Lithospheric erosion in the Patagonian slab window, and implications for glacial isostasy

Author Posting. © American Geophysical Union, 2022. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 49(2), (2022): e2021GL096863, https://doi.org/10.1029/2021GL096863.The Patagonian slab window has been proposed to enhance the solid Earth response to ice mass load changes in the overlying Northern and Southern Patagonian Icefields (NPI and SPI, respectively). Here, we present the first regional seismic velocity model covering the entire north-south extent of the slab window. A slow velocity anomaly in the uppermost mantle indicates warm mantle temperature, low viscosity, and possibly partial melt. Low velocities just below the Moho suggest that the lithospheric mantle has been thermally eroded over the youngest part of the slab window. The slowest part of the anomaly is north of 49°S, implying that the NPI and the northern SPI overlie lower viscosity mantle than the southern SPI. This comprehensive seismic mapping of the slab window provides key evidence supporting the previously hypothesized connection between post-Little Ice Age anthropogenic ice mass loss and rapid geodetically observed glacial isostatic uplift (≥4 cm/yr).The facilities of the IRIS Consortium are supported by the National Science Foundation’s SAGE Award under Cooperative Support Agreement EAR-1851048. The GUANACO project is funded by the National Science Foundation under grants EAR-1714154 to WUSTL and EAR-1714662 to SMU, and Erik R. Ivins was supported by NASA under grant NNH19ZDA001N-GRACEFO.2022-07-1

Observation-Driven Estimation of the Spatial Variability of 20th Century Sea Level Rise

Over the past two decades, sea level measurements made by satellites have given clear indications of both global and regional sea level rise. Numerous studies have sought to leverage the modern satellite record and available historic sea level data provided by tide gauges to estimate past sea level rise, leading to several estimates for the 20th century trend in global mean sea level in the range between 1 and 2 mm/yr. On regional scales, few attempts have been made to estimate trends over the same time period. This is due largely to the inhomogeneity and quality of the tide gauge network through the 20th century, which render commonly used reconstruction techniques inadequate. Here, a new approach is adopted, integrating data from a select set of tide gauges with prior estimates of spatial structure based on historical sea level forcing information from the major contributing processes over the past century. The resulting map of 20th century regional sea level rise is optimized to agree with the tide gauge-measured trends, and provides an indication of the likely contributions of different sources to regional patterns. Of equal importance, this study demonstrates the sensitivities of this regional trend map to current knowledge and uncertainty of the contributing processes

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Using plant wax markers to estimate the diet composition of grazing Holstein dairy cows

The objective of this study was to test whether diet selection of dairy cows under grazing conditions could be estimated using plant wax markers. Furthermore, differences between 2 cow strains and the effect of concentrate supplementation on plant species selection were investigated. The experiment was a study with a crossover design performed on an organic farm with 12 Swiss Holstein cows and 12 New Zealand Holstein cows. Both experimental periods consisted of a 21-d adaptation and a 7-d measurement period. All cows grazed full time in a rotational stocking system and received either no concentrate or 6 kg/d of a commercial cereal-grain mix. Representative herbage samples of each grazed paddock were taken and botanical composition of subsamples was manually determined. The average proportions of the plant species were 27.8% Lolium perenne, 6.1% Dactylis glomerata, 10.4% Trifolium repens, and 9.0% Taraxacum officinale. Other grass species were merged as "other grass" (38.2%) and other forb species as "other forbs" (8.5%). n-Alkanes, long-chain fatty acids, and long-chain alcohols (LCOH) were analyzed in the samples of plant species, concentrate, and feces from each cow. A linear discriminant analysis indicated that diet components were differentiated best with LCOH (96%) and worst with the combination of all marker groups together (12%). For each marker, the fecal marker recovery (FR) relative to dosed ytterbium was determined in 2 ways. Estimation of diet composition was performed with the software "EatWhat," and results were compared with botanical composition with the Aitchison distance. The results indicate that the diet composition of grazing dairy cows can be estimated using plant wax markers. Additionally, the calculation of FR led to mostly reliable results, yet this approach needs further validation. The most accurate estimation was achieved with the marker combination of n-alkanes and LCOH with a correction for FR. Less accurate estimations were achieved with long-chain fatty acids alone or in combination with n-alkanes. No difference relating to diet selection between the 2 cow strains was recorded, but supplemented cows apparently ingested higher proportions of T. repens than nonsupplemented cows. Awareness that supplementation influences selection behavior of grazing dairy cows may lead to adaptations in botanical composition of the pasture according to the demand of the animals

Who sleeps under bednets in Ghana? A doer/non-doer analysis of malaria prevention behaviours

BACKGROUND: Malaria prevention programmes should be based in part on knowledge of why some individuals use bednets while others do not. This paper identifies factors and characteristics of women that affect bednet use among their children less than five years of age in Ghana. METHODS: Data come from the baseline component of an evaluation of Freedom from Hunger's malaria curriculum. A quasi-experimental design was used to select clients (n = 516) of Credit with Education (an integrated package of microfinance and health education) and non-clients (n = 535). Chi-squares, Fisher's Exact tests and logistic regression were used to compare the characteristics of mothers whose children use bednets (doers) with those whose children do not (non-doers) and to identify factors associated with bednet use among children less than five years of age. RESULTS: The following factors were most closely associated with bednet use: region of residence; greater food security; and caregivers' beliefs about symptoms, causation and groups most vulnerable to malaria. Most respondents knew mosquitoes caused malaria; however, 20.6% of doers and 12.3% of non-doers (p = .0228) thought overworking oneself caused malaria. Ninety percent of doers and 77.0% of non-doers felt that sleeping under a net was protective against malaria (p = .0040). In addition, 16.5% of doers and 7.5% of non-doers (p = .0025) identified adult males as most vulnerable to malaria. CONCLUSION: Greater knowledge about malaria does not always translate into improved bednet use. Though culturally-based ideas about malaria may vary between communities, integrating them into traditional health education messages may enhance the effectiveness of public health efforts

MulTI-domain self-management in older People wiTh OstEoarthritis and multi-morbidities: protocol for the TIPTOE randomised controlled trial

Background Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone. Methods TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded ‘Study Within A Project’ (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups). Discussion TIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access. Trial registration ISRCTN 16024745. Registered on October 16, 2023

Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion and Differentiation through Integrins α2β1 and α3β1

BACKGROUND: Netrins have been extensively studied in the developing central nervous system as pathfinding guidance cues, and more recently in non-neural tissues where they mediate cell adhesion, migration and differentiation. Netrin-4, a distant relative of Netrins 1-3, has been proposed to affect cell fate determination in developing epithelia, though receptors mediating these functions have yet to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using human embryonic pancreatic cells as a model of developing epithelium, here we report that Netrin-4 is abundantly expressed in vascular endothelial cells and pancreatic ductal cells, and supports epithelial cell adhesion through integrins α2β1 and α3β1. Interestingly, we find that Netrin-4 recognition by embryonic pancreatic cells through integrins α2β1 and α3β1 promotes insulin and glucagon gene expression. In addition, full genome microarray analysis revealed that fetal pancreatic cell adhesion to Netrin-4 causes a prominent down-regulation of cyclins and up-regulation of negative regulators of the cell cycle. Consistent with these results, a number of other genes whose activities have been linked to developmental decisions and/or cellular differentiation are up-regulated. CONCLUSIONS/SIGNIFICANCE: Given the recognized function of blood vessels in epithelial tissue morphogenesis, our results provide a mechanism by which endothelial-derived Netrin-4 may function as a pro-differentiation cue for adjacent developing pancreatic cell populations expressing adhesion receptors α2β1 and α3β1 integrins

Transformation of Human Mesenchymal Cells and Skin Fibroblasts into Hematopoietic Cells

Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs) and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza) and the growth factors (GF) granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy

Modes of Aβ toxicity in Alzheimer’s disease

Alzheimer’s disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe