Impact of spatial resolution on large-scale ice cover modeling of mountainous regions

For reconstructing paleoclimate or studying glacial isostatic effects on the Earth’s lithosphere, increasingly more studies focus on modeling the large-scale ice cover in mountainous regions over long time scales. However, balancing model complexity and the spatial extent with computational costs is challenging. Previous studies of large-scale ice cover simulation in mountain areas such as the European Alps, New Zealand, and the Tibetan Plateau, typically used 1-2 km spatial resolution. However, mountains are characterized by high peaks and steep slopes - topographic features that are crucial for glacier mass balance and dynamics, but poorly resolved in coarse resolution topography. The Instructed Glacier Model (IGM) is a novel 3D ice model equipped with a physics-informed neural network to simulate ice flow. This results in a significant acceleration of run times, and thereby opening the possibility of higher spatial resolution runs. We use IGM to model the glaciation of the European Alps with different resolutions (2 km and 200 m) over a time period of 160,000 years. We apply a linear cooling rate to present-day climate until 6 °C colder to mimic ice age conditions. Preliminary results indicate systematic, resolution-related differences: At the beginning of cooling the 2 km resolution yields slightly more ice volume. However, this trend reverses when ice flows together from high elevations and fill large valleys with thick ice. When the Alps are fully ice covered, we find up to 14% more ice volume in the higher resolution models which, however, is not uniformly distributed in space

Contractual Interpretation

This article starts with some general points about the interpretation of contracts, before discussing in more detail the methodology of interpretation and, in particular, the modern purposive approach to interpretation with its greater use of extrinsic aids to interpretation

Glacial and erosional contributions to Late Quaternary uplift of the European Alps (GEOLQUEA)

Isostatic adjustments of the Earth’s surface to changes in water, ice, and sediment loading are important contributions to present-day uplift/subsidence rates in many regions on Earth. In the absence of significant horizontal tectonic shortening in the central and western parts of the European Alps, uplift rates larger than 2 mm/yr are difficult to explain by geodynamic processes and have been a matter of debate for many decades. Here we examine the likely contribution of glacial isostatic adjustment in the European Alps in response to changes in ice loading using state of the art ice flow and lithospheric numerical modeling. In contrast to a similar previous approach (Mey et al., 2016), we employ a transient ice sheet model over the last glacial cycle (100 kyr) in combination with a spherical viscoelastic solid earth model. We present ice model results using the Instructed Glacier Model (Jouvet et al., 2021), in which we tested the effect of spatial resolution on the growth and extent of the European ice cap. We found significant differences using a model resolution of 200 m compared to a resolution of 2000 m, which is commonly used in large-scale glacier modeling studies. These differences result in near-steady state volumetric differences at the maximum ice extent of +13% for the high compared to the low-resolution model. In addition, we observed periods of marked ice growth that initiated at significantly different times for the different resolution models. Therefore, we conclude that a realistic ice loading history requires a sufficiently high spatial resolution, which is significantly higher than used in previous models. Based on the modeled ice loading histories, we used the lithosphere and mantle model VILMA (Klemann et al., 2008, J. Geodyn.) to predict the vertical land motion. These estimates are based on a global 60 km thick elastic lithosphere, followed by a 200 km thick viscous layer with a viscosity of 1020 Pa s, which increases to 5 x 1020 Pa s down to 670 km depth, and 3.16 x 1021 Pa s to the core mantle boundary. Preliminary results indicate similar first-order lithospheric responses, with spatiotemporal differences in the magnitude of postglacial response. We hope to present more results based on further ice models that are forced by a more realistic climate history

MAVS Is essential for primary CD4 + T cell immunity but not for recall T cell responses following an attenuated West Nile virus infection

ABSTRACT The use of pathogen recognition receptor (PRR) agonists and the molecular mechanisms involved have been the major focus of research in individual vaccine development. West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined the role of mitochondrial antiviral signaling protein (MAVS), the adaptor protein for RIG-I-like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that Mavs −/− mice were more susceptible to NS4B-P38G priming than WT mice. Mavs −/− mice had a transiently reduced production of antiviral cytokines and an impaired CD4 + T cell response in peripheral organs. However, antibody and CD8 + T cell responses were minimally affected. NS4B-P38G induced lower type I interferon (IFN), IFN-stimulating gene, and proinflammatory cytokine responses in Mavs −/− dendritic cells and subsequently compromised the antigen-presenting capacity for CD4 + T cells. Interestingly, Mavs −/− mice surviving NS4B-P38G priming were all protected from a lethal WT WNV challenge. NS4B-P38G-primed Mavs −/− mice exhibited equivalent levels of protective CD4 + T cell recall response, a modestly reduced WNV-specific IgM production, but more robust CD8 + T cell recall response. Taken together, our results suggest that MAVS is essential for boosting optimal primary CD4 + T cell responses upon NS4B-P38G vaccination and yet is dispensable for host protection and recall T cell responses during secondary WT WNV infection. IMPORTANCE The production of innate cytokines induced by the recognition of pathogen recognition receptors (PRRs) via their cognate ligands are critical for enhancing antigen-presenting cell functions and influencing T cell responses during microbial infection. The use of PRR agonists and the underlying molecular mechanisms have been the major focus in individual vaccine development. Here, we determined the role of mitochondrial antiviral-signaling protein (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the live attenuated West Nile virus (WNV) vaccine strain, the nonstructural (NS) 4B-P38G mutant. We found that MAVS is important for boosting optimal primary CD4 + T cell response during NS4B-P38G vaccination. However, MAVS is dispensable for memory T cell development and host protection during secondary wild-type WNV infection. Overall, these results may be utilized as a paradigm to aid in the rational development of other efficacious live attenuated flavivirus vaccines

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt beta II-spectrin function and disturb cytoskeletal organization and dynamics. SPTBN1 encodes beta II-spectrin, the ubiquitously expressed beta-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal beta II-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays;mild to severe intellectual disability;autistic features;seizures;behavioral and movement abnormalities;hypotonia;and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect beta II-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of beta II-spectrin in the central nervous system

Global Tipping Points Report 2023: Ch1.5: Climate tipping point interactions and cascades.

This chapter reviews interactions between climate tipping systems and assesses the potential risk of cascading effects. After a definition of tipping system interactions, we map out the current state of the literature on specific interactions between climate tipping systems that may be important for the overall stability of the climate system. For this, we gather evidence from model simulations, observations and conceptual understanding, as well as archetypal examples of palaeoclimate reconstructions where propagating transitions were potentially at play. This chapter concludes by identifying crucial knowledge gaps in tipping system interactions that should be resolved in order to improve risk assessments of cascading transitions under future climate change scenarios

Climate tipping point interactions and cascades: A review

Climate tipping elements are large-scale subsystems of the Earth that may transgress critical thresholds (tipping points) under ongoing global warming, with substantial impacts on the biosphere and human societies. Frequently studied examples of such tipping elements include the Greenland Ice Sheet, the Atlantic Meridional Overturning Circulation (AMOC), permafrost, monsoon systems, and the Amazon rainforest. While recent scientific efforts have improved our knowledge about individual tipping elements, the interactions between them are less well understood. Also, the potential of individual tipping events to induce additional tipping elsewhere or stabilize other tipping elements is largely unknown. Here, we map out the current state of the literature on the interactions between climate tipping elements and review the influences between them. To do so, we gathered evidence from model simulations, observations, and conceptual understanding, as well as examples of paleoclimate reconstructions where multi-component or spatially propagating transitions were potentially at play. While uncertainties are large, we find indications that many of the interactions between tipping elements are destabilizing. Therefore, we conclude that tipping elements should not only be studied in isolation, but also more emphasis has to be put on potential interactions. This means that tipping cascades cannot be ruled out on centennial to millennial timescales at global warming levels between 1.5 and 2.0 ◦C or on shorter timescales if global warming surpassed 2.0 ◦C. At these higher levels of global warming, tipping cascades may then include fast tipping elements such as the AMOC or the Amazon rainforest. To address crucial knowledge gaps in tipping element interactions, we propose four strategies combining observation-based approaches, Earth system modeling expertise, computational advances, and expert knowledge

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation