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In a decarbonized future, electricity will likely play a much greater role in all aspects of the economy, while power generation will increasingly rely on intermittent sources such as wind and solar. In deep decarbonization studies of power systems, the most striking conclusions are usually on the generation side: the need of tens of GW of new clean generation capacities and storage are typical conclusions. However, these conclusions are the direct consequence of electricity demand projections, which usually get less attention and sometimes lack detailed explanation. At the very least, these projections are aggregated and suffer from a deficit of transparency in their methodology. A detailed knowledge of possible future load profiles, and how the evolution of their drivers influences their shape, is therefore very important to plan adequately energy and power requirements, as well as regional interconnections and storage. This paper uses a bottom-up approach based on the useful energy consumed in the residential, commercial, transportation and industrial sectors to explore the load profile sensitivity to key parameters. This approach is then used to provide hourly load profiles for a full year for the state of New York as an illustration. The impact of these key parameters is demonstrated through three scenarios: business as usual, accelerated electrification and energy efficiency breakthrough. Policy makers, planning for very ambitious penetration level of renewable energy generation capacity have to take into account the effect on electricity peak and total demand of their energy efficiency initiatives.

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain condition with critical symptoms of urinary urgency and frequency, persistent bladder-related pain, and reduced quality of life. Poor-quality sleep can lead to significant disturbances in daily life and increased pain in IC/BPS patients. Resilience, depressive symptoms, and pain catastrophizing have univariate associations with sleep and pain in IC/BPS, suggesting they may be mechanisms in this sleep and pain relationship., Methods: This online study recruited patients self-reporting a diagnosis of IC/BPS through support groups, social media posts (Facebook, Reddit, and Instagram), and urology clinic advertisements. Participants completed questionnaires on demographics, urologic symptoms, pain, pain catastrophizing, depressive symptoms, and resilience. Only those participants who met the RAND Interstitial Cystitis Epidemiology (RICE) criteria for IC/BPS diagnosis were included. A multiple mediation model was first examined, followed by a serial mediation model., Results: Seventy-four participants (M age = 47.0, standard deviation [SD ] 16.7, range 18-83 years) met inclusion criteria. A multiple mediation model showed greater sleep disturbance was associated with greater pain severity through depressive symptoms and pain catastrophizing, but not resilience (b=0.79, bootSE =0.26, bootCI [0.33, 1.35]). A serial mediation showed that the sleep-to-pain relationship had a significant indirect effect through pain catastrophizing and depressive symptoms (b=0.78, bootSE =0.26, bootCI [0.35, 1.32])., Conclusions: Findings suggest depressive symptoms and pain catastrophizing may be important psychosocial mechanisms in the sleep-to-pain relationship. These results help guide future sleep and pain research in IC/BPS and aid in developing and refining treatments.

Background: Infective endocarditis (IE) increasingly involves older patients. Geriatric status may influence diagnostic and therapeutic decisions., Aim: To describe transoesophageal echocardiography (TEE) use in elderly IE patients, and its impact on therapeutic management and mortality., Methods: A multicentre prospective observational study (ELDERL-IE) included 120 patients aged ≥75 years with definite or possible IE: mean age 83.1±5.0; range 75-101 years; 56 females (46.7%). Patients had an initial comprehensive geriatric assessment, and 3-month and 1-year follow-up. Comparisons were made between patients who did or did not undergo TEE., Results: Transthoracic echocardiography revealed IE-related abnormalities in 85 patients (70.8%). Only 77 patients (64.2%) had TEE. Patients without TEE were older (85.4±6.0 vs. 81.9±3.9 years; P=0.0011), had more comorbidities (Cumulative Illness Rating Scale-Geriatric score 17.9±7.8 vs. 12.8±6.7; P=0.0005), more often had no history of valvular disease (60.5% vs. 37.7%; P=0.0363), had a trend toward a higher Staphylococcus aureus infection rate (34.9% vs. 22.1%; P=0.13) and less often an abscess (4.7% vs. 22.1%; P=0.0122). Regarding the comprehensive geriatric assessment, patients without TEE had poorer functional, nutritional and cognitive statuses. Surgery was performed in 19 (15.8%) patients, all with TEE, was theoretically indicated but not performed in 15 (19.5%) patients with and 6 (14.0%) without TEE, and was not indicated in 43 (55.8%) patients with and 37 (86.0%) without TEE (P=0.0006). Mortality was significantly higher in patients without TEE., Conclusions: Despite similar IE features, surgical indication was less frequently recognized in patients without TEE, who less often had surgery and had a poorer prognosis. Cardiac lesions might have been underdiagnosed in the absence of TEE, hampering optimal therapeutic management. Advice of geriatricians should help cardiologists to better use TEE in elderly patients with suspected IE., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Fasciolosis is a worldwide spread parasitosis mainly caused by the trematode Fasciola hepatica. This disease is particularly important for public health in tropical regions, but it can also affect the economies of many developed countries due to large infections in domestic animals. Although several studies have tried to understand the transmission by studying the prevalence of different host species, only a few have used population genetic approaches to understand the links between domestic and wildlife infections. Here, we present the results of such genetic approach combined with classical parasitological data (prevalence and intensity) by studying domestic and wild definitive hosts from Camargue (southern France) where fasciolosis is considered as a problem. We found 60% of domestic hosts (cattle) infected with F. hepatica but lower values in wild hosts (nutria, 19%; wild boars, 4.5%). We explored nine variable microsatellite loci for 1,148 adult flukes recovered from four different populations (non-treated cattle, treated cattle, nutria and wild boars). Populations from the four groups differed, though we found a number of migrants particularly non-treated cattle and nutria. Overall, we detected 729 different multilocus genotypes (from 783 completely genotyped individuals) and only 46 genotypes repeated across samples. Finally, we experimentally infected native and introduced intermediate snail hosts to explore their compatibility with F. hepatica and assess the risks of fasciolosis expansion in the region. The introduced species Galba truncatula and Pseudosuccinea columella attained the higher values of overall compatibility in relation to the European species. However, concerning the origin, sympatric combinations of G. truncatula were more compatible (higher prevalence, intensity and survival) than the allopatric tested. According to our results, we should note that the assessment of epidemiological risks cannot be limited to a single host-parasite system, but should focus on understanding the diversity of hosts in the heterogeneous environment through space and time., (© 2020 Wiley-VCH GmbH.)

Domestic species such as cattle (Bos taurus taurus and B. t. indicus) represent attractive biological models to characterize the genetic basis of short-term evolutionary response to climate pressure induced by their post-domestication history. Here, using newly generated dense SNP genotyping data, we assessed the structuring of genetic diversity of 21 autochtonous cattle breeds from the whole Mediterranean basin and performed genome-wide association analyses with covariables discriminating the different Mediterranean climate subtypes. This provided insights into both the demographic and adaptive histories of Mediterranean cattle. In particular, a detailed functional annotation of genes surrounding variants associated with climate variations highlighted several biological functions involved in Mediterranean climate adaptation such as thermotolerance, UV protection, pathogen resistance or metabolism with strong candidate genes identified (e.g., NDUFB3, FBN1, METTL3, LEF1, ANTXR2 and TCF7). Accordingly, our results suggest that main selective pressures affecting cattle in Mediterranean area may have been related to variation in heat and UV exposure, in food resources availability and in exposure to pathogens, such as anthrax bacteria (Bacillus anthracis). Furthermore, the observed contribution of the three main bovine ancestries (indicine, European and African taurine) in these different populations suggested that adaptation to local climate conditions may have either relied on standing genomic variation of taurine origin, or adaptive introgression from indicine origin, depending on the local breed origins. Taken together, our results highlight the genetic uniqueness of local Mediterranean cattle breeds and strongly support conservation of these populations., (© 2019 John Wiley & Sons Ltd.)

Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

We report the design and synthesis of equipotent PPARalpha/gamma dual agonists starting from selective PPAR alpha agonist 1. In vivo data for 7 in the Zucker fa/fa rat are presented.

Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfonamides as potent PPARalpha agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.