Frédéric Joliot Institute for Life Sciences

Apelin, a (neuro) vasoactive peptide, plays a prominent role in controlling water balance and cardiovascular functions. Apelin and its receptor co-localize with vasopressin in magnocellular vasopressinergic neurons. Apelin receptors (Apelin-Rs) are also expressed in the collecting ducts of the kidney, where vasopressin type 2 receptors are also present. Apelin and vasopressin interact at the brain and renal levels to maintain body fluid homeostasis by regulating diuresis in opposite directions. Apelin and angiotensin II have opposite effects on the regulation of blood pressure (BP). Angiotensin II, by binding to AT1 receptors present in VSMCs, induces intracellular calcium mobilization and vasoconstriction, while apelin, by binding to Apelin-R present on vascular endothelium, increases nitric oxide production and induces vasodilation. Apelin also plays a crucial role in the regulation of cardiac function. Apelin-deficient and Apelin-R-deficient mice develop progressive myocardial dysfunction with ageing and are susceptible to heart failure in response to pressure overload. Since the half-life of apelin is very short in vivo (in the minute range), several metabolically stable apelin analogs and non-peptidic Apelin-R agonists have been developed, with potential applications in diverse diseases. In this review, we highlight the interaction between apelin and vasopressin in the regulation of water balance and that between apelin and angiotensin II in the regulation of BP. Additionally, we underline the protective effects of apelin in cardiac function. Lastly, we discuss the beneficial effects of Apelin-R activation in different pathological states such as hyponatremia, hypertension, and heart failure.

Background & aimDietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR. DesignThis study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36% for the control diet (CON-D) or 64% for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data. ResultsIn both arms CMR improved with time, with decreased body weight (-0.9%), insulin resistant (-34%, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11%). Diet had no effect on FMD or metabolic fluxes, but a trend was observed for a stronger decrease in HOMA-IR and lower postprandial glucose after FLEX-D vs CON-D. The abundance of 21 and 37 metabolites differed between diets at fasted and fed states, respectively, including food intake biomarkers of AP (methylhistidine, eicosapentaenoic acid, hydroxyprolines) and PP sources (trigonelline, N-acetyl-ornithine). In fasted or fed states, indole acrylic acid and indole propionic acid, both products of tryptophan catabolism, were higher after FLEX-D vs CON-D, while the indispensable amino acids-related metabolites alpha-aminoadipic acid, hydroxymethylbutyric acids and propionylcarnitine were lower. In the postprandial state only, the ω-oxidation products dodecanedioic, tetradecanedioic and hexadecanedioic acids were higher after FLEX-D vs CON-D. ConclusionsDespite little changes in risk factors after 4 wk, this study evidenced subtle metabolic adaptations in amino acids and lipid metabolism and gut microbiota activity occurring after higher PP source intake that may be beneficial to CMR. ClinicalTrials.gov study identifierNCT04236518 Clinical Trial RegistryNCT04236518 on ClinicalTrials.gov

ObjectiveTo update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. Materials and methodsFive major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. ResultsThe fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. ConclusionBased on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

Duchenne muscular dystrophy (DMD) is one of the most common forms of hereditary muscular dystrophies in childhood and is characterized by steady progression and early disability. It is known that physical therapy can slow down the rate of progression of the disease. According to global recommendations, pool exercises, along with stretching, are preferable for children with DMD, as these types of activities have a balanced effect on skeletal muscles and allow simultaneous breathing exercises. The present study aimed to evaluate the effectiveness of regular pool exercises in patients with Duchenne muscular dystrophy who are capable of independent movement during 4 months of training. 28 patients with genetically confirmed Duchenne muscular dystrophy, who were aged 6.9 ± 0.2 years, were examined. A 6-min distance walking test and timed tests, namely, rising from the floor, 10-meter running, and stair climbing and descending, muscle strength of the upper and lower extremities were assessed on the baseline and during dynamic observation at 2 and 4 months. Hydrorehabilitation course lasted 4 months and was divided into two stages: preparatory and training (depend on individual functional heart reserve (IFHR)). Set of exercises included pool dynamic aerobic exercises. Quantitative muscle MRI of the pelvic girdle and thigh was performed six times: before training (further BT) and after training (further AT) during all course. According to the results of the study, a statistically significant improvement was identified in a 6-min walking test, with 462.7 ± 6.2 m on the baseline and 492.0 ± 6.4 m after 4 months (p < 0.001). The results from the timed functional tests were as follows: rising from the floor test, 4.5 ± 0.3 s on the baseline and 3.8 ± 0.2 s after 4 months (p < 0.001); 10 meter distance running test, 4.9 ± 0.1 s on the baseline and 4.3 ± 0.1 s after 4 months (p < 0.001); 4-stair climbing test, 3.7 ± 0.2 s on the baseline and 3.2 ± 0.2 s after 4 months (p < 0.001); and 4-stair descent test, 3.9 ± 0.1 s on the baseline and 3.2 ± 0.1 s after 4 months (p < 0.001). Skeletal muscle quantitative MRI was performed in the pelvis and the thighs in order to assess the impact of the procedures on the muscle structure. Muscle water T2, a biomarker of disease activity, did not show any change during the training period, suggesting the absence of deleterious effects and negative impact on disease activity. Thus, a set of dynamic aerobic exercises in water can be regarded as effective and safe for patients with DMD.

Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly.This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration.

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&amp;lt;p&amp;gt;We investigated sodium/halides (F, Cl, Br and I) aqueous droplets &amp;lt;em&amp;gt;in vacuo&amp;lt;/em&amp;gt; at the microscopic level from molecular dynamics simulations at the 100 ns scale performed using a sophisticated polarizable all atom force field whose parameters are assigned only from high end quantum ab initio computations [1]. Long range electrostatic and polarizable forces are computed according to a Fast Multipole Method scheme devoted to polarizable force fields based on the induced dipole moment approach [2]. For Cl, Br and I we simulated 10k water droplets corresponding to 0.2, 0.6, 2.0 and 4.6 M salt concentrations and on a range of temperatures included between 260 and 320K. For F, we simulated 10k droplets corresponding to 0.2, 0.6, 0.8 and 1M salt concentrations. We also simulated a reduced set of salty droplets at 300K (in particular corresponding to NaCl salts) at the 100k (up to 100 ns) and at the 1M water molecules scale (up to 30 ns) [3]. We present here a detailed analysis of the structural properties of these droplets regarding ion spatial distributions, ion aggregates (size, composition, morphology, lifetime and distribution), water ordering (relative to pure&amp;amp;#160;water droplets) and droplet surface potentials. In the particular case of NaCl droplets, we also discuss droplet curvature effects on the latter properties from data corresponding to 10k, 100k and 1M systems.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;[1] Trumm &amp;lt;em&amp;gt;et al, Modeling the Hydration of Mono-Atomic Anions From the Gas Phase to the Bulk Phase: The Case of the Halide Ions F-, Cl-, and Br-&amp;lt;/em&amp;gt;, J. Chem. Phys., &amp;lt;strong&amp;gt;136&amp;lt;/strong&amp;gt; (2012) 044509.; R&amp;amp;#233;al F &amp;lt;em&amp;gt;et al&amp;lt;/em&amp;gt;,&amp;amp;#160; &amp;lt;em&amp;gt;Revisiting a Many-Body Model for Water Based on a Single Polarizable Site. From Gas Phase Clusters to Liquid and Air/Liquid Water Systems, &amp;lt;/em&amp;gt;J. Chem. Phys. &amp;lt;strong&amp;gt;139&amp;lt;/strong&amp;gt; (2013) 114502.; R&amp;amp;#233;al F &amp;lt;em&amp;gt;et al, Structural, Dynamical, and Transport Properties of the Hydrated Halides: How Do At- and I- Bulk Properties Compare with those of the other Halides, from F- to I-,&amp;lt;/em&amp;gt; J. Chem. Phys., &amp;lt;strong&amp;gt;144&amp;lt;/strong&amp;gt; (2016) 124513&amp;lt;/p&amp;gt;

The widespread use of magnetic resonance imaging (MRI) in the diagnosis of myopathies has made it possible to clarify the typical MRI pattern of dysferlinopathy. However, sufficient attention has not been given to the variability of MRI patterns in dysferlinopathy.Materials and methodsTwenty-five patients with the clinical manifestations of dysferlinopathy were examined. For all patients, creatine phosphokinase levels were measured and molecular genetics were examined. In two patients, immunohistochemical examinations of muscle biopsies were performed. MRI scanning was included T2 multi-slice multi-echo, T1 weighted, T2 weighted and Short Tau Inversion Recovery T2 weighted sequences. Quantitative and semi-quantitative evaluations of fatty replacement and swelling of the muscles were undertaken.ResultsVariability in the MRI patterns was lowest in the pelvis and leg muscles and highest in the thigh muscles. Three main types of MRI patterns were distinguished: posterior-dominant (80%), anterior-dominant (16%), and diffuse (4%). Among patients with the anterior-dominant pattern, the collagen-like variant (4%), proximal variant (4%) and pseudo-myositis (8%) were separately distinguished.ConclusionsAwareness of atypical MRI patterns in dysferlinopathy is important for increasing the efficiency of routine diagnostics and optimizing the search for causative gene mutations.