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Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features of CALR-mutated essential thrombocythemia and myelofibrosis patients. In most cases, CALRm were found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1 CALRm spreads more easily than the type 2 CALRm in lymphoid cells. The CALRm were also associated with an early clonal dominance at the level of hematopoietic stem and progenitor cells (HSPC) with no significant increase during granulo/monocytic differentiation in most cases. Moreover, we found that half of type 2 CALRm patients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2 CALRm progenitors. When associated mutations were present, CALRm were the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1 CALRm led to a greater increased number of all types of progenitors compared with the type 2 CALRm. However, both types of CALRm induced an increase in megakaryocytic progenitors associated with a ruxolitinib-sensitive independent growth and with a mild constitutive signaling in megakaryocytes. At the transcriptional level, type 1 CALRm seems to deregulate more pathways than the type 2 CALRm in megakaryocytes. Altogether, our results show that CALRm modify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2 CALRm.

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.

BackgroundLaparoscopic Nissen fundoplication (LNF) and gastrostomy tube (GT) placement may be performed concomitantly in children with gastro-esophageal reflux disease (GERD) and failure to thrive. We aimed to evaluate the rate and risk factors for LNF failure in children undergoing concomitant LNF/GT.MethodsA retrospective multi-institutional cohort study was conducted, reviewing patients that underwent LNF (2005–2014). Data collected included patient demographics, comorbidities, and type of GT (laparoscopy- or endoscopy-assisted). The primary outcome measure was LNF failure. Data was compared using contingency tables or Mann–Whitney tests, when appropriate. An exploratory analysis by Kaplan–Meier survival and Cox proportional hazards analysis was performed to determine predictors of time to LNF failure after LNF/GT.ResultsOf 189 children that underwent LNF, 99 (52%) had a concomitant GT (55% laparoscopy-, 45% endoscopy-assisted). LNF failed in 15% after LNF/GT and in 17% after LNF alone (p = 0.84), at a median age of 23 months (IQR 8–41). Using univariate analysis, we found that a younger age at the time of surgery (p = 0.05), prematurity (p = 0.0018), esophageal atresia (p = 0.01), and endoscopy-assisted GT (p = 0.02) were potential predictors of LNF failure after LNF/GT. After multivariate regression analysis, prematurity (p = 0.007) remained significantly associated with LNF failure after LNF/GT. No predictive factors for LNF failure after LNF alone were identified.ConclusionsConcomitant GT insertion and LNF is a common practice, as half of the children that undergo LNF also received GT insertion. Children born preterm or with esophageal atresia comprise a fragile population at high-risk of LNF failure after LNF/GT. Prospective, multicentric studies are needed to evaluate the best GT technique to use in children undergoing LNF.

Hydropower remains a key renewable energy source in the pursuit of the decarbonization of the economy, although the relatively high potential impact of the hydro-morphological alterations it may cause poses significant concerns for aquatic ecosystems. In the last years, new technologies and practices have been increasingly adopted to minimize the impacts of hydropower plants, while improving efficiency and flexibility of energy generation. The overall effect of these innovations may be a more sustainable design and operation of hydropower, striking a better balance between the objectives of decarbonization and ecosystem protection. This contribution presents and discusses a few representative examples of hydropower installations from companies in Italy, France, Switzerland, Belgium and the USA, where solutions have been adopted in this direction. The case studies cover (1) ecologically improved and low head hydropower converters (Vortex turbine, Hydrostatic Pressure Machine, VLH and Girard-optimized turbines, hydrokinetic turbines), hydropeaking reduction (2) new control systems, governors and digitalization, (3) hydropower as a strategy for local sustainable development and (4) energy recovery in existing hydraulic infrastructures and aqueducts. It was found that better-governing systems can extend the life span of runners, for example avoiding the runner uplift during a trip. Digitalization can improve efficiency by 1.2%. New sustainable practices and turbines with better ecological behavior can minimize environmental impacts, like the reduction of fish mortality, improvement of fish habitat availability, reduction of oil for lubrication purposes and generation of economic incomes for local development. The use of existing structures reduces the total installation cost: examples are the total saving of 277 €/kW by reusing irrigation pipes and reservoirs, or the reduction of the investment period from 9 years to 6 years by turbining the environmental flow. Innovative low head hydropower converters can exhibit good ecological behavior, with reduced costs (<5000 €/kW) especially when installed in existing weirs. Results are discussed, contextualized and generalized to provide engineering data and tools to support future realizations of similar case studies; normalized costs, efficiency improvement, best practices and new technologies are discussed.