Observed crustal uplift near the Southern Patagonian Icefield constrains improved viscoelastic Earth model

Thirty‒one GPS geodetic measurements of crustal uplift in southernmost South America determined extraordinarily high trend rates (> 35 mm/yr) in the north‒central part of the Southern Patagonian Icefield. These trends have a coherent pattern, motivating a refined viscoelastic glacial isostatic adjustment model to explain the observations. Two end‒member models provide good fits: both require a lithospheric thickness of 36.5 ± 5.3 km. However, one end‒member has a mantle viscosity near η =1.6 ×1018 Pa s and an ice collapse rate from the Little Ice Age (LIA) maximum comparable to a lowest recent estimate of 1995–2012 ice loss at about −11 Gt/yr. In contrast, the other end‒member has much larger viscosity: η = 8.0 ×1018 Pa s, half the post–LIA collapse rate, and a steadily rising loss rate in the twentieth century after AD 1943, reaching −25.9 Gt/yr during 1995–2012.Fil: Lange, H.. Technische Universitaet Dresden; AlemaniaFil: Casassa, G.. Centro de Estudios Cientificos; Chile. Universidad de Magallanes; ChileFil: Ivins, E. R.. Institute of Technology. Jet propulsion Laboratory; Estados UnidosFil: Schroeder, L.. Technische Universitaet Dresden; AlemaniaFil: Fritsche, M.. Technische Universitaet Dresden; AlemaniaFil: Richter, Andreas Jorg. Technische Universitaet Dresden; Alemania. Universidad Nacional de la Plata. Facultad de Ciencias Astronómicas y Geofísicas. Departamento de Astrometría; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Groh, A.. Technische Universitaet Dresden; AlemaniaFil: Dietrich, R.. Technische Universitaet Dresden; Alemani

Future Antarctic bed topography and its implications for ice sheet dynamics

The Antarctic bedrock is evolving as the solid Earth responds to the past and ongoing evolution of the ice sheet. A recently improved ice loading history suggests that the Antarctic Ice Sheet (AIS) has generally been losing its mass since the Last Glacial Maximum. In a sustained warming climate, the AIS is predicted to retreat at a greater pace, primarily via melting beneath the ice shelves. We employ the glacial isostatic adjustment (GIA) capability of the Ice Sheet System Model (ISSM) to combine these past and future ice loadings and provide the new solid Earth computations for the AIS. We find that past loading is relatively less important than future loading for the evolution of the future bed topography. Our computations predict that the West Antarctic Ice Sheet (WAIS) may uplift by a few meters and a few tens of meters at years AD 2100 and 2500, respectively, and that the East Antarctic Ice Sheet is likely to remain unchanged or subside minimally except around the Amery Ice Shelf. The Amundsen Sea Sector in particular is predicted to rise at the greatest rate; one hundred years of ice evolution in this region, for example, predicts that the coastline of Pine Island Bay will approach roughly 45 mm yr−1 in viscoelastic vertical motion. Of particular importance, we systematically demonstrate that the effect of a pervasive and large GIA uplift in the WAIS is generally associated with the flattening of reverse bed slope, reduction of local sea depth, and thus the extension of grounding line (GL) towards the continental shelf. Using the 3-D higher-order ice flow capability of ISSM, such a migration of GL is shown to inhibit the ice flow. This negative feedback between the ice sheet and the solid Earth may promote stability in marine portions of the ice sheet in the future

Observed crustal uplift near the Southern Patagonian Icefield constrains improved viscoelastic Earth model

Thirty‒one GPS geodetic measurements of crustal uplift in southernmost South America determined extraordinarily high trend rates (> 35 mm/yr) in the north‒central part of the Southern Patagonian Icefield. These trends have a coherent pattern, motivating a refined viscoelastic glacial isostatic adjustment model to explain the observations. Two end‒member models provide good fits: both require a lithospheric thickness of 36.5 ± 5.3 km. However, one end‒member has a mantle viscosity near η =1.6 ×1018 Pa s and an ice collapse rate from the Little Ice Age (LIA) maximum comparable to a lowest recent estimate of 1995–2012 ice loss at about −11 Gt/yr. In contrast, the other end‒member has much larger viscosity: η = 8.0 ×1018 Pa s, half the post–LIA collapse rate, and a steadily rising loss rate in the twentieth century after AD 1943, reaching −25.9 Gt/yr during 1995–2012.Facultad de Ciencias Astronómicas y Geofísica

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

Argonne National Laboratory Report ANL-76-9

Progress report describing the research and management efforts of Argonne National Laboratory's program on high-performance lithium/metal sulfide batteries during the period July-December 1975. The batteries are being developed for two applications: off-peak energy storage in electric utility networks and electric-vehicle propulsion. The battery designs for the two applications differ, particularly in cell configuration and electrode design because of the differing performance requirements

Automated virtual reality cognitive therapy versus virtual reality mental relaxation therapy for the treatment of persistent persecutory delusions in patients with psychosis (THRIVE): a parallel-group, single-blind, randomised controlled trial in England with mediation analyses

Background: Persecutory delusions are a major psychiatric problem that often do not respond sufficiently to standard pharmacological or psychological treatments. We developed a new brief automated virtual reality (VR) cognitive treatment that has the potential to be used easily in clinical services. We aimed to compare VR cognitive therapy with an alternative VR therapy (mental relaxation), with an emphasis on understanding potential mechanisms of action. Methods: THRIVE was a parallel-group, single-blind, randomised controlled trial across four UK National Health Service trusts in England. Participants were included if they were aged 16 years or older, had a persistent (at least 3 months) persecutory delusion held with at least 50% conviction, reported feeling threatened when outside with other people, and had a primary diagnosis from the referring clinical team of a non-affective psychotic disorder. We randomly assigned (1:1) patients to either THRIVE VR cognitive therapy or VR mental relaxation, using a permuted blocks algorithm with randomly varying block size, stratified by severity of delusion. Usual care continued for all participants. Each VR therapy was provided in four sessions over approximately 4 weeks, supported by an assistant psychologist or clinical psychologist. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 2 (therapy mid-point), 4 (primary endpoint, end of treatment), 8, 16, and 24 weeks. The primary outcome was persecutory delusion conviction, assessed by the Psychotic Symptoms Rating Scale (PSYRATS; rated 0–100%). Outcome analyses were done in the intention-to-treat population. We assessed the treatment credibility and expectancy of the interventions and the two mechanisms (defence behaviours and safety beliefs) that the cognitive intervention was designed to target. This trial is prospectively registered with the ISRCTN registry, ISRCTN12497310. Findings: From Sept 21, 2018, to May 13, 2021 (with a pause due to COVID-19 pandemic restrictions from March 16, 2020, to Sept 14, 2020), we recruited 80 participants with persistent persecutory delusions (49 [61%] men, 31 [39%] women, with a mean age of 40 years [SD 13, range 18–73], 64 [80%] White, six [8%] Black, one [1%] Indian, three [4%] Pakistani, and six [8%] other race or ethnicity). We randomly assigned 39 (49%) participants assigned to VR cognitive therapy and 41 (51%) participants to VR mental relaxation. 33 (85%) participants who were assigned to VR cognitive therapy attended all four sessions, and 35 (85%) participants assigned to VR mental relaxation attended all four sessions. We found no significant differences between the two VR interventions in participant ratings of treatment credibility (adjusted mean difference –1·55 [95% CI –3·68 to 0·58]; p=0·15) and outcome expectancy (–0·91 [–3·42 to 1·61]; p=0·47). 77 (96%) participants provided follow-up data at the primary timepoint. Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater improvement in persecutory delusions (adjusted mean difference –2·16 [–12·77 to 8·44]; p=0·69). Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater reduction in use of defence behaviours (adjusted mean difference –0·71 [–4·21 to 2·79]; p=0·69) or a greater increase in belief in safety (–5·89 [–16·83 to 5·05]; p=0·29). There were 17 serious adverse events unrelated to the trial (ten events in seven participants in the VR cognitive therapy group and seven events in five participants in the VR mental relaxation group). Interpretation: The two VR interventions performed similarly, despite the fact that they had been designed to affect different mechanisms. Both interventions had high uptake rates and were associated with large improvements in persecutory delusions but it cannot be determined that the treatments accounted for the change. Immersive technologies hold promise for the treatment of severe mental health problems. However, their use will likely benefit from experimental research on the application of different therapeutic techniques and the effects on a range of potential mechanisms of action. Funding: Medical Research Council Developmental Pathway Funding Scheme and National Institute for Health and Care Research Oxford Health Biomedical Research Centre

An attenuated strain of Bacillus anthracis (CDC 684) has a large chromosomal inversion and altered growth kinetics

BackgroundAn isolate originally labeled Bacillus megaterium CDC 684 was found to contain both pXO1 and pXO2, was non-hemolytic, sensitive to gamma-phage, and produced both the protective antigen and the poly-D-glutamic acid capsule. These phenotypes prompted Ezzell et al., (J. Clin. Microbiol. 28:223) to reclassify this isolate to Bacillus anthracis in 1990.ResultsWe demonstrate that despite these B. anthracis features, the isolate is severely attenuated in a guinea pig model. This prompted whole genome sequencing and closure. The comparative analysis of CDC 684 to other sequenced B. anthracis isolates and further analysis reveals: a) CDC 684 is a close relative of a virulent strain, Vollum A0488; b) CDC 684 defines a new B. anthracis lineage (at least 51 SNPs) that includes 15 other isolates; c) the genome of CDC 684 contains a large chromosomal inversion that spans 3.3 Mbp; d) this inversion has caused a displacement of the usual spatial orientation of the origin of replication (ori) to the termination of replication (ter) from 180° in wild-type B. anthracis to 120° in CDC 684 and e) this isolate also has altered growth kinetics in liquid media.ConclusionsWe propose two alternative hypotheses explaining the attenuated phenotype of this isolate. Hypothesis 1 suggests that the skewed ori/ter relationship in CDC 684 has altered its DNA replication and/or transcriptome processes resulting in altered growth kinetics and virulence capacity. Hypothesis 2 suggests that one or more of the single nucleotide polymorphisms in CDC 684 has altered the expression of a regulatory element or other genes necessary for virulence

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

Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae

Background Chlamydophila (Chlamydia) pneumoniae is an intracellular bacterium that has been identified within cells in areas of neuropathology found in Alzheimer disease (AD), including endothelia, glia, and neurons. Depending on the cell type of the host, infection by C. pneumoniae has been shown to influence apoptotic pathways in both pro- and anti-apoptotic fashions. We have hypothesized that persistent chlamydial infection of neurons may be an important mediator of the characteristic neuropathology observed in AD brains. Chronic and/or persistent infection of neuronal cells with C. pneumoniae in the AD brain may affect apoptosis in cells containing chlamydial inclusions. Results SK-N-MC neuroblastoma cells were infected with the respiratory strain of C. pneumoniae, AR39 at an MOI of 1. Following infection, the cells were either untreated or treated with staurosporine and then examined for apoptosis by labeling for nuclear fragmentation, caspase activity, and membrane inversion as indicated by annexin V staining. C. pneumoniae infection was maintained through 10 days post-infection. At 3 and 10 days post-infection, the infected cell cultures appeared to inhibit or were resistant to the apoptotic process when induced by staurosporine. This inhibition was demonstrated quantitatively by nuclear profile counts and caspase 3/7 activity measurements. Conclusion These data suggest that C. pneumoniae can sustain a chronic infection in neuronal cells by interfering with apoptosis, which may contribute to chronic inflammation in the AD brai