What causes a heavy precipitation period to become extreme? The exceptional October of 2018 in the Western Mediterranean

The Mediterranean region is particularly exposed to heavy precipitation and flash flooding. Every autumn the region is affected by these weather-related hazards, frequently with immense costly and deadly consequences. What makes an already potentially damaging period in terms of heavy precipitation, even more intense? This is the underlying question in this study, in which the atmosphere and the ocean conditions in October 2018 are examined to identify anomalies favoring this intensification. Furthermore, the model representativity of the over-averaged precipitation period and underlying anomalies is analyzed across scales using climatological, seasonal, and event-based COSMO high-resolution model simulations. Our investigation shows that October-2018, in the context of the climatological series from 1982 to 2018, could be marked as an unprecedented period because of the presence of intense and numerous low-pressure systems. Additionally, atmospheric moisture values placed this time above the climatological average, mainly for the high percentiles of the TCWV hourly anomalies. Specific humidity showed similar behaviour as TCWV except for pressure levels lower than 700 hPa, probably in relation to the evolution of the former Hurricane Leslie. The atmosphere-ocean interaction presented combined strong sea surface temperature (SST) and evaporation anomalies. April to October SST clearly exceeds climatological values while October-2018 presents both strong monthly anomaly and intense evaporation peaks preceding the most intense precipitation events. These large-scale features’ anomalies were in general well captured by the high-resolution regional climate model simulations at climatic and seasonal scales leading to an accurate representation of accumulated precipitation for the October period. However, the numerical weather prediction simulations on an event scale revealed low predictability, in agreement with former investigations, due to differences at the location and intensity of the cut-off lows and particularly at the atmospheric moisture field. The conclusions of this study show that it is not the most extreme period in terms of single anomalies which lead to extreme wet seasons, but the synergy of atmospheric and oceanic anomaly conditions with a constant interplay which made Autumn/October 2018 an extreme season/month

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Contains fulltext : 88508.pdf (publisher's version ) (Closed access)Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.1 september 201

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®