Correction: The Endocytic Adaptor Eps15 Controls Marginal Zone B Cell Numbers.

Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220⁺ bone marrow cells, CD19⁻ thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis

COVID-19 Detection from Mass Spectra of Exhaled Breath

According to the World Health Organization, the SARS-CoV-2 virus generated a global emergency between 2020 and 2023 resulting in about 7 million deaths out of more than 750 million individuals diagnosed with COVID-19. During these years, polymerase-chain-reaction and antigen testing played a prominent role in disease control. In this study, we propose a fast and non-invasive detection system exploiting a proprietary mass spectrometer to measure ions in exhaled breath. We demonstrated that infected individuals, even if asymptomatic, exhibit characteristics in the air expelled from the lungs that can be detected by a nanotech-based technology and then recognized by soft-computing algorithms. A clinical trial was ran on about 300 patients: the mass spectra in the 10-351 mass-to-charge range were measured, suitably pre-processed, and analyzed by different classification models; eventually, the system shown an accuracy of 95% and a recall of 94% in identifying cases of COVID-19. With performances comparable to traditional methodologies, the proposed system could play a significant role in both routine examination for common diseases and emergency response for new epidemics.Comment: 15 page

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Determining effective forecast horizons for multi-purpose reservoirs with short- and long-term operating objectives

ISSN:1029-7006ISSN:1607-796

Alpine hydropower in the decline of the nuclear era: trade-off between revenue and production in the Swiss Alps

Hydropower systems contribute to the welfare of a country by producing renewable and clean electricity and by generating revenue. Market liberalization and increasing share of new renewable energy sources, with associated increase in price volatility, are profoundly reshaping hydropower operations in many countries where these developments have already taken place. In this evolving context, some European countries are phasing out nuclear power plants and looking for alternatives to replace the lost production share. Hydropower is one of the candidates, particularly in water-abundant hydrological regions, where large storage hydropower systems contribute a big share of the production. Yet, shifting current revenue-oriented operations toward a production-maximizing strategy might come to the cost of a reduction in income for hydropower companies. In this paper, we specifically explore trade-offbetween maximizing hydropower electricity production and revenue in deregulated markets. We focus on a case study in the Swiss Alps that can be considered as paradigmatic of most hydropower systems in mountainous regions worldwide. We developed a stochastic biobjective optimal control problem, which allows the design alternative hydropower operating strategies differently balancing electricity production and revenue maximization, accounting for both the variability of reservoir inflow and electricity price. Our results show that a production-driven operation might have strong consequences on the hydropower company income, suggesting that there is a low rate of substitution between the two objectives in the current energy market situation. The proposed approach can support policy makers in analyzing the dualism production/revenue in any hydropower system under complex natural and socioeconomic constraints and represents a benchmark to test different types of mechanisms to promote favorable economic conditions to hydropower companies to increase electricity production.</p

Informing the operations of water reservoirs over multiple temporal scales by direct use of hydro-meteorological data

Water reservoir systems may become more adaptive and reliable to external changes by enlarging the information sets used in their operations. Models and forecasts of future hydro-climatic and socio-economic conditions are traditionally used for this purpose. Nevertheless, the identification of skillful forecasts and models might be highly critical when the system comprises several processes with inconsistent dynamics (fast and slow) and disparate levels of predictability. In these contexts, the direct use of observational data, describing the current conditions of the water system, may represent a practicable and zero-cost alternative. This paper contrasts the relative contribution of state observations and perfect forecasts of future water availability in improving multipurpose water reservoirs operation over short- and long-term temporal scales. The approach is demonstrated on the snow-dominated Lake Como system, operated for flood control and water supply. The Information Selection Assessment (ISA) framework is adopted to retrieve the most relevant information to be used for conditioning the operations. By explicitly distinguishing between observational dataset and future forecasts, we quantify the relative contribution of current water system state estimates and perfect streamflow forecasts in improving the lake regulation with respect to both flood control and water supply. Results show that using the available observational data capturing slow dynamic processes, particularly the snow melting process, produces a 10% improvement in the system performance. This latter represents the lower bound of the potential improvement, which may increase to the upper limit of 40% in case skillful (perfect) long-term streamflow forecasts are used.</p

On the effects of adaptive reservoir operating rules in hydrological physically-based models

ISSN:1029-7006ISSN:1607-796