A subset of the sinuous ridges (SRs) in the Aeolis/Zephyria Plana (AZP) region of Mars has been previously hypothesized to be inverted fluvial features, although the precise induration and erosion ...mechanisms were not specified. Morphological observations and thermal inertia data presented here support this hypothesis. A variety of mechanisms can cause inversion, and identification of the specific events that lead to fluvial SR formation can provide insights into the sedimentological, geochemical, and climatic processes of the region. Reconnaissance of two terrestrial lava‐capped ridges suggests some criteria that may be used to identify inverted fluvial features formed by lava infill on Mars, but these criteria are not satisfied by the majority of the AZP fluvial SRs. Armoring also appears inconsistent with terrestrial analogs. Layering and surface textures of fluvial SRs indicate that the most likely induration mechanism was geochemical cementation of fluvial sediments, and that the primary erosional mechanism that exposed the fluvial SRs was aeolian abrasion. This analysis of formation mechanism provides a foundation for estimating paleodischarge using an empirical form‐discharge approach, to which we have applied scaling, for Martian gravity. For those fluvial SRs meeting a set of criteria for accurate paleodischarge estimates, paleodischarge values generally range between 101 and 103 m3 s−1. The largest of these initial estimates are comparable to paleodischarge estimates for some late‐stage Noachian fluvial channels on Mars, and provide a constraint on the atmospheric conditions at this equatorial location during the late Hesperian to early Amazonian time frame.
The clinical effectiveness of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear.
We linked ...4 national registries to retrospectively identify laboratory-confirmed SARS-CoV-2 infections and deaths within 28 d in England between September 1, 2020, and August 31, 2021, comparing unvaccinated adult SOT recipients and those who had received 2 doses of ChAdOx1-S or BNT162b2 vaccine. Infection incidence rate ratios were adjusted for recipient demographics and calendar month using a negative binomial regression model, with 95% confidence intervals. Case fatality rate ratios were adjusted using a Cox proportional hazards model to generate hazard ratio (95% confidence interval).
On August 31, 2021, it was found that 3080 (7.1%) were unvaccinated, 1141 (2.6%) had 1 vaccine dose, and 39 260 (90.3%) had 2 vaccine doses. There were 4147 SARS-CoV-2 infections and 407 deaths (unadjusted case fatality rate 9.8%). The risk-adjusted infection incidence rate ratio was 1.29 (1.03-1.61), implying that vaccination was not associated with reduction in risk of testing positive for SARS-CoV-2 RNA. Overall, the hazard ratio for death within 28 d of SARS-CoV-2 infection was 0.80 (0.63-1.00), a 20% reduction in risk of death in vaccinated patients (P = 0.05). Two doses of ChAdOx1-S were associated with a significantly reduced risk of death (hazard ratio, 0.69; 0.52-0.92), whereas vaccination with BNT162b2 was not (0.97; 0.71-1.31).
Vaccination of SOT recipients confers some protection against SARS-CoV-2-related mortality, but this protection is inferior to that achieved in the general population. SOT recipients require additional protective measures, including further vaccine doses, antiviral drugs, and nonpharmaceutical interventions.
Numerous studies have described the effects of matrix stiffening on cell behavior using two-dimensional synthetic surfaces; however, less is known about the effects of matrix stiffening on cells ...embedded in three-dimensional in vivo-like matrices. A primary limitation in investigating the effects of matrix stiffness in three dimensions is the lack of materials that can be tuned to control stiffness independently of matrix density. Here, we use collagen-based scaffolds where the mechanical properties are tuned using non-enzymatic glycation of the collagen in solution, prior to polymerization. Collagen solutions glycated prior to polymerization result in collagen gels with a threefold increase in compressive modulus without significant changes to the collagen architecture. Using these scaffolds, we show that endothelial cell spreading increases with matrix stiffness, as does the number and length of angiogenic sprouts and the overall spheroid outgrowth. Differences in sprout length are maintained even when the receptor for advanced glycation end products is inhibited. Our results demonstrate the ability to de-couple matrix stiffness from matrix density and structure in collagen gels, and that increased matrix stiffness results in increased sprouting and outgrowth.
Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the ...hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
Rapid growth and perivascular invasion are hallmarks of glioblastoma (GBM) that have been attributed to the presence of cancer stem-like cells (CSCs) and their association with the perivascular ...niche. However, the mechanisms by which the perivascular niche regulates GBM invasion and CSCs remain poorly understood due in part to a lack of relevant model systems. To simulate perivascular niche conditions and analyze consequential changes of GBM growth and invasion, patient-derived GBM spheroids were co-cultured with brain endothelial cells (ECs) in microfabricated collagen gels. Integrating these systems with 3D imaging and biochemical assays revealed that ECs increase GBM invasiveness and growth through interleukin-8 (IL-8)-mediated enrichment of CSCs. Blockade of IL-8 inhibited these effects in GBM-EC co-cultures, while IL-8 supplementation increased CSC-mediated growth and invasion in GBM-monocultures. Experiments in mice confirmed that ECs and IL-8 stimulate intracranial tumor growth and invasion in vivo. Collectively, perivascular niche conditions promote GBM growth and invasion by increasing CSC frequency, and IL-8 may be explored clinically to inhibit these interactions.
The landing site for the Curiosity rover is located at the distal end of the Peace Vallis fan in Gale Crater. Peace Vallis fan covers 80 km2 and is fed by a 730 km2 catchment, which drains an upland ...plains area through a 15 km wide gap in the crater rim. Valley incision into accumulated debris delivered sediment through a relatively low density valley network to a main stem channel to the fan. An estimated total fan volume of 0.9 km3 matches the calculated volume of removal due to valley incision (0.8 km3) and indicates a mean thickness of 9 m. The fan profile is weakly concave up with a mean slope of 1.5% for the lower portion. Numerous inverted channels outcrop on the western surface of the fan, but on the eastern portion such channels are rare suggesting a change in process from distributary channel domination on the west to sheet flow on the eastern portion of the fan. Runoff (discharge/watershed area) to produce the fan is estimated to be more than 600 m, perhaps as much as 6000 m, indicating a hydrologic cycle that likely lasted at least thousands of years. Atmospheric precipitation (possibly snow) not seepage produced the runoff. Based on topographic data, Peace Vallis fan likely onlapped Bradbury Rise and spilled into a topographic low to the east of the rise. This argues that the light‐toned fractured terrain within this topographic low corresponds to the distal deposits of Peace Vallis fan, and in such a setting, lacustrine deposits are expected.
Key Points
Distal end of Peace Vallis fan was near MSL landing
Sediment in the fan was derived from valley incision into colluvium
Fan morphology consistent with fluvial processes
Fibrillar collagen, being highly noncentrosymmetric, possesses a tremendous nonlinear susceptibility. As a result, second-harmonic generation (SHG) microscopy of collagen produces extremely bright ...and robust signals, providing an invaluable tool for imaging tissue structure with submicron resolution. Here we discuss fundamental principles governing SHG phase matching with the tightly focusing optics used in microscopy. Their application to collagen imaging yields several biophysical features characteristic of native collagen structure: SHG radiates from the shell of a collagen fibril, rather than from its bulk. This SHG shell may correspond to the supporting element of the fibril. Physiologically relevant changes in solution ionic strength alter the ratio of forward-to-backward propagating SHG, implying a resulting change in the SHG shell thickness. Fibrillogenesis can be resolved in immature tissue by directly imaging backward-propagating SHG. Such findings are crucial to the design and development of forthcoming diagnostic and research tools.
Robustness to perturbation is a fundamental feature of complex organisms. Mutations are the raw material for evolution, yet robustness to their effects is required for species survival. The ...mechanisms that produce robustness are poorly understood. Nonlinearities are a ubiquitous feature of development that may link variation in development to phenotypic robustness. Here, we manipulate the gene dosage of a signaling molecule, Fgf8, a critical regulator of vertebrate development. We demonstrate that variation in Fgf8 expression has a nonlinear relationship to phenotypic variation, predicting levels of robustness among genotypes. Differences in robustness are not due to gene expression variance or dysregulation, but emerge from the nonlinearity of the genotype-phenotype curve. In this instance, embedded features of development explain robustness differences. How such features vary in natural populations and relate to genetic variation are key questions for unraveling the origin and evolvability of this feature of organismal development.
Values of the public are a key and dynamic component of bushfire governance SES. Learning to work with these values is a significant challenge for government and environmental managers and an ...important aspect of policy transition in many contexts. During such transitions, collaborative research can play a key role in social learning, but this may be particularly challenging for agencies with dominant expertise in technical and ecological domains. We examined how collaborative research supported social learning to incorporate values of the public in bushfire governance in the State of Victoria, Australia. Following disruption of a major bushfire, new policy directions were established, including greater attention to expectations and participation of communities in bushfire management. Among other actions, the state environmental agency supported this policy transition by establishing a 3-year research collaboration to better understand and incorporate values of the public in their decision making. As both participants and observers of this research, we analyzed publications, unpublished internal reports, and notes from meetings and workshops to identify how the collaborative research facilitated and constrained learning. Analysis revealed how collaborative research presents interruptions in the form of questioning of plans and routines (including of researchers), joint concept development, collection and sharing of new information, tensions within the research collaboration, idea generation building on research insights, and action research to develop new tools or frameworks. These forms of disruption operated in different ways, involving different groups of actors, levels of collaboration, and opportunities for feedback, and these in turn had implications for the forms of learning that occurred. Collaborative research also identified constraints to learning that, in some instances, set the stage for further learning, for example through capacity building and further research.
Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the ...development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two- and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma.
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