitriol directs the differentiation of bone marrow (BM) ILC progenitors (ILCPs) into anti-inflammatory ILC3s with therapeutic potential in alloimmune diseases. Using murine vitamin D models, integrated omics, 13 C-glucose tracing, humanized mouse models, and clinical samples, we show that calcitriol, through the vitamin D receptor (VDR), selectively promotes the expansion and differentiation of BM ILCPs into IL-10 + IL-22 + ILC3s that exert tissue-protective effects in the intestine. Calcitriol-primed BM ILCP cell therapy attenuates intestinal inflammation in an alloimmune setting. Mechanistically, a VDR–SYK axis triggers nuclear translocation of pyruvate kinase M2 (PKM2). Nuclear PKM2 phosphorylates STAT3 at Tyr705, forming a dimerization complex with c-JUN that drives Il10 transcription. Simultaneously, cytosolic PKM2 channels pyruvate into pyruvate carboxylase–mediated mitochondrial anaplerosis, sustaining oxidative phosphorylation while suppressing reverse electron transport-driven mitochondrial ROS production. In human studies, patients with severe alloimmune complications exhibit reduced circulating ILCPs and low serum 25(OH)D levels. Calcitriol-treated human CD117 + ILCPs efficiently generate IL-10-producing ILCs in vitro and in humanized models, potently suppressing alloreactive T cell responses. Collectively, calcitriol reprograms BM ILCPs via the VDR–SYK–PKM2 axis to generate dual-cytokine IL-10 + IL-22 + ILC3s, establishing PKM2 as a key immunometabolic target and supporting calcitriol-primed ILCP-based cell therapy as a promising approach for alloimmune diseases.

Quantifying environmental co-benefits of nitrogen-based crop restructuring and its implications on India’s interstate trade network

Abstract Addressing sustainability within food systems is challenging due to their multifaceted nature. Here, we evaluate crop-restructuring pathways for Indian agricultural system by integrating nutrient, water, greenhouse gas, economic, and interstate trade-network accounting. We show that the nitrogen-focused crop restructuring strategy reduces nitrogen surplus by 13.4% and water use by 18.6%. This approach maintains baseline calorie production, narrows the benchmarked cereal net-return deficit, and mitigates greenhouse gas emissions by 8.7%. Relative to water-focused restructuring, the nitrogen-focused strategy delivers larger reciprocal co-benefits by about 4.6-fold, resulting in a decrease in socio-environmental costs associated with nitrogen pollution of around $1.19 billion USD. The resulting agricultural restructuring substantially expands alternative-cereal trade in the interstate trade network. Overall, our analysis shows that integrating nutrient management into crop-restructuring strategies can support food-system sustainability in India and other resource-constrained agricultural systems.

Correction for Zhang et al., Host genetic regulation of rumen 6-hydroxymelatonin reduces methane emissions in dairy cattle

Neonatal inflammation disrupts a temporally restricted postnatal Numb-enriched microglial state in mice

Abstract Early-life microglia are diverse and support brain development beyond immune surveillance, but the transient states associated with postnatal maturation remain poorly understood. Here we show, using a time-resolved single-cell atlas of neonatal mouse brain immune cells, that a postnatal Numb -enriched microglial state emerges during early postnatal development, expands during the second postnatal week and subsequently declines. This state is characterized by neurodevelopment-related gene expression programs and distinct metabolic features. Trajectory inference, cross-atlas mapping and RNAscope validation support its temporal pattern. During the period when this state expands, microglial depletion preserves gross myelination but alters synaptic protein composition and disrupts dendritic and cortical layer maturation, particularly in the primary somatosensory cortex. Neonatal lipopolysaccharide challenge impairs the establishment of the Numb -enriched state and induces an early glycolytic response followed by recovery-phase inflammatory states. These findings identify a developmentally timed microglial state associated with cortical maturation and vulnerable to neonatal inflammation in mice.

Rapid microbial production of long-lived dissolved organic carbon in the global ocean

Marine microbes have long been regarded as central to replenishing the ocean’s reservoir of recalcitrant dissolved organic matter (RDOM). However, molecular-level evidence for their role remains inconclusive because RDOM persists for years to millennia, far exceeding timescales accessible to laboratory experiments, and because conventional analytical approaches lack the resolution to discern structural isomers of RDOM that confer functionally important differences in persistence. Using polarity-based liquid chromatography coupled to ultrahigh-resolution mass spectrometry capable of discriminating RDOM isomer clusters, we reveal that marine microbial consortia rapidly (≤ 90 d) convert diverse organic substrates into RDOM with extensive structural isomerism that closely mirrors natural seawater RDOM. A subset of these microbially derived RDOM compounds exhibits near-ubiquitous occurrence (> 99%) in a global dataset and accumulates progressively in the ocean’s interior. Together, our findings substantiate the direct microbial contribution to the long-lived oceanic carbon reservoir through the rapid diversification of RDOM isomers, a mechanism that contributes to sustaining the complexity and long-term persistence of the planetary-scale carbon reservoir.

A prolonged hydrothermal past at Santorini Caldera revealed by sedimentary trace metal and microbial signatures

Abstract Hydrothermal systems in volcanic calderas are critical in signalling volcanic unrest, forming ore deposits, and sustaining chemosynthetic microorganisms. Analysis of a ~3500-year sequence of sediments collected from the Santorini caldera, Greece, during International Ocean Discovery Program (IODP) Expedition 398 reveals the behaviour of a prolonged paleo-hydrothermal system. Sediment geochemical and metagenomic data record vigorous hydrothermal activity and metal fluxes for ~1100 years, within a 2270-year window between two major eruptions. Sediment hydrothermally-derived trace metals are significantly enriched over background (~200-fold for As and Hg, and 10–50-fold for Mn, Sb, Mo, and V), with long-term metal fluxes (9 t yr −1 As, 2.5 t yr −1 Cu, 7 kg yr −1 Ag) comparable to fluxes from present-day geothermal fields in the Taupo Volcanic Zone. Metagenomic analysis identifies elevated metal resistance genes—signals of microbial adaptation to heightened hydrothermal stressors. Here we integrate geological and genomic evidence to decipher the paleoenvironmental and biogeochemical history of the past hydrothermal system at Santorini caldera.

The free-living wellspring of symbiotic nitrogen fixation in <i>Bradyrhizobium</i>

The evolutionary origin of nitrogen-fixing symbiosis has been a long-standing question. To address this, we focused on Bradyrhizobium , a globally abundant bacterial genus that includes classic symbiotic lineages, which rely on the common Nod factor signaling pathway to form nodules, and close relatives capable of fixing nitrogen in a free-living state. We isolated 88 strains carrying the key genes for nitrogen fixation ( nif ) from nonlegume environments and analyzed them alongside 586 public Bradyrhizobium genomes harboring these genes to reconstruct a robust phylogeny of nif genes. Analysis suggests that the earliest-diverging nif lineages are members capable of free-living nitrogen fixation, supporting the interpretation that this lifestyle is ancestral. The Nod factor-dependent symbiotic lineages are polyphyletic, with our data supporting at least three independent origins via horizontal acquisition of symbiosis islands. This evolutionary history is reflected in a genomic dichotomy: lineages capable of free-living nitrogen fixation possess a conserved nif island architecture that consistently includes the oxygen-protective gene glbO , whereas the symbiotic nif -associated regions are highly variable and universally lack glbO . Using both loss-of-function and gain-of-function genetic approaches, we show that glbO contributes significantly to nitrogenase activity under free-living conditions, whereas it is dispensable within the protected nodule environment. This work provides a framework for the evolution of nitrogen-fixing symbiosis, supporting the view that free-living nitrogen-fixing ancestors gave rise repeatedly and independently to symbiotic lineages in Bradyrhizobium .

Quantum-memory-assisted on-demand microwave-optical transduction

Correction for Madangopal et al., Distinct prelimbic cortex ensembles encode response execution and inhibition

Technoeconomic competitiveness of small modular reactors across U.S. power and industrial sectors

Ancestral gene content estimates under gain–loss–duplication depend on the chosen observation threshold

Peri-weaning, diet-induced activation of an IFNγ-mediated regulatory circuit promotes cDC1 maturation and CD8+ T cell differentiation

Abstract Maintaining a balanced immunity between pathogen defense and tolerance to environmental antigens in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals, type 1 conventional dendritic cells (cDC1) contribute to both processes but how the balance may be achieved is unclear. Here, we uncover an interferon (IFN)γ-driven regulatory circuit in early life that relays dietary cues to spleen cDC1. IFNγ-mediated STAT1-signaling induces an immunogenic maturation program in spleen cDC1 that enables them to shape the effector differentiation of antigen-experienced effector memory CD8⁺ T cells. This cDC1 program emerges during the transition from breastfeeding to solid food at weaning, occurs in germ-free mice, and remains operative to dietary intervention in adult mice. At weaning, this IFNγ signal enables spleen cDC1 to shape the effector phenotype of food-antigen-specific CD8 + T cells in a feedforward manner, thereby recalibrating the developing T cell pool. Our findings identify diet as a modifiable cue that can tune systemic cDC1-mediated immunity, opening new opportunities to steer immune responses during early life and beyond.

Nanobody regulation of C-type inactivation in Kv1.3 channels

Abstract Nanobodies are powerful tools for modulating ion channels for mechanistic investigations and developing new therapeutics. The Kv1.3 channel is highly expressed in T-lymphocytes where it promotes sustained T-cell activation, its expression is elevated in autoimmune disorders and inhibitory nanobodies are immunosuppressive. The A019400G09 nanobody (NB1.3) binds to the external surface of Kv1.3 and inhibits the channel by promoting slow C-type inactivation of the ion selectivity filter. Here we explore the mechanism by which NB1.3 promotes inactivation by determining a series of cryo-EM structures of Kv1.3 and mutating the interface between NB1.3 and the channel. Our results reveal that interaction of NB1.3 with both the S1-S4 voltage-sensing domain and the turret within the pore domain are required to promote inactivation. We also identify a network of interacting hydrophobic residues linking the turret to the ion selectivity filter that stabilizes the conducting state and mediate the actions of NB1.3. These findings provide a foundation for developing therapeutics targeting Kv1.3 channels and exploring how nanobodies can interact with other tetrameric cation channels to modulate their activity.

Dual control of PIP2 drives germline/soma segregation in <i>Drosophila</i>

Embryonic cell fate decisions require precise spatial coordination between competing lineage determinants. In the syncytial Drosophila embryo, primordial germ cells (PGCs) and posterior endoderm are specified at the posterior pole in overlapping domains, creating a conflict between germline and somatic fates. PGC formation depends on germ granules, which locally promote production of the phospholipid PIP2 at the posterior plasma membrane. PIP2 regulates actin dynamics leading to membrane protrusions that generate PGCs. We find that the posterior endoderm determinant, the receptor tyrosine kinase (RTK) Torso, antagonizes germ granule activity by activating phosphoinositide 3-kinase (PI3K) which converts PIP2 to PIP3. PIP3 prevents PGC formation, ensuring endoderm specification. Loss of Torso or PI3K expands the posterior PIP2 domain, increasing both the number and spatial extent of PGCs. Germ granules counteract this activity through production of the E3 ubiquitin ligase Germ cell-less (Gcl), which locally eliminates Torso and prevents PI3K-mediated PIP2 depletion at the posterior pole. In gcl mutants, PIP3 accumulates at the posterior membrane and PGC formation fails, a defect that can be partially rescued by targeted posterior expression of the PIP3 phosphatase Pten. Together, these findings demonstrate that mutual antagonism between germ granules and Torso signaling generates a PIP2/PIP3 boundary in the plasma membrane that governs the earliest germline–soma fate decision. Our work reveals how opposing maternal cues can be integrated at the level of membrane phospholipids to pattern cell fate during the earliest stages of development.

Can stimulating ownership increase fertility: Evidence from housing interventions in China

Declining fertility and the emergence of very low TFR’s in the Asian economies has increased the focus on how to change the direction of the fertility trend. Several countries in Europe and Asia have explored a variety of stimulus packages to increase the overall TFR. In this research we review those policies and examine one of those interventions which has the potential to stimulate fertility—the role of access to housing. The core of housing approaches to stimulating fertility is to make housing more accessible and to use various forms of credit assistance with the aim of making ownership easier and more attractive to young families. The research asks how effective are these approaches to reversing the decline in fertility? And, are they a solution to very low fertility? The results provide some evidence that the focus on housing stimulus packages may increase fertility although most successfully for socioeconomically advantaged households.

Abrupt transition to irreversible damage in the overdrafted Sacramento Valley aquifer system

Groundwater extraction decreases water pressure in aquifer systems, causing reversible or irreversible deformation of the water-bearing layers that manifests as recoverable or permanent displacements of the land surface, respectively. Detecting and forecasting when and where an aquifer system transitions from a reversible, poroelastic regime, to an irreversible, inelastic regime remains a crucial challenge given the complex, heterogeneous nature of aquifer systems. Here we leverage high-resolution measurements of ground deformation and groundwater levels from 2016 to 2022 to characterize both regimes at the regional scale and show that a critical transition occurred in large areas of the Sacramento Valley during California’s 2020–2022 extreme drought. Our analysis reveals that, while deformation remained primarily poroelastic during the 2016–2020 interdrought period, land subsidence in areas of intense groundwater extraction accelerated abruptly in 2021, with subsidence rates exceeding the inferred poroelastic rates by several decimeters per year. Such rapid and extensive land subsidence indicates severe inelastic compaction and loss of storage capacity of the underlying aquifer system, which pose a serious threat to California’s water resources and infrastructure. A comparison of present-day deformation with historical groundwater levels reveals that this abrupt transition was not predictable based on the available groundwater records alone.

Discovery of a phenazine–thiol conjugase from sparse data using genome-informed machine learning

Machine learning has enabled powerful biological discoveries using models trained on large datasets. However, for many important biological questions, such as identifying enzymes that transform understudied substrates, sparsity of training data is often a major bottleneck. Here, using phenazine natural products as a case study, we show that integrating genome-informed data augmentation with contrastive learning in protein language space enables identification of phenazine-interacting proteins starting from only 14 known phenazine modifying sequences. We name this approach ML-CITO (Machine Learning for genomic Context-Informed Transferable discOvery). Applying this framework led to the discovery of PTC (phenazine–thiol conjugase), an enzyme known to catalyze phenazine thioconjugation, a phenazine modification reaction long observed but previously presumed to occur only through nonenzymatic chemistry. In silico simulation and experimental measurements demonstrate that PTC binds to both phenazine and glutathione as substrates. Recombinant expression and biochemical characterization reveal that PTC promotes glutathione-dependent modification of phenazines, yielding distinct reaction outcomes that depend on substrate identity. Although thiol-conjugated phenazine products exhibit reduced toxicity to bacterial cells, deletion of the gene encoding PTC does not confer a strong fitness disadvantage, illustrating how direct learning of sequences can uncover relevant enzymes that might evade phenotype-based genetic screens. Together, these results demonstrate that coupling comparative genomics with protein machine learning can convert “small data” typically outside the scope of machine learning into actionable predictive power, thereby facilitating enzyme discovery.

Coupled metabolic reactions relevant to early biological evolution

Dominant functional group explains global bird diversity responses to farmland abandonment

Reversing biodiversity declines will require redesigning agricultural landscapes and their management. Farmland abandonment and intensification are emerging as major drivers of biodiversity changes, and their consequences vary widely from negative to positive among continents. Despite decades of research on agricultural biodiversity, no generalizable framework has been established to predict these variations globally, hindering the development of effective conservation strategies. Here, we combine broad-scale, multiseason avian field surveys across Japan with a global meta-analysis spanning four continents. In field surveys, we compared avian species richness among 2-ha plots in abandoned farmland (≤ 50 y since abandonment), traditional farmland, and intensive farmland, controlling for the surrounding land-use cover. We showed that the dominant functional group robustly explains the direction and strength of community-level responses to abandonment and intensification. When mature-habitat species comprise over 50% of communities, abandonment enhances species richness by over 240%, reaching levels comparable to natural wetlands. Abandoned farmlands hold the potential to offset past biodiversity declines and thus merit considerations for inclusion within the conservation area networks. Conversely, when disturbed-habitat species comprise more than 48% of communities, abandonment and intensification reduce species richness, underscoring the importance of biodiversity-friendly farming. This study provides a basis to understand how to address varied spatial variations in biodiversity responses to management and land-cover changes—a long-standing hurdle in conservation science. Complex bird diversity responses can be predicted globally by simply identifying the dominant functional group, thereby helping develop the most effective conservation strategies. Transferability beyond birds and across taxa should be evaluated empirically.