Explore the vast range of titles available.

Continental crust is buoyant compared with its oceanic counterpart and resists subduction into the mantle. When two continents collide, the mass balance for the continental crust is therefore assumed to be maintained. Here we use estimates of pre-collisional crustal thickness and convergence history derived from plate kinematic models to calculate the crustal mass balance in the India–Asia collisional system. Using the current best estimates for the timing of the diachronous onset of collision between India and Eurasia, we find that about 50% of the pre-collisional continental crustal mass cannot be accounted for in the crustal reservoir preserved at Earth’s surface today—represented by the mass preserved in the thickened crust that makes up the Himalaya, Tibet and much of adjacent Asia, as well as southeast Asian tectonic escape and exported eroded sediments. This implies large-scale subduction of continental crust during the collision, with a mass equivalent to about 15% of the total oceanic crustal subduction flux since 56 million years ago. We suggest that similar contamination of the mantle by direct input of radiogenic continental crustal materials during past continent–continent collisions is reflected in some ocean crust and ocean island basalt geochemistry. The subduction of continental crust may therefore contribute significantly to the evolution of mantle geochemistry. Buoyant continental crust is thought to resist subduction. Calculation of the crustal mass balance during the collision between India and Eurasia indicates that about 50% of pre-collisional continental crust has been subducted into the mantle.

Earth's topography arises from the linear superposition of isostatic and dynamic contributions. The isostatic contribution reflects the distribution of thickness and density of the crust overlying a static, non‐convecting mantle. We argue that isostatic topography should be limited to the crust, thereby delimiting all sources for dynamic topography below the Moho. Dynamic topography is the component of the topography produced by normal stresses acting on the Moho that deflect the isostatic topography away from crustal isostatic equilibrium largely as a consequence of mantle flow dynamics. These normal stresses arise from pressure variations and vertical gradients of the radial flow in the convecting mantle. The best estimate of dynamic topography is from the residual topography, which is the difference between observed topography and crustal isostatic topography. Dynamic and residual topography are the same. It is clear that thermal anomalies horizontally advected by plate motions would not exist if the mantle were not convecting, therefore their contribution to topography is inherently dynamic in origin. The global integral of dynamic topography that encompasses all non‐crustal buoyancy sources is demonstrated to be equal to zero. It follows that mantle convection cannot change the mean radius or mean elevation of the Earth. Since changes in ocean basin volume driven by changes in mean depth of the oceans are inherently part of dynamic topography, thereby requiring that continental elevations must also change, such that the global integral of these perturbations must also be equal to zero. This constraint has important implications for global long‐term sea level and the stratigraphic record, among other features of the Earth system impacted by changes in Earth's dynamic topography. Key Points Earth's topography arises from the linear superposition of crustal isostatic and dynamic contributions The global integral of dynamic topography that encompasses all non‐crustal buoyancy sources equals zero The best estimate of Earth's dynamic topography is the difference between observed and crustal isostatic topography

The elevation history of the Tibetan plateau provides direct insight into the tectonic processes associated with continent–continent collisions. Here we present oxygen-isotope-based estimates of the palaeo-altimetry of late Eocene and younger deposits of the Lunpola basin in the centre of the plateau, which indicate that the surface of Tibet has been at an elevation of more than 4 kilometres for at least the past 35 million years. We conclude that crustal, but not mantle, thickening models, combined with plate-kinematic solutions of India–Asia convergence, are compatible with palaeo-elevation estimates across the Tibetan plateau. A high old time in Tibet The Himalayan mountains are testament to the massive forces involved when continents collide, and the elevation history of the adjoining Tibetan plateau provides an extended record of the event. An analysis of palaeo-altitude at the centre of the Tibetan Plateau, using oxygen-isotope based measurements of carbonates, more than doubles the period of known existence of the central region of the plateau, to 35 million years. The surface elevation of Tibet has been more than 4 kilometres for all of that time. The new data are consistent with models that explain plateau uplift as a consequence of crustal thickening, rather than mantle thickening and convective removal

Significance Recruitment, proliferation, and differentiation of myofibroblasts are common in many disease states. Mechanisms that regulate proliferation and differentiation are poorly understood, although TGF-β is a key inducer of differentiation. Here, we report, for the first time to our knowledge, that runt-related transcription factor 1 (RUNX1) regulates mesenchymal stem cell (MSC) biology and progenitor cell commitment to myofibroblasts. In this work, we describe the first identification, to our knowledge, of tissue-resident MSCs from adult normal human prostate gland and the role of these MSCs as myofibroblast precursors. We also pinpoint the role of RUNX1 in regulating proliferation and differentiation in both marrow-derived and tissue-resident MSCs. Perturbation of RUNX1 activity may provide insights for developing antifibrotic and anticancer therapies via targeting the reactive stroma microenvironment. Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate-derived mesenchymal stem cells (MSCs) and the TGF-β1–regulated pathways that modulate MSC proliferation and myofibroblast differentiation. Human prostate MSCs combined with prostate cancer cells expressing TGF-β1 resulted in commitment to myofibroblasts. TGF-β1–regulated runt-related transcription factor 1 (RUNX1) was required for cell cycle progression and proliferation of progenitors. RUNX1 also inhibited, yet did not block, differentiation. Knockdown of RUNX1 in prostate or bone marrow-derived MSCs resulted in cell cycle arrest, attenuated proliferation, and constitutive differentiation to myofibroblasts. These data show that RUNX1 is a key transcription factor for MSC proliferation and cell fate commitment in myofibroblast differentiation. This work also shows that the normal human prostate gland contains tissue-derived MSCs that exhibit multilineage differentiation similar to bone marrow-derived MSCs. Targeting RUNX1 pathways may represent a therapeutic approach to affect myofibroblast proliferation and biology in multiple disease states.

Sedimentary rocks from Virginia through Florida record marine flooding during the mid-Pliocene. Several wave-cut scarps that at the time of deposition would have been horizontal are now draped over a warped surface with a maximum variation of 60 meters. We modeled dynamic topography by using mantle convection simulations that predict the amplitude and broad spatial distribution of this distortion. The results imply that dynamic topography and, to a lesser extent glacial isostatic adjustment account for the current architecture of the coastal plain and proximal shelf. This confounds attempts to use regional stratigraphie relations as references for longer-term sea-level determinations. Inferences of Pliocene global sea-level heights or stability of Antarctic ice sheets therefore cannot be deciphered in the absence of an appropriate mantle dynamic reference frame.

Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus.

On a spherical Earth, the mean elevation (approximately -2440 m) would be everywhere at a mean Earth radius from the center. This directly links an elevation at the surface to physical dimensions of Earth, including surface area and volume, which are at most very slowly evolving components of the Earth system. Earth's mean elevation thus provides a framework within which to consider changes in height of Earth's solid surface as a function of time. In this article, the focus will be on long-term, nonglacially controlled sea level. Long-term sea level has long been argued to be largely controlled by changes in ocean basin volume related to changes in the area-age distribution of oceanic lithosphere. As generally modeled by Walter Pitman and subsequent workers, the age-depth relationship of oceanic lithosphere, including both the ridge depth and the coefficients describing the age-depth relationship, are assumed constant. This article examines the consequences of adhering to these assumptions when placed within the larger framework of maintaining a constant mean radius of Earth. Self-consistent estimates of long-term sea level height and changes in the mean depth of the oceanic crust are derived from the assumption that the mean elevation and corresponding mean radius are unchanging aspects of Earth's shorter-term evolution. Within this context, changes in the mean depth of the oceanic crust, corresponding with changes in the mean age of oceanic lithosphere, acting over the area of the oceanic crust represent a volume change that is required to be balanced by a compensating equal but opposite volume change under the area of the continental crust. Models of cumulative paleohypsometry derived from a starting glacial isostatic adjustment (GIA)-corrected ice-free hypsometry that conserve mean elevation provide a basis for understanding how these compensating changes impact global hypsometry and particularly estimates of global mean shoreline height. Paleoshoreline height and areal extent of flooding can be defined as the height and corresponding cumulative area of the solid surface of Earth at which the integral of area as a function of elevation, from the maximum depth upward, equals the volume of ocean water filling it with respect to cumulative paleohypsometry. The present height of the paleoshoreline is the height on the GIA-corrected cumulative hypsometry at an area equal to the areal extent of flooding. Paleogeographic estimates of the global extent of ocean flooding from the Middle Jurassic to end Eocene, when combined with conservation of mean elevation and ocean water volume, allow an explicit estimate of the paleoheight and the present height of the paleoshoreline. The best-fitting estimate of the present height of the paleoshoreline, equivalent to a long-term \"eustatic\" sea level curve, implies very modest (25±22 m) changes in long-term sea level above the ice-free sea level height of approximately +40 m. These, in turn, imply quite limited changes in the mean depth of the oceanic crust (15±11 m) and in the mean age of the oceanic lithosphere (∼62.1±2.4 My) since the Middle Jurassic.

The oceanic age-depth relationship is a fundamental consequence of Earth's convective system. The new analysis presented here integrates four major data sets to assess the global age-depth distribution of the oceanic lithosphere. First, the distribution of depths along the modern mid-oceanic-ridge axis was obtained using an updated digitized divergent plate-boundary data set for the main ocean basins. Mid-ocean ridges vary in depth by ∼8 km, from -6453 m to +1998 m, with a median depth of -3000 m, modal depth of -2670 m (with a second mode at -2770 m), and area-weighted mean depth of -3044 m. Ridge depth has some correlation with spreading rate up to about 50 mm/yr if the hotspot-impacted North Atlantic and Sheba Ridges are excluded. Second, zero-age crustal thickness, based on a compilation of ∼1000 estimates, was used to test the relationship of oceanic crustal thickness with axial depth. There is some correlation, but it is not a compact correlation, implying that other processes are contributing to both axial depth and crustal thickness variations. Third, a revised sediment-load correction is presented based on assessment of 9,260,185 records from 1263 deep-sea drilling sites with wet bulk density measurements. This can be extrapolated to thicknesses in excess of 8000 m, with an exponential porosity-depth relationship with an initial porosity of φ0 = 0.61. Dispersion of integrated wet bulk density measurement-derived sediment-load corrections for the 1263 sites implies ∼±100 m uncertainty in the sediment-load correction at 1300 m sediment thickness. Fourth, the age-depth relationship of oceanic lithosphere was derived based on sediment-load corrected depths of ∼90,000 explicitly dated, globally distributed magnetic reversal picks restricted to the main ocean basins and filtered to exclude large igneous provinces and trench-impacted locations. A best-fit global age-median sediment-corrected depth relationship was derived using a plate model with zero-age ridge depth of -2309 m, temperature difference of 1304 °C, and asymptotic plate thickness of 122 km. The dispersion of sediment-load corrected depths as a function of age is comparable to that observed along the mid-oceanic-ridge system, suggesting that zero-age depths contribute to dispersion at all ages. This is borne out for oceanic lithosphere at relatively young ages (ca. <70 Ma), but the dispersion at older ages appears to be dominated by superposition of hotspots and other large-scale perturbations. In addition, a comparison was made with various vintages of age-grid-derived age-depth distributions, as well as previous age-depth models. The implied age-depth relationship using older versions of the age grid deviates significantly from the age-depth relationship obtained using the magnetic reversal picks alone. There is considerable disparity between pick ages and corresponding grid cell ages for these data sets. In contrast, the most recent age grid (2016) more closely matches the age-depth relationship derived here and shows significantly less disparity with magnetic reversal pick ages. A qualitative suggestion is made that the deviation of the age-depth relationship from a half-space cooling to exponential model reflects the advective contribution of asthenospheric flow associated with asthenospheric tractions contributing to plate-driving forces.

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.