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Mountains are vital water sources for humans and ecosystems, continuously replenishing lowland aquifers through surface runoff and mountain recharge. Quantifying these fluxes and their relative importance is essential for sustainable water resource management. However, our mechanistic understanding of the flow and transport processes determining the connection between the mountain block and the basin aquifer remains limited. Traditional conceptualizations assume groundwater circulation within the mountain block is predominantly shallow. This view neglects the role of deep groundwater flowpaths significantly contributing to the water, solute, and energy budgets. Overcoming these limitations requires a holistic characterization of the multiscale nature of groundwater flow along the mountain‐to‐valley continuum. As a proof‐of‐concept, we use a coupled groundwater flow and transport model to design a series of numerical experiments that explore the role of geology, topography, and weathering rates in groundwater circulation and their resulting resistivity patterns. Our results show that accumulating solutes near stagnation zones create contrasting electrical resistivity patterns that separate local, intermediate, and regional flow cells, presenting a target for magnetotelluric observations. To demonstrate the sensitivity of magnetotelluric data to features in our resistivity models, we use the MARE2DEM electromagnetic modeling code to perform forward and inverse simulations. This study highlights the potential of magnetotelluric surveys to image the resistivity structure resulting from multiscale groundwater circulation through relatively impervious crystalline basement rocks in mountainous terrains. This capability could change our understanding of the critical zone, offering a holistic perspective that includes deep groundwater circulation and its role in conveying solutes and energy. Mountains are vital water sources for humans and ecosystems, continuously replenishing lowland aquifers through surface runoff and mountain recharge. Quantifying these fluxes and their relative importance is essential for sustainable water resource management. Here, we present a novel approach to characterize the nested nature of groundwater flow along the mountain‐to‐valley continuum by combining flow and transport models and magnetotelluric (MT) geophysical surveys. We assess the approach’s potential by creating virtual realities that mimic realistic patterns of subsurface electrical resistivity. Then, using an inverse modeling approach, we test the ability of different MT survey configurations to reconstruct the resistivity fields. Our analysis shows that the accumulation of solutes in subsurface low‐velocity zones (i.e., stagnation zones) results in resistivity fields with enough contrast to image the local, intermediate, and regional groundwater flow cells. While this study is conceptual in nature, we aim to offer a framework for geophysical exploration that can characterize the critical zone without neglecting deep groundwater circulation and its role in conveying solutes and energy. We use a coupled flow and transport model to explore the role of deep groundwater circulation in mountain‐to‐valley systemsRegional groundwater circulation conveys significant amounts of water, energy, and solutes through relatively impervious depthsMagnetotelluric surveys can potentially map the resistivity patterns created by the solute concentration patterns within the mountain block We use a coupled flow and transport model to explore the role of deep groundwater circulation in mountain‐to‐valley systems Regional groundwater circulation conveys significant amounts of water, energy, and solutes through relatively impervious depths Magnetotelluric surveys can potentially map the resistivity patterns created by the solute concentration patterns within the mountain block

Zircon (U‐Th)/He (ZHe) and zircon fission track thermochronometric data for 47 samples spanning the areally extensive Willard thrust sheet within the western part of the Sevier fold‐thrust belt record enhanced cooling and exhumation during major thrust slip spanning approximately 125–90 Ma. ZHe and zircon fission track age‐paleodepth patterns along structural transects and age‐distance relations along stratigraphic‐parallel traverses, combined with thermo‐kinematic modeling, constrain the fault slip history, with estimated slip rates of ~1 km/Myr from 125 to 105 Ma, increasing to ~3 km/Myr from 105 to 92 Ma, and then decreasing as major slip was transferred onto eastern thrusts. Exhumation was concentrated during motion up thrust ramps with estimated erosion rates of ~0.1 to 0.3 km/Myr. Local cooling ages of approximately 160–150 Ma may record a period of regional erosion, or alternatively an early phase of limited (<10 km) thrust slip. Propagation of the Sevier wedge front and major thrust slip during the late Early to mid‐Cretaceous were synchronous with increasing subsidence and deposition of thick synorogenic strata in the foreland, crustal thickening in the hinterland, growing igneous activity in the Sierran magmatic arc, and increasing plate convergence rates. Along‐strike, other parts of the Cordilleran retroarc fold‐thrust belt also experienced major shortening during the late Early to mid‐Cretaceous, following a period of earlier Cretaceous quiescence. Late Jurassic shortening was concentrated nearer the arc, and thus mostly in the hinterland at the latitude of northern Utah, related to width and location of the passive‐margin sedimentary wedge relative to the plate margin. New thermochronometric data constrain the fault slip and exhumation history of the Willard thrust sheet, western Sevier beltMajor slip on the Willard thrust from 125 to 90 Ma was synchronous with increased foreland sedimentation and hinterland crustal thickeningFault‐slip histories of dominant thrust sheets in the Sevier belt reflect evolving plate margin dynamics and primary crustal architecture

Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability.

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+intestinal stem cells (ISCs). R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD–LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

The engineering of broadband absorbers to harvest white light in thin-film semiconductors is a major challenge in developing renewable materials for energy harvesting. Many solution-processed materials with high manufacturability and low cost, such as semiconductor quantum dots, require the use of film structures with thicknesses on the order of 1 μm to absorb incoming photons completely. The electron transport lengths in these media, however, are 1 order of magnitude smaller than this length, hampering further progress with this platform. Herein, we show that, by engineering suitably disordered nanoplasmonic structures, we have created a new class of dispersionless epsilon-near-zero composite materials that efficiently harness white light. Our nanostructures localize light in the dielectric region outside the epsilon-near-zero material with characteristic lengths of 10–100 nm, resulting in an efficient system for harvesting broadband light when a thin absorptive film is deposited on top of the structure. By using a combination of theory and experiments, we demonstrate that ultrathin layers down to 50 nm of colloidal quantum dots deposited atop the epsilon-near-zero material show an increase in broadband absorption ranging from 200% to 500% compared to a planar structure of the same colloidal quantum-dot-absorber average thickness. When the epsilon-near-zero nanostructures were used in an energy-harvesting module, we observed a spectrally averaged 170% broadband increase in the external quantum efficiency of the device, measured at wavelengths between 400 and 1200 nm. Atomic force microscopy and photoluminescence excitation measurements demonstrate that the properties of these epsilon-near-zero structures apply to general metals and could be used to enhance the near-field absorption of semiconductor structures more widely. We have developed an inexpensive electrochemical deposition process that enables scaled-up production of this nanomaterial for large-scale energy-harvesting applications.

A critical step in the pathogenesis of acute lung injury (ALI) is excessive recruitment of polymorphonuclear neutrophils (PMNs) into the lungs, causing significant collateral tissue damage. Defining the molecular and cellular steps that control neutrophil infiltration and activation during ALI is therefore of important therapeutic relevance. Based on previous findings implicating the transcription factor Tbet in mucosal Th1-inflammation, we hypothesized a detrimental role for Tbet during ALI. In line with our hypothesis, initial studies of endotoxin-induced lung injury revealed a marked protection of Tbet-/-mice, including attenuated neutrophilia compared to WT counterparts. Surprisingly, subsequent studies identified natural killer (NK) cells as the major source of pulmonary Tbet during ALI. In addition, a chemokine screen suggested that mature Tbet+NK-cells are critical for the production of pulmonary CXCL1 and -2, thereby contributing to pulmonary PMN recruitment. Indeed, both NK-cell Ab depletion and adoptive transfer studies provide evidence for NK cells in the orchestration of neutrophil recruitment during endotoxin-induced ALI. Taken together, these findings identify a novel role for Tbet+NK-cells in initiating the early events of noninfectious pulmonary inflammation.