Physical organogenesis of the gut.

The gut has been a central subject of organogenesis since Caspar Friedrich Wolff's seminal 1769 work 'De Formatione Intestinorum'. Today, we are moving from a purely genetic understanding of cell specification to a model in which genetics codes for layers of physical-mechanical and electrical properties that drive organogenesis such that organ function and morphogenesis are deeply intertwined. This Review provides an up-to-date survey of the extrinsic and intrinsic mechanical forces acting on the embryonic vertebrate gut during development and of their role in all aspects of intestinal morphogenesis: enteric nervous system formation, epithelium structuring, muscle orientation and differentiation, anisotropic growth and the development of myogenic and neurogenic motility. I outline numerous implications of this biomechanical perspective in the etiology and treatment of pathologies, such as short bowel syndrome, dysmotility, interstitial cells of Cajal-related disorders and Hirschsprung disease.

Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

STUDY QUESTION: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol? SUMMARY ANSWER: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years. WHAT IS KNOWN ALREADY: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise. STUDY DESIGN, SIZE, DURATION: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8. MAIN RESULTS AND THE ROLE OF CHANCE: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively). LIMITATIONS, REASONS FOR CAUTION: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias. WIDER IMPLICATIONS OF THE FINDINGS: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification. STUDY FUNDING/COMPETING INTEREST(S): Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02884245. TRIAL REGISTRATION DATE: 29 August 2016. DATE OF FIRST PATIENT'S ENROLMENT: 4 November 2016.

Tetrodotoxin-resistant mechanosensitivity and L-type calcium channel-mediated spontaneous calcium activity in enteric neurons.

Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high- and low-frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic-motility stages E18.5-P3 showed that CaV1.2-positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2-aminoethoxydiphenyl borate (2-APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2-APB resistant. We extended our results on L-type channel-dependent spontaneous activity and TTX-resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro-mechanical sensitivity in the enteric nervous system. HIGHLIGHTS: What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L-type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin-resistant mechanosensitive response. Abstract figure legend Tetrodotoxin-resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum.

Is Physical Activity an Efficient Strategy to Control the Adverse Effects of Persistent Organic Pollutants in the Context of Obesity? A Narrative Review.

Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs' adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis, and gut microbiota dysbiosis, that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery, where weight loss promotes POPs' blood release.

Critical Overview on Endocrine Disruptors in Diabetes Mellitus.

Diabetes mellitus is a major public health problem in all countries due to its high human and economic burden. Major metabolic alterations are associated with the chronic hyperglycemia that characterizes diabetes and causes devastating complications, including retinopathy, kidney failure, coronary disease and increased cardiovascular mortality. The most common form is type 2 diabetes (T2D) accounting for 90 to 95% of the cases. These chronic metabolic disorders are heterogeneous to which genetic factors contribute, but so do prenatal and postnatal life environmental factors including a sedentary lifestyle, overweight, and obesity. However, these classical risk factors alone cannot explain the rapid evolution of the prevalence of T2D and the high prevalence of type 1 diabetes in particular areas. Among environmental factors, we are in fact exposed to a growing amount of chemical molecules produced by our industries or by our way of life. In this narrative review, we aim to give a critical overview of the role of these pollutants that can interfere with our endocrine system, the so-called endocrine-disrupting chemicals (EDCs), in the pathophysiology of diabetes and metabolic disorders.

Understanding autonomous behaviour development: Exploring the developmental contributions of context-tracking and task selection to self-directed cognitive control.

Gaining autonomy is a key aspect of growing up and cognitive control development across childhood. However, little is known about how children engage cognitive control in an autonomous (or self-directed) fashion. Here, we propose that in order to successfully engage self-directed control, children identify, and achieve goals by tracking contextual information and using this information to select relevant tasks. To disentangle the respective contributions of these processes, we manipulated the difficulty of context-tracking via altering the presence or absence of contextual support (Study 1) and the difficulty of task selection by varying task difficulty (a)symmetry (Study 2) in 5-6 and 9-10-year-olds, and adults. Results suggested that, although both processes contribute to successful self-directed engagement of cognitive control, age-related progress mostly relates to context-tracking.

Regulatory and academic studies to derive reference values for human health: The case of bisphenol S.

The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 µg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies.

Embryonic Development of Motility: Lessons from the Chicken.

I outline here the development of intestinal motility in the chicken embryo. The first contractile events are circular smooth muscle driven calcium waves (E6), that gain a clock-like regularity when interstitial cells of Cajal become electrically active (E14). Soon after longitudinal smooth muscle contractions become prominent (E14), the enteric nervous system starts controlling motility (E16) by coupling the longitudinal and circular contractions via inhibitory neurotransmission. It gives rise to circular-longitudinal antagonism, to the migrating motor complex, and to the polarized ascending contraction-descending relaxation pressure response known as the "law of the intestine". The kinetics of gut development in the chicken appears to follow faithfully that of humans by simply converting embryonic days of chicken development into embryonic weeks of human development.

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways.

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health-such as obesity, fertility disorders and cancers-by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10-6 M to 10-12 M; cytotoxicity and proliferation were monitored using the IncuCyte® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10-12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10-6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10-12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens.

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

AIMS/HYPOTHESIS: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). METHODS: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. RESULTS: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. CONCLUSIONS/INTERPRETATION: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04324736.

Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice.

BACKGROUND: Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype. METHODS: We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin. RESULTS: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype. CONCLUSIONS: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.

Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

AIM: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study. MATERIALS AND METHODS: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW). RESULTS: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death. CONCLUSIONS: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.

Disentangling the Respective Contribution of Task Selection and Task Execution to Self-Directed Cognitive Control Development.

Task selection and task execution are key constructs in cognitive control development. Yet, little is known about how separable they are and how each contributes to task switching performance. Here, 60 4- to 5-year olds, 60 7- to 8-year olds, and 60 10- to 11-year olds children completed the double registration procedure, which dissociates these two processes. Task selection yielded both mixing and switch costs, especially in younger children, and task execution mostly yielded switch costs at all ages, suggesting that task selection is costlier than task execution. Moreover, both task selection and execution varied with task self-directedness (i.e., to what extent the task is driven by external aids) demands. Whereas task selection and task execution are dissociated regarding performance costs, they nevertheless both contribute to self-directed control.

Understanding and Supporting Inhibitory Control: Unique Contributions From Proactive Monitoring and Motoric Stopping to Children's Improvements With Practice.

Children struggle to stop inappropriate behaviors. What interventions improve inhibitory control, for whom, and why? Prior work suggested that practice proactively monitoring for relevant signals improved children's inhibitory control more than practice with motoric stopping. However, these processes were not clearly dissociated. This study tested 162 seven- to nine-year-old children (89 female, 72 male, 1 unreported; 82% White) on the stop-signal task, following monitoring or stopping-focused practice. Both methods improved inhibitory control, supported generalization, and interacted ( η p 2 = .20-.73). Practice approaches differentially impacted variability ( η p 2 = .01-.09). Only monitoring benefits showed signs of depending upon proactive control ( η p 2 = .02). These findings highlight unique contributions of attentional and stopping processes to inhibitory control, suggesting possibilities for tailored interventions.

Midfrontal theta oscillations and conflict monitoring in children and adults.

Conflict monitoring is central in cognitive control, as detection of conflict serves as a signal for the need to engage control. This study examined whether (1) midfrontal theta oscillations similarly support conflict monitoring in children and adults, and (2) performance monitoring difficulty influences conflict monitoring and resolution. Children (n = 25) and adults (n = 24) completed a flanker task with fair or rigged response feedback. Relative to adults, children showed a smaller congruency effect on midfrontal theta power, overall lower midfrontal theta power and coherence, and (unlike adults) no correlation between midfrontal theta power and N2 amplitude, suggesting that reduced neural communication efficiency contributes to less efficient conflict monitoring in children than adults. In both age groups, response feedback fairness affected response times and the P3, but neither midfrontal theta oscillations nor the N2, indicating that performance monitoring difficulty influenced conflict resolution but not conflict monitoring.

Regulation of Monocytes/Macrophages by the Renin-Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study.

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.

Shifting into high gear: how interstitial cells of Cajal change the motility pattern of the developing intestine.

The first contractile waves in the developing embryonic gut are purely myogenic; they only involve smooth muscle. Here, we provide evidence for a transition from smooth muscle to interstitial cell of Cajal (ICC)-driven contractile waves in the developing chicken gut. In situ hybridization staining for anoctamin-1 (ANO1), a known ICC marker, shows that ICCs are already present throughout the gut, as from embryonic day (E)7. We devised a protocol to reveal ICC oscillatory and propagative calcium activity in embryonic gut whole mount and found that the first steady calcium oscillations in ICCs occur on (E14). We show that the activation of ICCs leads to an increase in contractile wave frequency, regularity, directionality, and velocity between E12 and E14. We finally demonstrate that application of the c-KIT antagonist imatinib mesylate in organ culture specifically depletes the ICC network and inhibits the transition to a regular rhythmic wave pattern. We compare our findings to existing results in the mouse and predict that a similar transition should take place in the human fetus between 12 and 14 wk of development. Together, our results point to an abrupt physiological transition from smooth muscle mesenchyme self-initiating waves to ICC-driven motility in the fetus and clarify the contribution of ICCs to the contractile wave pattern.NEW & NOTEWORTHY We reveal a sharp transition from smooth muscle to interstitial cell of Cajal (ICC)-driven motility in the chicken embryo, leading to higher-frequency, more rhythmic contractile waves. We predict the transition to happen between 12 and 14 embryonic wk in humans. We image for the first time the onset of ICC activity in an embryonic gut by calcium imaging. We show the first KIT and anoctamin-1 (ANO1) in situ hybridization micrographs in the embryonic chicken gut.

Real-world effectiveness of Fertistartkit® treatment in women undergoing ART in French clinical practice: a retrospective multicentre study.

RESEARCH QUESTION: What is the real-world effectiveness of Fertistartkit® in women undergoing assisted reproductive technology (ART)? DESIGN: Retrospective cohort study including anonymized data of women undergoing ovarian stimulation for ART with Fertistartkit between April 2016 and November 2017 and follow-up of clinical outcomes up to February 2018. Data were collected from the electronic patient databases of 12 French ART centres. The main outcome was number of oocytes retrieved. All data were categorized according to female age (<25, 25-29, 30-34, 35-37, 38-39 and >39 years). RESULTS: A total of 1006 cycles from 914 women treated with Fertistartkit were included. At the time of first ovarian stimulation in the study, women were 34.9 ± 5.0 years old, with a median body mass index of 22.7 kg/m². Couples had been infertile for more than 4 years, with all patterns of causes of infertility. Ovarian stimulation was started with a median dose of 300 IU (interquartile range [IQR]: 150-300 IU) of Fertistartkit for 10 days (IQR: 9-11 days), so a median total dose of 2700 IU (IQR: 1800-3300 IU). The mean number of oocytes retrieved per cycle was 9.5 ± 6.8, and the mean number of mature oocytes per cycle was 7.4 ± 5.5. The obtained ongoing pregnancy per started cycle was 26.0% (95% confidence interval [CI]: 24.1-27.9) and the obtained ongoing pregnancy per puncture was 27.0% (95% CI: 25.0-29.0). CONCLUSIONS: This is the first cohort to describe Fertistartkit treatment management in real-life conditions. The real-world data show that Fertistartkit is an effective option for ovarian stimulation.

Encouraging performance monitoring promotes proactive control in children.

Monitoring progression towards one's goals is essential for efficient cognitive control. Immature performance monitoring may contribute to suboptimal cognitive control engagement in childhood, potentially explaining why children engage control reactively even when proactive control would be more effective. This study investigated whether encouraging children to actively monitor their performance results in more mature control engagement. Electroencephalography data were collected while children and adults performed a flanker task in three conditions in which they were provided no feedback, standard feedback, or were asked to estimate their own feedback. Both age groups accurately estimated their own feedback. Critically, feedback estimation promoted online performance monitoring and proactive engagement of attention and inhibition during the flanker period in children. These findings indicate that proactive control engagement in childhood can be effectively supported by encouraging performance monitoring.

How bilingual experience and executive control influence development in language control among bilingual children.

This longitudinal study investigates whether the development in executive control and bilingual experience predicts change in language control in bilingual children. Children were tested twice over the course of 1 year, using the language-switching paradigm and the Simon task. The participants were Japanese-English bilingual "returnee" children (ages 7-13), who returned to their first language (L1) environment after spending some years in a second language (L2) dominant environment. Testing these children upon their return to the L1 environment allowed us to disentangle the effect of age from bilingual experience, as they experienced an increase in age but a decrease in L2 exposure over time. Children who had less L2 exposure showed smaller improvement in baseline performance when naming pictures in English (i.e., when English was relevant across all trials). Moreover, development in trials where children had to switch between languages were modulated by development in executive control. That is, children who increased their performance in the English mixed repetition trials also performed better on the executive control task over time. Thus, development in executive control modulated change in language control among bilingual children, suggesting a positive relationship between language control and executive control in children's development.