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BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A (Advanced) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M (Mild) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Precipitation sustains life and supports human activities, making its prediction one of the most societally relevant challenges in weather and climate modeling. Limitations in modeling precipitation underscore the need for diagnostics and metrics to evaluate precipitation in simulations and predictions. While routine use of basic metrics is important for documenting model skill, more sophisticated diagnostics and metrics aimed at connecting model biases to their sources and revealing precipitation characteristics relevant to how model precipitation is used are critical for improving models and their uses. This paper illustrates examples of exploratory diagnostics and metrics including 1) spatiotemporal characteristics metrics such as diurnal variability, probability of extremes, duration of dry spells, spectral characteristics, and spatiotemporal coherence of precipitation; 2) process-oriented metrics based on the rainfall–moisture coupling and temperature–water vapor environments of precipitation; and 3) phenomena-based metrics focusing on precipitation associated with weather phenomena including low pressure systems, mesoscale convective systems, frontal systems, and atmospheric rivers. Together, these diagnostics and metrics delineate the multifaceted and multiscale nature of precipitation, its relations with the environments, and its generation mechanisms. The metrics are applied to historical simulations from phases 5 and 6 of the Coupled Model Intercomparison Project. Models exhibit diverse skill as measured by the suite of metrics, with very few models consistently ranked as top or bottom performers compared to other models in multiple metrics. Analysis of model skill across metrics and models suggests possible relationships among subsets of metrics, motivating the need for more systematic analysis to understand model biases for informing model development.

Abstract Primary cardiac mesenchymal stromal cells (C-MSCs) can promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM) by differentiating into adipocytes and myofibroblasts. These cells’ limitations, including restricted access to primary material and its manipulation have been overcome by the advancement of human induced pluripotent stem cells (hiPSCs), and their ability to differentiate towards the cardiac stromal population. C-MSCs derived from hiPSCs make it possible to work with virtually unlimited numbers of cells that are genetically identical to the cells of origin. We performed in vitro experiments on primary stromal cells (Primary) and hiPSC-derived stromal cells (hiPSC-D) to compare them as tools to model ACM. Both Primary and hiPSC-D cells expressed mesenchymal surface markers and possessed typical MSC differentiation potentials. hiPSC-D expressed desmosomal genes and proteins and shared a similar transcriptomic profile with Primary cells. Furthermore, ACM hiPSC-D exhibited higher propensity to accumulate lipid droplets and collagen compared to healthy control cells, similar to their primary counterparts. Therefore, both Primary and hiPSC-D cardiac stromal cells obtained from ACM patients can be used to model aspects of the disease. The choice of the most suitable model will depend on experimental needs and on the availability of human source samples.

Abstract European windstorms cause socioeconomic losses due to wind damage. Projections of future losses from such storms are subject to uncertainties from the frequency and tracks of the storms, their intensities and definitions thereof, and socio-economic scenarios. We use two storm severity indices applied to objectively identified extratropical cyclone footprints from a multi-model ensemble of state-of-the-art climate models under different future socio-economic scenarios. Here we show storm frequency increases across northern and central Europe, where the meteorological storm severity index more than doubles. The population-weighted storm severity index more than triples, due to projected population increases. Adapting to the increasing wind speeds using future damage thresholds, the population weighted storm severity index increases are only partially offset, despite a reduction in the meteorological storm severity through adaptation. Through following lower emissions scenarios, the future increase in risk is reduced, with the population-weighted storm severity index increase more than halved.

Extra-tropical cyclones (ETCs) are the main cause of precipitation in the mid-latitudes, and there is substantial evidence that ETC-related precipitation will increase in the future. However, little is known about how this will impact on the dynamical strength of ETCs, and whether the impact will differ for different types of ETCs. We quantify the linear relationship between maximum vorticity and ETC-related precipitation in the current and idealised future climates and determine how this relationship depends on the structure and characteristics of the ETC. Three 10-year-long aqua-planet simulations are performed with a state-of-the-art global model, OpenIFS, that differ in their specified sea surface temperature (SST) distributions. A control simulation, a uniform warming simulation, and a polar amplification simulation are performed. ETCs are objectively identified using the feature-tracking software TRACK, and k-means clustering is applied to the ETC precipitation field to group the ETCs into clusters with similar precipitation structures. In all experiments, ETCs with stronger maximum vorticity are associated with more precipitation. For all cyclones considered together, we find that the slope of the linear relationship between maximum cyclone vorticity and ETC precipitation is larger in the uniform warming and polar amplification simulations than in the control simulation. We hypothesise that if an increase in precipitation in warmer climates were to feed back, via diabatic heating and potential vorticity anomalies, onto the dynamical intensity of the ETCs, precipitation and vorticity would increase at similar rates, and hence the slope of the linear regression line between precipitation and vorticity would remain similar. Our results indicate either that there is no feedback or that the increase in vorticity due to diabatic heating is masked by the decrease in the Eady growth rate which occurs in both the uniform warming and polar amplification simulations compared to the control. The k-means clustering identifies four distinct and physically realistic types of ETCs which are present in all experiments meaning that the average precipitation patterns associated with ETCs are unlikely to change in the future. The strongest dependency between ETC maximum vorticity and precipitation occurs for ETCs that have the most precipitation associated with the warm front. ETCs with the heaviest precipitation along the cold front, which are the most intense storms in terms of maximum vorticity, also exhibit a strong dependency between precipitation and maximum vorticity, but this dependency is weaker and has a smaller correlation coefficient than the warm-front ETCs. Not all ETC types exhibit a strong dependency between precipitation and maximum vorticity. ETCs located at high latitudes with weak precipitation show little dependency due to the lack of moisture, whereas ETCs with the precipitation located mainly in the centre of the ETCs have the weakest linear regression slope, which is likely due to the lack of upper-level forcing. These results stress that despite small changes in the strength of the cyclones, the precipitation increases are large, indicating potential future increases in flooding associated with cyclones.

Abstract Background The tobacco thrips (Frankliniella fusca Hinds; family Thripidae; order Thysanoptera) is an important pest that can transmit viruses such as the tomato spotted wilt orthotospovirus to numerous economically important agricultural row crops and vegetables. The structural and functional genomics within the order Thysanoptera has only begun to be explored. Within the > 7000 known thysanopteran species, the melon thrips (Thrips palmi Karny) and the western flower thrips (Frankliniella occidentalis Pergrande) are the only two thysanopteran species with assembled genomes. Results A genome of F. fusca was assembled by long-read sequencing of DNA from an inbred line. The final assembly size was 370 Mb with a single copy ortholog completeness of ~ 99% with respect to Insecta. The annotated genome of F. fusca was compared with the genome of its congener, F. occidentalis. Results revealed many instances of lineage-specific differences in gene content. Analyses of sequence divergence between the two Frankliniella species’ genomes revealed substitution patterns consistent with positive selection in ~ 5% of the protein-coding genes with 1:1 orthologs. Further, gene content related to its pest status, such as xenobiotic detoxification and response to an ambisense-tripartite RNA virus (orthotospovirus) infection was compared with F. occidentalis. Several F. fusca genes related to virus infection possessed signatures of positive selection. Estimation of CpG depletion, a mutational consequence of DNA methylation, revealed that F. fusca genes that were downregulated and alternatively spliced in response to virus infection were preferentially targeted by DNA methylation. As in many other insects, DNA methylation was enriched in exons in Frankliniella, but gene copies with homology to DNA methyltransferase 3 were numerous and fragmented. This phenomenon seems to be relatively unique to thrips among other insect groups. Conclusions The F. fusca genome assembly provides an important resource for comparative genomic analyses of thysanopterans. This genomic foundation allows for insights into molecular evolution, gene regulation, and loci important to agricultural pest status.