Browse Articles

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.

From fruit flies to football: Violent <i>Drosophila</i> provide novel ideas about CTE

Climate warming and atmospheric deposition jointly accelerate the Antarctic Peninsula atmosphere–glacier–land–ocean mercury loop

Mercury (Hg) is a toxic pollutant of global concern that threatens ecosystem and human health. Its cycle is being jointly reshaped by anthropogenic emissions and polar warming, yet the response of the Antarctic system remains poorly constrained. Here, we reconstruct the past 200 y of Hg source–sink dynamics in the Antarctic Peninsula (AP), Antarctica’s fastest-warming region with the most pronounced glacier melting, by combining geochemical and isotopic records from 16 sediment cores collected across the AP shelf, with a developed observation-constrained multimedia Hg budget model. We find that despite its remoteness from anthropogenic emission sources, the modern AP shelf exhibits an Hg accumulation rate of 93 ± 58 µg m −2 y −1 , twice the global shelf average. Since industrialization, this accumulation rate has increased by 160%, making the AP one of the major hotspots of marine Hg enrichment. The model further reveals that this acceleration is driven by two coupled mechanisms: 1) enhanced atmospheric deposition and expanding open water strengthen the direct uptake of atmospheric Hg by seawater within the atmosphere–ocean loop, and 2) ice melt and erosion activate the long-overlooked atmosphere–glacier–land–ocean loop, remobilizing legacy Hg stored on land. The coupling of these two loops has increased ice melt-driven terrestrial Hg release by 550% and air–sea exchange by 350%. Thus, climate warming is turning the large historical Hg reservoir in Antarctica into an active secondary pollution source, amplifying polar Hg pollution risk.

Counting birds while taking fire: Biodiversity monitoring in a war zone

Reply to Topaz and Bahl: Interpreting a post-2022 lexical shift in academic prose

Correction for Wu et al., Paramyxovirus infection driven by heteromultivalent sialoglycotope binding

Sterilization mechanism and material compatibility of low-pressure RF water plasma for spacecraft surface decontamination

Heat tolerance decreases and cold tolerance increases with elevation for a species-rich insect family on a tropical volcano

The climate crisis is moving the high ambient temperatures common in lower elevation tropical forests upslope into areas where they would not have occurred historically. Tropical invertebrates may be particularly vulnerable to such changes. Here, our goal was to understand whether the distribution of heat and cold tolerances along an elevational gradient in northwestern Costa Rica predicted by theory were present for a leaf-litter inhabiting insect community of rove beetles (Staphylinidae: Coleoptera). We found that heat tolerance decreased, and cold tolerance increased with elevation, supporting the predictions. High elevation communities may not be capable of tolerating the rising temperatures that come with climate change, while low elevation communities are already experiencing environmental temperatures that may meet or exceed their thermal limits. While the forests in the low elevation more frequently exhibit temperatures that meet or exceed the heat tolerances for the beetle community, the soil will offer a buffered refuge for some time. The decline in thermal tolerance that we show here is predicted by theory yet is inconsistent with the values for insect species in the thermal tolerance literature. This reinforces the need for a better understanding of the thermal tolerances of diverse assemblages of tropical species that are likely to experience complicated and negative impacts of climate change.

High-purity type I collagen wrap is associated with improved functional recovery after extensor tendon repair: a multicentre randomized trial

Abstract Extensor tendon repairs of the hand, particularly in zones VI–VIII, are frequently complicated by peritendinous adhesions, resulting in reduced tendon glide, extensor lag, and suboptimal functional recovery. This multicentre randomized controlled trial evaluated whether adjunctive high-purity type I collagen (HPTC) wrapping was associated with improved functional recovery and reduced adhesion-related morbidity following extensor tendon repair. In this multicentre randomized controlled trial, 60 adult patients with acute extensor tendon injuries in zones VI–VIII were randomized to undergo standard tendon repair with adjunctive HPTC wrap (n = 30) or standard repair alone (n = 30). Primary outcome was TAM at 8 weeks, with extended follow-up assessments at 3- and 5-months evaluating durability of functional recovery. Secondary outcomes included QuickDASH scores, extensor lag, grip strength, adhesion-related functional limitation, and complications. Outcomes were assessed by blinded evaluators. Statistical analysis was performed using intention-to-treat principles. At eight weeks, mean TAM was significantly higher in the HPTC group compared with controls (232.4 ± 21.6 vs. 201.3 ± 26.8 degrees; p  &lt; 0.001), with a large effect size (Cohen’s d = 1.30). The HPTC group demonstrated significantly lower QuickDASH scores, reduced extensor lag, and greater grip strength recovery (all p  &lt; 0.001). Adhesion-related functional limitation occurred in 6.7% of patients in the HPTC group versus 30.0% in controls ( p  = 0.01). No collagen-related adverse events were observed. Extended follow-up demonstrated sustained functional benefit in the HPTC group through five months, including superior total active motion, lower QuickDASH disability scores, reduced extensor lag, greater grip strength recovery, and fewer secondary procedures related to adhesion formation. Adjunctive use of high-purity type I collagen wrap significantly improves early functional outcomes and reduces adhesion-related morbidity following extensor tendon repair. HPTC was associated with improved early and intermediate-term functional recovery and reduced adhesion-related morbidity, with longer follow-up with larger cohorts needed to confirm durability of these benefits.

PLCβs are recruited to the plasma membrane in macrophages by both Gβγ and Gα _q

PLCβ enzymes cleave PIP2 from the plasma membrane, producing IP3 and DAG, which regulate intracellular Ca 2+ levels and protein kinase C activity, respectively. They are regulated by GPCR signaling through the G proteins Gβγ and Gα q and have been shown to function as coincidence detectors for dual stimulation of Gα q - and Gα i -coupled receptors via these G proteins. PLCβs are aqueous-soluble enzymes, but partition onto the membrane surface to access their lipid substrate. We previously demonstrated that membrane recruitment and orientation of the catalytic core on the membrane surface underlie Gβγ-dependent regulation of PLCβ enzymes. Using macrophages as a model system, where PLCβ signaling is essential for responses to infection and tissue injury, we investigated the contribution of Gβγ-dependent regulation and membrane recruitment of PLCβ in the context of endogenous signaling. By measuring Ca 2+ mobilization, we demonstrate that both Gα i - and Gα q -coupled receptors independently stimulate PLCβ activity. Using total internal reflection fluorescence and stimulated emission depletion microscopy, we demonstrate that most of the PLCβ3 in the cell is localized away from the plasma membrane at rest but is rapidly recruited to the plasma membrane upon stimulation by both Gα i - and Gα q -coupled receptors, illustrating that both Gβγ and Gα q recruit PLCβ to the plasma membrane. These results support an updated model for G protein–dependent regulation of PLCβ enzymes, where Gβγ-induced regulation in the absence of Gα q can occur and is apparently dictated by the local concentration of receptor, G proteins, and PLCβ.