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Antagonists of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds to treat hyponatremia or polycystic kidney diseases. Compounds such as Tolvaptan (TVP) and Conivaptan are marketed drugs but their mechanisms of inhibition are not known. In addition, TVP presents unwanted side effects such as serious liver injury. Conivaptan also targets AVP V1a receptor subtype and thus is not selective to V2R. To develop novel molecules with less side effects and better selectivity, rational drug design based on experimental three-dimensional G protein-coupled receptor (GPCR) structures is a powerful and successful avenue. The lack of antagonist-bound V2R structures has however impaired this strategy for this GPCR. To fill this gap of knowledge, we solved here the cryo-electron microscopy structures of the vasopressin V2R in complex with two selective antagonists, the nonpeptide TVP and the green mamba snake Mambaquaretin toxin (MQ1). Both ligands, known to be competitive, bind into the orthosteric AVP binding site but with substantial differences. The small molecule binds deeper than MQ1, and directly contacts the toggle switch residue W2846.48 in the transmembrane domain 6 (TM6), whereas the peptide Kunitz-fold toxin presents more extensive contacts with the receptor through additional interactions with extracellular and transmembrane residues. As anticipated from the pharmacological properties of TVP and MQ1, both structures represent inactive conformations of the V2R. Their comparison with those of the active AVP-bound V2R reveals the molecular mechanisms modulating receptor activity. Finally, the structure of the V2R bound to a mini-protein such as MQ1 opens a new pharmacology era in the field of water homeostasis and renal diseases.Competing Interest StatementThe authors have declared no competing interest.

The aim of this paper is twofold: on one hand we study the invariants of traces of quadratic forms over a finite field of characteristic two. On the other hand, we give results about the zeta functions of certain curves studied by van der Geer and ven der Vlugt.

Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2′-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with ‘ferroptosis’, a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.

Background Timely recognition of sepsis in emergency department (ED) is challenging. We evaluated the impact of implementing the biomarker monocyte distribution width (MDW) at bedside, on the time to anti-infective administration. Methods We conducted a before-and-after cohort study in the ED of an academic hospital in Paris, to compare sepsis patients care and outcomes, before and after the implementation of point of care (POC) MDW measurement in the ED. During post-implementation period (period-2), MDW was measured with complete blood count by ED nurses with results given in 2 min: if above 21.5 units, ED physicians were asked to consider sepsis and to start an anti-infectious as soon as possible. Primary endpoint was time to anti-infectious administration (TTA) from ED arrival, and secondary endpoints were TTA from sepsis onset (TTAS), length of stay, mortality, and hospitalization rates. Results In total, 255 patients (period-1) and 180 patients (period-2) with sepsis were included. The TTA was 5.4 h (3.5–7.7) period-1 and 4.9 h (IQR 2.5–7.1) in period-2 ( p  = 0.06). MDW implementation significantly reduced the median TTAS from to 3.7 h (IQR 1.5–5.8) in period-1, to 2.2 h (IQR 0.5–4.5) in period-2 ( p  < 0.001). Mortality rates remained similar between the two periods (18% vs. 16% respectively, p  = 0.4), as did hospitalization rates (93% vs. 91%, p  = 0.4) and ED length of stay (7.2 h (5.3–9.8) vs 7.0 (5.4–9.4), p  = 0.7). Conclusion Implementing POC MDW measurement in the ED protocols enhances the timeliness of anti-infective administration from sepsis onset, meeting current sepsis management guidelines.

Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. To compare CPM to methylprednisolone (MP) in SPMS. Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. Clinicaltrials.gov NCT00241254.

The question of the collimation of relativistic jets is the subject of a lively debate in the community. We numerically compute the apparent velocity and the Doppler factor of a non homokinetic jet using different velocity profile, to study the effect of collimation on the appearance of relativistic jets (apparent velocity and Doppler factor). We argue that if the motion is relativistic, the high superluminal velocity are possible only if the geometrical collimation is smaller than the relativistic beaming angle γ−1. In the opposite case, the apparent image will be dominated by the part of the jet traveling directly towards the observer resulting in no apparent velocity. Furthermore, getting rid of the homokinetic hypothesis yields a complex relation between the observing angle and the Doppler factor, resulting in important consequences for the numerical computation of AGN population and unification scheme model.

This work aims to introduce a design methodology of Time-to-Digital Converters (TDCs) on low cost Field-Programmable Gate Array (FPGA) targets. First, the paper illustrates how to take advantage of the presence of carry chains in elementary logic elements of the FPGA in order to enhance the TDC resolution. Then, it describes how to use the Chip Planner tool to place the partitions composing the system in user specified physical regions. This allows the placement of TDC partitions so that the routing paths are constrained. As a result, the user controls the propagation delay effectively through the connection network. The paper ends by applying the presented methodology to a case study showing the design and implementation of high resolution TDC dedicated to time correlated single photon counting system. The resolution of 42 ps as well as the INL, DNL and mean Jitter values (22 ps rms, 13 ps rms and 26 ps rms, respectively) obtained using a low cost FPGA target Cyclone family are very promising and suitable for a large amount of fast applications.

Increasing penetration of decentralized energy resources (DER) is currently disrupting distribution grid's monopoly. Basic tariff structures, mostly based on energy charges, are being outdated. Prosumers, a new class of residential ratepayers being both producers and consumers of electricity keep using the grid while their financial contribution is decreasing, causing tariff rises and inequities among users. This phenomenon, known under the term of \"utility death spiral\", represents a major threat to utilities' profitability. To tackle those new challenges, Distribution System Operators (DSOs) must improve their rate policies. In Europe, each utility is unbundled, allowing high flexibility in setting rates design. This results in a lot of different grid tariff structures applied, some of them being particularly daring. In North America, the situation is particularly unclear due to the heterogeneity of actor's nature. Though, most utilities still seem to rely mostly on volumetric and fixed charges. Finally, this report aims to offer a global overview of the current challenges faced by grid utilities, and on how some DSOs are trying to move forward. By doing so, we hope that rate politics' stakeholders will have a broader vision on the range of decent practices. Le developpement des technologies decentralisees remet en question la place des reseaux dans le marche de l'electricite. Les structures tarifaires standards, principalement basees sur la quantite d'energie consommee, ne sont desormais plus adaptees, et entrainent des risques de baisse de revenus pour les operateurs de reseaux. Les consommacteurs, une nouvelle classe d'usagers qui investit dans les technologies de production et de stockage a domicile, continuent de beneficier des avantages du reseau sans en payer une juste part. Ce phenomene, connu sous le nom de \" spirale de la mort \", est susceptible d'avoir des consequences tres nefastes sur la stabilite financiere des operateurs de reseau, et contrevient au