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PsDMAP1/PsTIP60-regulated H4K16ac is required for ROS-dependent virulence adaptation of <i>Phytophthora sojae</i> on host plants

Host plants and various fungicides inhibit plant pathogens by inducing the release of excessive reactive oxygen species (ROS) and causing DNA damage, either directly or indirectly leading to cell death. The mechanisms by which the oomycete Phytophthora sojae manages ROS stress resulting from plant immune responses and fungicides remains unclear. This study elucidates the role of histone acetylation in ROS-induced DNA damage responses (DDR) to adapt to stress. Mechanistically, the P. sojae DNA methyltransferase 1-associated protein (PsDMAP1) binds Tat-interactive protein 60 (PsTIP60) to comediate histone H4 acetylation on lysine 16 (H4K16ac). This regulation affects RNA polymerase II (pol II) recruitment, transcriptional induction of DDR-related genes, and the enrichment of histone H2Ax phosphorylated on serine 137 (γH2Ax) in response to both plant immunity and fungicide stress. The resulting H4K16ac serves as a crucial transgenerational epigenetic signal for virulence adaptation of P. sojae on plants, as a result of adaptation to ROS stress.

Metabolic enhancement contributed by horizontal gene transfer is essential for dietary specialization in leaf beetles

Horizontal gene transfer (HGT) from bacteria to insects is widely reported and often associated with the adaptation and diversification of insects. However, compelling evidence demonstrating how HGT-conferred metabolic adjustments enable species to adapt to surrounding environment remains scarce. Dietary specialization is an important ecological strategy adopted by animals to reduce inter- and intraspecific competition for limited resources. Adults of the leaf beetle Plagiodera versicolora (Coleoptera) preferentially consume new leaves; nevertheless, we found that they selectively oviposit on mature leaves, thereby establishing a distinct dietary niche separation between adults and larvae. Based on the de novo assembled chromosome-level genome, we identified two horizontally transferred genes with cellulose degradation potential, belonging to the glycosyl hydrolase 48 family ( GH48-1 and GH48-2 ). Prokaryotic expression of the HGTs confirmed the cellulose degradation capability of the two genes. Knockdown of GH48 significantly hampered the growth and survival rate of larvae feeding on mature leaves compared to wild-type larvae, with no similar effect observed in adults. Replenishing the GH48-expressing bacteria compensated for the knockdown of these two genes and recurred larval adaptability to mature leaves. Taken together, our results highlight the advantage and metabolic enhancement conferred by the two cellulose-degrading HGTs in P. versicolora larvae, enabling their development on cellulose-enriched mature leaves and underscoring the indispensable role of HGTs in facilitating the adaptation of leaf beetles to plants.

Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.

Population encoding of observed and actual somatosensations in the human posterior parietal cortex

Cognition relies on transforming sensory inputs into a generalizable understanding of the world. Mirror neurons have been proposed to underlie this process, mapping visual representations of others’ actions and sensations onto neurons that mediate our own, providing a conduit for understanding. However, this theory has limitations. Here, we hypothesize that mirror-like responses represent one facet of a broader framework in which our brains engage internal models for cognition. We recorded populations of single neurons in the human posterior parietal cortex (PPC) of a brain–machine interface clinical trial participant implanted with a microelectrode array while she either experienced actual touch, or observed diverse tactile stimuli applied to other individuals. Two body locations were tested, on each of the participant and other individuals. Some neurons exhibited mirror-like properties, consistent with earlier literature. However, they were fragile, breaking with increased task complexity. Population responses were better characterized by generalizable and compositional basic-level features encoded within neural subspaces. These features enable the population to respond to diverse actual and observed touch stimuli and are recruited similarly for similar forms of touch. Mirror-like neurons belong within these subspaces, contributing more globally to compositionality and generalizability. We speculate that at a population-level, human PPC manifests an internal model for touch, and that cognition unfolds in the high-level human cortex by versatility in its representational building blocks. In a broad sense, we speculate that the population features we demonstrate support a broad mechanism by which the high-level human cortex enables understanding.

Dissecting the cellular architecture and genetic circuitry of the soybean seed

Seeds are complex structures composed of three regions, embryo, endosperm, and seed coat, with each further divided into subregions that consist of tissues, cell layers, and cell types. Although the seed is well characterized anatomically, much less is known about the genetic circuitry that dictates its spatial complexity. To address this issue, we profiled mRNAs from anatomically distinct seed subregions at several developmental stages. Analyses of these profiles showed that all subregions express similar diverse gene numbers and that the small gene numbers expressed subregion specifically provide information about the biological processes that occur in these seed compartments. In parallel, we profiled RNAs in individual nuclei and identified nuclei clusters representing distinct cell identities. Integrating single-nucleus RNA and subregion mRNA transcriptomes allowed most cell identities to be assigned to specific subregions and cell types and/or cell states. The number of cell identities exceeds the number of anatomically distinguishable cell types, emphasizing the spatial complexity of seeds. We defined gene coexpression networks that underlie distinct biological processes during seed development. We showed that network distribution among subregions and cell identities is highly variable. Some networks operate in single subregions and/or cell identities, and many coexpression networks operate in multiple subregions and/or cell identities. We also showed that single subregions and cell identities possess several networks. Together, our studies provide unique insights into the biological processes and genetic circuitry that underlie the spatial landscape of the seed.

Climate change could amplify weak synchrony in large marine ecosystems

Climate change is increasing the frequency of large-scale, extreme environmental events and flattening environmental gradients. Whether such changes will cause spatially synchronous, large-scale population declines depends on mechanisms that limit metapopulation synchrony, thereby promoting rescue effects and stability. Using long-term data and empirical dynamic models, we quantified spatial heterogeneity in density dependence, spatial heterogeneity in environmental responses, and environmental gradients to assess their role in inhibiting synchrony across 36 marine fish and invertebrate species. Overall, spatial heterogeneity in population dynamics was as important as environmental drivers in explaining population variation. This heterogeneity leads to weak synchrony in the California Current Ecosystem, where populations exhibit diverse responses to shared, large-scale environmental change. In contrast, in the Northeast U.S. Shelf Ecosystem, gradients in average environmental conditions among locations, filtered through nonlinear environmental response curves, limit synchrony. Simulations predict that environmental gradients and response diversity will continue to inhibit synchrony even if large-scale environmental extremes become common. However, if environmental gradients weaken, synchrony and periods of large-scale population decline may rise sharply among commercially important species on the Northeast Shelf. Our approach thus allows ecologists to 1) quantify how differences among local communities underpin landscape-scale resilience and 2) identify the kinds of future climatic changes most likely to amplify synchrony and erode species stability.

Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody–drug conjugates

Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA. This variant, with only two mutations (T30S/D31A) located on its heavy chain, effectively reinstates binding to the mutated antigen, at the expense of a 35-fold reduction in binding affinity to HER2 (S310F) compared to the wild-type pair. Subsequently, Ptz-SA demonstrates potent killing capacity through antigen-dependent cytotoxicity. Moreover, upon engineering Ptz-SA into antibody–drug conjugates, such as Ptz-SA-MMAE, it manifests notable in vitro and in vivo antitumor efficacy by efficiently delivering cytotoxic payload into tumor cells expressing HER2 (S310F). Cryoelectron microscopy studies elucidate the molecular mechanism underlying the restored binding ability of Ptz-SA toward the S310F mutation. The steric hindrance induced by the S310F mutation is efficiently circumvented by the T30S and D31A mutations, which provides adequate space to accommodate the larger phenylalanine. Additionally, Ptz-SA also exhibits binding capacity to HER2 (S310Y), another mutation occurring at the S310 site of HER2 with high frequency. The computational-aided evolution of pertuzumab provides an alternative strategy for overcoming point mutation-mediated resistance to therapeutic antibodies.

<i>Salmonella</i> infection accelerates postnatal maturation of the intestinal epithelium

Postnatal establishment of enteric metabolic, host–microbial and immune homeostasis is the result of precisely timed and tightly regulated developmental and adaptive processes. Here, we show that infection with the invasive enteropathogen Salmonella Typhimurium results in accelerated maturation of the neonatal epithelium with premature appearance of antimicrobial, metabolic, developmental, and regenerative features of the adult tissue. Using conditional Myd88-deficient mice, we identify the critical contribution of immune cell-derived mediators. Cytokine stimulation of neonatal intestinal epithelial stem cell organoids suggests a network of synergistic and antagonistic cytokine effects with a significant contribution of IL-22, IL-4/IL-13, TNF, and IL-6 to infection-induced enterocyte reprogramming. Our findings demonstrate that the infection-associated immune cell activation disrupts physiological postnatal tissue maturation and may thereby worsen clinical outcomes and alter the neonatal-adult transition.

A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release

Neurotransmitter release is triggered in microseconds by Ca 2+ -binding to the Synaptotagmin-1 C 2 -domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca 2+ -sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C 2 B domain to SNARE complexes through a “primary interface” comprising two regions (I and II). The Synaptotagmin-1 Ca 2+ -binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca 2+ -binding loops away from the fusion site, hindering these putative activities. To clarify this paradox, we have used NMR and fluorescence spectroscopy. NMR experiments reveal that binding of C 2 B domain arginines to SNARE acidic residues at region II remains after disruption of region I, and that a mutation that impairs spontaneous and Ca 2+ -triggered neurotransmitter release enhances binding through region I. Moreover, fluorescence assays show that Ca 2+ does not induce dissociation of Synaptotagmin-1 from membrane-anchored SNARE complex but causes reorientation of the C 2 B domain. Based on these results and electrophysiological data described by Toulme et al. ( https://doi.org/10.1073/pnas.2409636121 ), we propose that upon Ca 2+ binding the Synaptotagmin-1 C 2 B domain reorients on the membrane and dissociates from the SNAREs at region I but not region II, acting remotely as a lever that pulls the SNARE complex and facilitates linker zippering or other SNARE structural changes required for fast membrane fusion.

Oncogenic IDH1 ^mut drives robust loss of histone acetylation and increases chromatin heterogeneity

Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2 mut ) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDH mut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.

US Corn Belt enhances regional precipitation recycling

Precipitation recycling, where evapotranspiration (ET) from the land surface contributes to precipitation within the same region, is a critical component of the water cycle. This process is especially important for the US Corn Belt, where extensive cropland expansions and irrigation activities have significantly transformed the landscape and affected the regional climate. Previous studies investigating precipitation recycling typically relied on analytical models with simplifying assumptions, overlooking the complex interactions between groundwater hydrology and agricultural management. In this study, we use high-resolution climate models coupled with an explicit water vapor tracer algorithm to quantify the impacts of shallow groundwater, dynamic crop growth, and irrigation on regional precipitation recycling in the US Corn Belt. We find that these coupled groundwater–crop–irrigation processes reduce surface temperatures and increase the growing season precipitation. The increase in precipitation is attributed to a significant enhancement of the precipitation recycling ratio from 14 to 18%. This enhanced precipitation recycling is stronger in a dry year than normal and wet years, depending on both large-scale moisture transport and local ET. Our study underscores the critical role of groundwater hydrology and agricultural management in altering the regional water cycle, with important implications for regional climate predictions and food and water security.

Deciphering the artificial evolution of domesticated plants within dynamic habitats

Development of precision medicine approaches to advance clinical trials for autism and social behavior: A research imperative

The return of stagnant slab recorded by intraplate volcanism

Subducted plates often stagnate in the mantle transition zone (MTZ), and the fate of the stagnant slabs is still debatable. They may sink into the lower mantle, or remain partially trapped in the MTZ, but it is uncertain whether they can return to the upper mantle. We report geochemical evidence of late-Miocene (~6 Ma) basalts from, and upper mantle seismic evidence beneath Shuangyashan, an area above the slab tear of the stagnant Pacific plate in eastern Asia, to show how the slab returns to the upper mantle from the MTZ. Remarkably high δ 57 Fe, Gd/Yb and low δ 26 Mg, Ti/Eu, CaO/Al 2 O 3 values of Shuangyashan basalts suggest that the subducted Pacific oceanic crust had been entrained to their upper mantle source. Therefore, the return of oceanic crust from the MTZ to the upper mantle appears to have been driven by upwelling triggered by tearing of the stagnant slab right beneath this area. Meanwhile, local shear splitting measurements reveal a circular pattern of anisotropy in the upper mantle with delay times diminishing toward the slab tear, suggesting that the slab-fragment-bearing upwelling subsequently turned into lateral flows in the upper mantle, and contributed to a wider intraplate magmatism above the stagnant slab. This finding, together with other widespread intraplate volcanism from eastern Asia, extending for approximately 6,000 km, demonstrates that a subduction-induced tear can lead to the destruction and partial return of stagnant slab material, and thus lead to the cycling of subducted crustal materials and the generation of subduction-induced intraplate magmatism.

Metastable state preceding shear zone instability: Implications for earthquake-accelerated landslides and dynamic triggering

Understanding the dynamic response of granular shear zones under cyclic loading is fundamental to elucidating the mechanisms triggering earthquake-induced landslides, with implications for broader fields such as seismology and granular physics. Existing prediction methods struggle to accurately predict many experimental and in situ landslide observations due to inadequate consideration of the underlying physical mechanisms. The mechanisms that influence landslide dynamic triggering, a transition from static (or extremely slow creeping) to rapid runout, remain elusive. Herein, we focus on the inherent physics of granular shear zones under dynamic loading using ring shear experiments. Except for coseismic slip caused by the dynamic load, varying magnitudes of postseismic creep with increasing cycles of dynamic loading are observed, highlighting the effects of coseismic weakening (shear zone fatigue) and subsequent postseismic healing. A metastable state, characterized by a significant increase in postseismic creep, typically precedes shear zone instability. The metastable state may arise as weakened shear resistance approaches the applied shear stress, demonstrating a phase transition from a solid-like state to a fluid state (plastic granular flow). The metastable state may potentially indicate the shear zone’s stress state and serve as a precursor to impending instability. Furthermore, the proposed mechanisms offer a compelling explanation for the widespread postseismic landslide movement following earthquakes. Incorporating these mechanisms into the Newmark method has the potential to improve the prediction of earthquake-induced landslide displacement and enhance our understanding of dynamic triggering.

How and why funders support engaged research

Research that better aligns policy, practice, and research communities is gaining momentum around the world. This includes engaged research strategies that bring partners, and their diverse perspectives and kinds of knowledge, together to shape research agendas with on-the-ground-needs and to create dynamic problem-solving processes. These approaches aim to generate more equitable and effective solutions to societal challenges. Although many of these partnered strategies have a longstanding history, entrenched research cultures, practices, and institutional structures stand in the way of scaling them. Given the outsized role funders play in shaping research efforts, funders are a critical lever for change. This perspective describes the efforts of a global collaborative of philanthropic and public funders who are adapting their practices, supporting the development of infrastructure (e.g., capacity-strengthening, facilitation expertise, processes to guide relational work, etc.), and targeting system-level challenges to enable engaged research to maximize its potential. The authors integrate insights from different issue areas, geographies, and funding areas to provide concrete examples of funder activities that support engaged research and to suggest areas for further action. Recommendations include scaling changes in funding practices, deepening understanding of how and when engaged research leads to improved outcomes, and reshaping how success is defined and measured.

Evidence for a metal–bosonic insulator–superconductor transition in compressed sulfur

The abrupt drop of resistance to zero at a critical temperature is a key signature of the current paradigm of the metal–superconductor transition. However, the emergence of an intermediate bosonic insulating state characterized by a resistance peak preceding the onset of the superconducting transition has challenged this traditional understanding. Notably, this phenomenon has been predominantly observed in disordered or chemically doped low-dimensional systems, raising intriguing questions about the generality of the effect and its underlying fundamental physics. Here, we present a systematic experimental study of compressed elemental sulfur, an undoped three-dimensional (3D) high-pressure superconductor, with detailed measurements of electrical resistance as a function of temperature, magnetic field, and current. The anomalous resistance peak observed in this 3D system is interpreted based on an empirical model of a metal–bosonic insulator–superconductor transition, potentially driven by vortex dynamics under magnetic field and energy dissipation processes. These findings offer a fresh platform for theoretical analysis of the decades-long enigmatic of the underlying mechanism of this phenomenon.

Comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and Tibetan highlanders during ascent to 4,300 m

With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid–base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid–base acclimatization (PCO 2 , [HCO 3 − ], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO 2 ( P &lt;0.0001) and [HCO 3 − ] ( P &lt;0.0001), and higher pH ( P = 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO 2 ( P &lt; 0.0001) and [HCO 3 − ] ( P &lt; 0.0001), but unchanged pH ( P = 0.1), suggesting full renal compensation, with significantly lower PCO 2 ( P = 0.01), [HCO 3 − ] ( P &lt; 0.0001) and pH ( P = 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization.

Integration of basal and apical embryo lineage regulators controls F-actin cable integrity and zygote asymmetry in <i>Arabidopsis</i>

In many plants, the asymmetric division of the zygote sets up the apical–basal body axis. In the cress Arabidopsis , the zygote coexpresses regulators of the apical and basal embryo lineages, the transcription factors WOX2 and WRKY2/WOX8, respectively. WRKY2/WOX8 activity promotes nuclear migration, cellular polarity, and mitotic asymmetry of the zygote, which are hallmarks of axis formation in many plant species. However, the role of WOX2 and how the antagonistic WOX2 and WRKY2/WOX8 functions are integrated in the zygote have remained a long-standing question. Here, we report that WOX2 loss-of-function completely suppresses the reduced zygote asymmetry of wrky2 mutants and that WOX2 overexpression mimics the wrky2 phenotype. At the molecular level, WRKY2 downregulates WOX2 transcription in the zygote and the basal embryo lineage, in addition to promoting WOX8 expression. WOX2 antagonizes WRKY2 function by repressing WOX8 transcription. As a physiological readout, the WRKY2/WOX8-WOX2 balance regulates the integrity of F-actin cables in the zygote, providing a mechanistic framework for the role of WRKY2/WOX8-WOX2-mediated zygote asymmetry.

Liquid-nano-liquid interface–oriented anisotropic encapsulation

Emulsion interface engineering has been widely employed for the synthesis of nanomaterials with various morphologies. However, the instability of the liquid–liquid interface and uncertain interfacial interactions impose significant limitations on controllable fabrications. Here, we developed a liquid-nano-liquid interface–oriented anisotropic encapsulation strategy for fabricating asymmetric nanohybrids. Specifically, functional nanoparticles such as magnetic nanoparticles, lanthanide fluorescent nanoparticles, and Au nanorods were anisotropically encapsulated by mesoporous polydopamine (mPDA). In this emulsion system, the wetting behavior of functional nanoparticles at the water/oil interface could be manipulated by the stabilizer of the emulsion (surfactant), leading to the anisotropic assembly of mPDA shell and resulting in various nanostructures, including core–shell, yolk–shell with small opening, ball-in-bowl, and multipetal structures. Due to their structural asymmetry, inherent magnetic properties, and photothermal properties, the ball-in-bowl structured Fe 3 O 4 @SiO 2 &amp;mPDA nanohybrids, serving as proof of concept for nanomotors, demonstrated effective penetration of bacterial biofilm and promotion of infected wound healing. Overall, our approach offers a different perspective for designing morphologically controllable asymmetric structures based on liquid-nano-liquid interface in microemulsion systems that hold great potential for establishing innovative functional nanomaterials.