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The genital microbiota actively participates in women's reproductive health. Indeed, a genital dysbiosis (microbial imbalance associated with adverse effects on host health) can lead to vaginal infections (such as mycoses or bacterial vaginosis). Recent data reported that genital dysbiosis (e.g. vaginal or endometrial) was associated with fewer chances of live births in assisted reproductive technologies (ART), via decreased pregnancy rates and an increased risk of miscarriages. The presence or diversity of certain bacterial strains (in particular Gardenellavaginalis, Proteobacteria, Lactobacillusjensenii, Lactobacilluscrispatus or Atopobiumvaginae) within the genital microbiota seem to be associated with the outcomes of ART cycles, suggesting new approaches to improve ART results. In this review, we aim at presenting the state of art on the association between the female genital microbiota and ART success. The diagnostic and therapeutic approaches (i.e. probiotics, antibiotic therapy and transplantation of vaginal microbiota) in the management of patients with altered microbiota will also be discussed. The confirmation of these data in the coming years could significantly improve the management of infertile patients in ART with a more personalized approach partially based on the female genital microbiotic profile.

Infertility affects between 8 and 12% of reproductive-age couples worldwide. Despite improvements in assisted reproductive techniques (ART), live birth rates are still limited. In clinical practice, imaging and microscopy are currently widely used, but their diagnostic effectiveness remains limited. In research, the emergence of innovative techniques named OMICS would improve the identification of the implantation window, while progressing in the understanding of the pathophysiological mechanisms involved in embryo implantation failures. To date, transcriptomic analysis seems to be the most promising approach in clinical research. The objective of this review is to present the results obtained with the different approaches available in clinical practice and in research to assess endometrial receptivity in patients undergoing ART., L’infertilité touche entre 8 et 12 % des couples en âge de procréer à travers le monde. Malgré l’amélioration des techniques d’aide médicale à la procréation (AMP), les taux de naissances vivantes restent toujours limités. En pratique clinique, l’imagerie et la microscopie sont actuellement largement utilisées, mais leur efficacité diagnostique reste limitée. En recherche, l’émergence des techniques innovantes dites OMICS permettrait d’améliorer l’identification de la fenêtre implantatoire, tout en progressant dans la compréhension des mécanismes physiopathologiques impliqués dans les échecs d’implantation embryonnaire. À ce jour, l’approche transcriptomique semble être la piste la plus prometteuse en recherche clinique. L’objectif de cette revue est de faire un état des lieux des résultats obtenus à ce jour avec les différentes approches disponibles en pratique clinique et en recherche pour évaluer la réceptivité endométriale chez les patientes prises en charge en AMP.

This work is rooted in the embodied cognition paradigm applied to the evaluation of visuospatial memory span. We aimed to test whether manuospatial incompatibility affects the evaluation of visuospatial working memory. Older and younger participants were tested under two different spatial field conditions, namely manuospatial incompatibility and manuospatial compatibility, using the standard Corsi Block Tapping Task. The results show that a manuospatial compatibility condition helped both younger and older participants to increase their visuospatial working memory span compared to the traditional manuospatial incompatibility condition. By analyzing the data, our results showed an increase of visuospatial memory span in manuospatial compatibility condition (i.e., the experimenter using his left hand and the participant his right hand) compared to manuospatial incompatibility condition for younger and older adults. We recommend that the interaction between body and cognition would be taken into account in clinical evaluation methods.

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction.We aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

International audience; A previous study on ideomotor action control showed that predictable action effects in the agent’s environment influenced how an action is carried out. If participants were required to perform a forceful keypress, they exerted more force when these actions would produce a quiet compared to a loud tone, and this observation suggests that anticipated proprioceptive and auditory action effects are integrated with each other during action planning and control. In light of the typically weak influence of body-related effect found in recent work, we aimed to extend this pattern of results to the intra-modal case of integrating proprioceptive/tactile feedback of a movement and following vibro-tactile effects. Our results suggest that the same weighted integration process as for the cross-modal case applies to the intra-modal case. These observations support the idea of a common mechanism which binds all action-related features in an integrated action representation, irrespective of whether these features relate to exafferent or reafferent signals.

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.

IntroductionIndividuals with brain injuries experience cognitive and emotional changes that have long-lasting impacts on everyday life. In the context of rehabilitation, surveys have stressed the importance of compensating for memory disturbances to ease the impact of disorders on day-to-day autonomy. Despite extensive research on the nature of neurocognitive impairments following brain injury, few studies have looked at patients’ perceptions of these day-to-day compensations. This study examines these perceptions; in particular, what brain-injured people believe they do to compensate for memory deficiencies in everyday life. It also investigates the determinants of reported compensation strategies (age, gender, perceived stress, change awareness and motivation to succeed).MethodsEighty patients and 80 controls completed the French Memory Compensation Questionnaire, a self-report measure of everyday memory compensation. Five forms of compensation were investigated: External and Internal strategies, Reliance on social help, and investments in Time and Effort, along with two general factors: the degree of importance attached to Success (motivation) and perceptions of Change. Participants also completed measures of demographic and emotional aspects that may affect everyday compensation perceptions.ResultsThe brain-injured group reported significantly more frequent use of memory compensation strategies than controls, with the exception of External aids. Large effects were observed for Reliance and Effort. Demographic, motivation and perception of change determinants were found to have different effects depending on the compensation strategy, and mediated the direct effect of brain injury on reported compensation.ConclusionClinical and rehabilitation neuropsychologists often seek to have a better sense of how their patients perceive their compensatory behaviors. In practice, such an understanding is needed to help select appropriate methods and improve the long-term impact of rehabilitation programs: memory rehabilitation will fail if neuropsychologists do not deal, first and foremost, with the emotional and metacognitive issues surrounding traumatic brain injury (TBI), rather than focusing on cognitive efficiency.

De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

Design Retrospective analyses of congenital scoliosis patients at 2 tertiary care pediatric hospitals. Objective This study objectives were (1) to report the rates of anomalies of 10 organ systems in congenital scoliosis patients and (2) to determine whether the presence of a single organ system anomaly increases the rate of nonspinal organ system defects. Summary of background data Intraspinal, cardiac, renal, and gastrointestinal anomalies have been reported to occur at higher rates in congenital scoliosis than the normal population. It is unknown whether the presence of 1 organ system defect increases the risk of nonspinal organ system anomalies. Methods All patients diagnosed, evaluated in the outpatient setting, with congenital scoliosis who were below 18 years of age at time of presentation with available cardiac echo, renal ultrasound, or magnetic resonance imaging were included in this study. Results There were 305 patients (161 females, 53%) whose mean age was 7+3 years. In total, 84% of patients were observed to have at least 1 organ defect. Overall, 22% of patients had 1 organ defect, 19% had 2, 18% had 3, and 18% had ≥4 organ defects. There was an average of 2.2 anomalies per patient (range=0 to 8). Intraspinal anomalies were documented in 43% of patients; syrinx occurred most frequently. Urogenital anomalies were documented in 39% of patients; solitary kidney was most prevalent. Cardiac anomalies were documented in 54% of patients; ventricular septal defect was most common. In 12% of patients, the triad of spinal, urogenital, and cardiac defects was observed. Multiple organ systems were found to have significant associations (P Conclusions Cardiac anomalies were the most common defect (54%), and occurred at a rate >2 times higher than previously reported. The high rate of intraspinal, cardiac, and urogenital defects makes magnetic resonance imaging, echocardiography, and renal ultrasound a critical part of evaluation for all congenital scoliosis patients. Level of evidence Level II.

International audience; Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Qmales and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7140Q/5Qmice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.SIGNIFICANCE STATEMENTSpinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment.

Background Neuroinflammation is an underlying pathology of all neurological conditions, the understanding of which is still being comprehended. A specific molecular pathway that has been overlooked in neuroinflammation is glycosylation (i.e., post-translational addition of glycans to the protein structure). N-glycosylation is a specific type of glycosylation with a cardinal role in the central nervous system (CNS), which is highlighted by congenital glycosylation diseases that result in neuropathological symptoms such as epilepsy and mental retardation. Changes in N-glycosylation can ultimately affect glycoproteins’ functions, which will have an impact on cell machinery. Therefore, characterisation of N-glycosylation alterations in a neuroinflammatory scenario can provide a potential target for future therapies. Methods With that aim, the unilateral intrastriatal injection of lipopolysaccharide (LPS) in the adult rat brain was used as a model of neuroinflammation. In vivo and post-mortem, quantitative and spatial characterisation of both neuroinflammation and N-glycome was performed at 1-week post-injection of LPS. These aspects were investigated through a multifaceted approach based on positron emission tomography (PET), quantitative histology, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), liquid chromatography and matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI). Results In the brain region showing LPS-induced neuroinflammation, a significant decrease in the abundance of sialylated and core fucosylated structures was seen (approximately 7.5% and 8.5%, respectively), whereas oligomannose N-glycans were significantly increased (13.5%). This was confirmed by MALDI-MSI, which provided a high-resolution spatial distribution of N-glycans, allowing precise comparison between normal and diseased brain hemispheres. Conclusions Together, our data show for the first time the complete profiling of N-glycomic changes in a well-characterised animal model of neuroinflammation. These data represent a pioneering step to identify critical targets that may modulate neuroinflammation in neurodegenerative diseases.

Huntington’s disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington’s disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington’s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington’s disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington’s disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington’s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms.

Spinocerebellar ataxia type 3 (SCA3/MJD) is caused by CAG expansion mutation resulting in a long polyQ domain in mutant ataxin-3. The mutant protein is a special type of protease, deubiquitinase, which may indicate its prominent impact on the regulation of cellular proteins levels and activity. Yet, the global model picture of SCA3 disease progression on the protein level, molecular pathways in the brain, and neurons, is largely unknown. Here, we investigated the molecular SCA3 mechanism using an interdisciplinary research paradigm combining behavioral and molecular aspects of SCA3 in the knock-in ki91 model. We used the behavior, brain magnetic resonance imaging (MRI) and brain tissue examination to correlate the disease stages with brain proteomics, precise axonal proteomics, neuronal energy recordings, and labeling of vesicles. We have demonstrated that altered metabolic and mitochondrial proteins in the brain and the lack of weight gain in Ki91 SCA3/MJD mice is reflected by the failure of energy metabolism recorded in neonatal SCA3 cerebellar neurons. We have determined that further, during disease progression, proteins responsible for metabolism, cytoskeletal architecture, vesicular, and axonal transport are disturbed, revealing axons as one of the essential cell compartments in SCA3 pathogenesis. Therefore we focus on SCA3 pathogenesis in axonal and somatodendritic compartments revealing highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. We demonstrate the accumulation of axonal vesicles in neonatal SCA3 cerebellar neurons and increased phosphorylation of SMI-312 positive adult cerebellar axons, which indicate axonal dysfunction in SCA3. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of various components of protein synthesis machinery in axons.

SummarySperm morphometric and morphologic data have been shown to represent useful tools for monitoring fertility, improving assisted reproduction techniques and conservation of genetic material as well as detecting inbreeding of endangered primates. We provide here for the first time sperm morphologic and morphometric data fromCercopithecus neglectus,Cercopithecus cephus,Papio papioand critically endangeredCercopithecus roloway, as well as comparative data from otherCercopithecinaespecies, i.e.Allochrocebus lhoesti,Mandrillus sphinxandPapio anubis. Following collection from the epididymis, spermatozoa were measured for each species for the following parameters: head length, head width, head perimeter, head area, midpiece length and total flagellum length, and the head volume, ellipticity, elongation, roughness and regularity were then calculated. Our data are consistent with both the general morphology and the morphometric proportions ofCercopithecinaesperm. Some specificities were observed, withC. cephusdisplaying a narrow head (width = 2.76 ± 0.26 µM) andC. rolowaydisplaying a short midpiece (6.65 ± 0.61 µM). This data set represents an important contribution, especially forCercopithecus roloway, one of the most endangered monkeys in the world, and further data on additional specimens coupled to data on mating systems and reproductive ecology should allow a better understanding of the mechanisms underlying these morphological differences across primate species.

The mere perception of manipulable objects usually grasped with a power-grip (e.g., an apple) or a precision-grip (e.g., a cherry) potentiate power-grip- and precision-grip-responses, respectively. This effect is seen as to be driven by automatic access of the representation of manipulable objects that includes a motor representation of usually performed grasping behaviors (i.e., the embodied view). Nevertheless, a competing account argues that this effect could be due to an overlapping of size codes used to represent both manipulable objects and response options. Indeed, objects usually grasped with a power- and a precision-grip (e.g., an apple vs. a cherry) could be coded as large- and small-objects, respectively; and power- and precision-grip responses as large- and small-responses, respectively. We conducted 4 experiments to test this hypothesis. In Experiment 1, the response device usually used in studies reporting a potentiation effect is fixed horizontally (the grasping component of responses was removed). We instructed participants to press the small-switch with their index-digit and the large-switch with their palm-hand. In line with the size-coding-hypothesis, responses on the small-switch performed with the index-digit led to shorter RTs when objects usually associated with a precision-grip (e.g., a cherry) were presented compared to objects usually associated with a power-grip (e.g., an apple). A reverse pattern was obtained for responses on the large-switch performed with the palm-hand. In Experiments 2, 3 and 4, we went further by investigating which factors of Experiment 1 allow the size coding of responses: the size of switch and/or the size of the effector part used. Data confirmed the critical involvement of the size of switches and the possible involvement of the size of the effector part used. Thus, data support the possibility that the potentiation of grasping is due to a compatibility/incompatibility between size codes rather than involving motor representations of usually performed grasping behaviors as advocated in several embodied views. Moreover, data support the possibility that responses are coded thanks to a size code that extends the Theory of Event Coding.

International audience; Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of in vitro, physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.

International audience; Human ovarian tissue cryopreservation (OTC) is increasingly used worldwide to preserve female fertility in prepubertal girls and women at risk of premature ovarian insufficiency (POI) in the context of urgent gonadotoxic treatments or ovarian surgery. Fertility preservation is challenging because there is no consensus regarding patient management, preservation fertility strategies, or even technical laboratory protocols, which implies that each procedure must be adapted to the characteristics of the patient profile and its own risk-benefit ratio. During OTC, mature/immature oocytes can be aspirated directly from large/small antral follicles within ovarian tissue samples and/or be released into culture media from growing follicles during ovarian tissue dissection in prepubertal girls and women. In this manuscript, we present a protocol that combines ovarian tissue freezing with the cryopreservation of mature/immature oocytes retrieved from ovarian tissue samples, improving the reproductive potential of fertility preservation. Appropriate collection, handling, and storage of ovarian tissue and oocytes before, during, and after the cryopreservation will be described. The subsequent use and safety of cryopreserved/thawed ovarian tissue samples and oocytes will also be discussed, as well as the optimal timing for in vitro maturation of immature oocytes. We recommend the systematic use of this protocol in fertility preservation of prepubertal girls and women as it increases the whole reproductive potential of fertility preservation (i.e., oocyte vitrification in addition of OTC) and also improves the safety and use of fertility preservation (i.e., thawing of oocytes versus ovarian graft), maximizing the chance of successful childbirth for the patients at risk of POI.

International audience; Objective To characterise the role of VEGF, EG-VEGF and its receptors in the development and progression of HNC. Design Human serum and tissues samples were collected from healthy, epulis and HNC patients and used for ELISA assays and immunohistochemistry studies, respectively. Setting Ibn Rochd Hospital of Casablanca (Morocco), INSERM and University of Grenoble Alpes (France). Participants We used serum from 64 patients with head and neck cancers and from 71 controls without general pathology. Tissues samples were collected from seven patients with OSCC and from seven patients with Epulis. Main outcome measures We compared circulating VEGF and EG-VEGF in normal and HNC patients and determined the expression, localisation and quantification of VEGF, EG-VEGF and its receptors; PROKR1 and PROKR2 as well as Ki67, CD31 and CD34 in OSCC and Epulis patients. Results Both EG-VEGF and VEGF circulating levels were significantly decreased in the HNC (P < .01). OSCC patients expressed less EG-VEGF and VEGF proteins, higher PROKR1 and PROKR2 with no change in CD31 and CD34 levels. A significant increase in Ki67 was observed in OSCC. Conclusions We demonstrated that circulating VEGF and EG-VEGF are downregulated in HNC patients and in OSCC tissue. EG-VEGF receptors were increased in OSCC, along with a stabilisation of two key markers of angiogenesis. These findings strongly suggest that downregulation of angiogenesis in HNC might explain its moderate metastatic feature.

BACKGROUNDA dynamic balance between pro- and anti-inflammatory factors contributes to regulating human female reproduction. Chronic low-grade inflammation has been detected in several female reproductive conditions, from anovulation to embryo implantation failure. C-reactive protein (CRP) is a reliable marker of inflammation that is extensively used in clinical practice. Recent studies quantified CRP in the serum of infertile women undergoing ART and suggested its potential for the prediction of ART reproductive outcomes.OBJECTIVE AND RATIONALEThe first objective of this systematic review of the available literature was to evaluate the association between pre-implantation circulating CRP concentration and pregnancy rates in women undergoing ART. The second objective was to describe serum CRP concentration changes after early embryo implantation. The changes in circulating CRP throughout the ART cycle, clinical implications of CRP quantification for the management of women undergoing ART, and future therapeutic options will also be discussed.SEARCH METHODSThe MEDLINE database was systematically searched from inception to March 2019 using the following key words: (C-reactive protein) AND (assisted reproductive techniques OR ovulation induction OR insemination OR in vitro fertilization). Only articles in English were considered. Studies were selected based on title and abstract. The full text of potentially relevant articles was retrieved and assessed for inclusion by two reviewers (S.B. and S.H.). The protocol was registered in the International prospective register of systematic reviews (PROSPERO; registration number: CRD148687).OUTCOMESIn total, 10 studies were included in this systematic review. Most of these studies reported lower circulating CRP values before the window of implantation and higher circulating CRP values during the peri-implantation period in women with successful ART outcome (biochemical or clinical pregnancy) compared to women without a successful outcome. Several lifestyle factors and/or drugs that reduce the concentration of circulating CRP significantly improve ART outcomes. Subgroup analyses according to female BMI and baseline circulating CRP concentration are highly recommended in future analyses.WIDER IMPLICATIONSThese findings highlight a possible detrimental impact of preconception high circulating CRP concentration on ART outcomes. However, the biochemical or clinical pregnancy rate endpoints used in the studies examined here are insufficient (there were no data on live birth outcome), and the impact of major variables that can influence CRP and/or ART, for example maternal age, BMI, number of transferred embryos, and use of anti-inflammatory drugs, were not considered in the analyses. CRP quantification may be a potential marker of ART outcome, but its predictive value still needs to be investigated in large prospective studies. In future, the quantification of circulating CRP before starting ART could help to identify patients with a poor ART prognosis, leading to ART cycle cancellation or to preconception treatment to minimize the medical risks and costs.

International audience; This is a retrospective study to evaluate if the miRNome profile of endometrium samples collected during the implantation window predicts Assisted Reproduction Technology (ART) outcomes. We first investigated the endometrial miRNome profile according to the receptivity status in 20 patients with repeated implantation failures (RIF) (discovery cohort). After customized embryo transfer, the miRNome profiles of receptive patients with a positive or negative β-hCG, and with early miscarriage or live birth were analysed. Some differentially expressed miRNAs were selected for validation by RT-qPCR in endometrial samples from 103 RIF patients (validation cohort). Analysis of the different miRNome profiles identified endometrial receptivity, implantation failure, and early miscarriage-associated miRNA signatures that included 11, 261, and 76 miRNAs, respectively. However, only four miRNAs associated with the endometrial receptivity status (miR-455-3p and miR-4423-3p) and implantation failure (miR-152-3p and miR-155-5p) were significantly validated in endometrial samples. The miRNome profile of endometrial tissues during the implantation window can predict the pregnancy outcome. These data are crucial for opening new perspectives to predict implantation failure and consequently, to increase ART success.

International audience; The G2019S substitution in the kinase domain of LRRK2 (LRRK2 G2019S) is the most prevalent mutation associated with Parkinson's disease (PD). Neurotoxic effects of LRRK2 G2019S are thought to result from an increase in its kinase activity as compared to wild type LRRK2. However, it is unclear whether the kinase domain of LRRK2 G2019S is sufficient to trigger degeneration or if the full length protein is required. To address this question, we generated constructs corresponding to the C-terminal domain of LRRK2 (ΔLRRK2). A kinase activity that was increased by G2019➔S substitution could be detected in ΔLRRK2. However biochemical experiments suggested it did not bind or phosphorylate the substrate RAB10, in contrast to full length LRRK2. The overexpression of ΔLRRK2 G2019S in the rat striatum using lentiviral vectors (LVs) offered a straightforward and simple way to investigate its effects in neurons in vivo. Results from a RT-qPCR array analysis indicated that ΔLRRK2 G2019S led to significant mRNA expression changes consistent with a kinase-dependent mechanism. We next asked whether ΔLRRK2 could be sufficient to trigger neurodegeneration in the substantia nigra pars compacta (SNc) in adult rats. Six months after infection of the substantia nigra pars compacta (SNc) with LV-ΔLRRK2 WT or LV-ΔLRRK2 G2019S , the number of DA neurons was unchanged. To examine whether higher levels of ΔLRRK2 G2019S could trigger degeneration we cloned ΔLRRK2 in AAV2/9 construct. As expected, AAV2/9 injected in the SNc led to neuronal expression of ΔLRRK2 WT and ΔLRRK2 G2019S at much higher levels than those obtained with LVs. Six months after injection, unbiased stereology showed that AAV-ΔLRRK2 G2019S produced a significant~30% loss of neurons positive for tyrosine hydroxylase-and for the vesicular dopamine transporter whereas AAV-ΔLRRK2 WT did not. These findings show that overexpression of the C-terminal part of LRRK2 containing the mutant kinase domain is sufficient to trigger degeneration of DA neurons, through cell-autonomous mechanisms, possibly independent of RAB10.

International audience; Identification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant biomarkers by combining biological specificity provided by 1H‐MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)—the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD—were used. Animals were scanned at 11.7 T using a protocol combining 1H‐MRS and gluCEST imaging. We measured a significant decrease in levels of N‐acetyl‐aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that 1H‐MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarkers

International audience; Objective: Most studies about HIV-1 molecular evolution have shown the lack of viral evolution on effective antiretroviral therapy (ART), although controversial results have been documented. We therefore aimed to look for evidence of HIV-1 evolution in patients who initiated ART at the time of primary HIV-1 infection (PHI).Design: We included retrospectively 20 patients diagnosed at PHI, treated at the time of acute infection and with subsequent effective long-term suppressive ART (HIV viral load

Robertsonian translocations (RobT) are common structural chromosome rearrangements where carriers display a majority of chromosomally balanced spermatozoa from alternate segregation mode. According to some monotony observed in the rates of balanced segregation, is sperm FISH analysis obsolete for RobT carriers?Retrospective cohort research study on 23 patients analyzed in our center from 2003 to 2017 and compared to the data of 187 patients in literature from 1983 to 2017.Robertsonian translocation carriers were divided in six groups according to the chromosomes involved in the translocation: 9 patients from our center and 107 from literature carrying 45,XY,der(13;14) karyotype, 3 and 35 patients respectively with 45,XY,der(14;21), 5 and 11 patients respectively with 45,XY,der(13;15), 4 and 7 patients respectively with 45,XY,der(14;15), 1 and 4 patients respectively with 45,XY,der(13;22),and 1 and 10 patients respectively with 45,XY,der(14;22).Alternate segregation mode is predominant in our group of Robertsonian translocation carriers with 73.45% ±8.05 of balanced spermatozoa (min 50.92%; max 89.99%). These results are compliant with the data from literature for all translocations types (According to the discrepancies observed between der(13;15) and all the other Rob T carriers, the differences observed among patients presenting normal and abnormal sperm parameters and the input in genetical counselling, sperm FISH does not seem obsolete for these patients. Moreover, it seems important to collect more data for rare RobT.Le mode de ségrégation chromosomique le plus fréquemment observé chez les patients porteurs de translocation robertsonienne est. un mode équilibré. Les données semblent varier peu selon la translocation analysée. La relative constance des résultats dans le cas de ces translocations robertsoniennes rend elle inutile ces analyses chromosomiques pour ces patients?Nous avons analysé de façon rétrospective les données spermatiques et de ségrégation méiotique de 23 patients porteurs de translocation robertsonienne, de 2003 à 2017 et comparé les résultats observés à ceux décrits dans la littérature pour 187 patients.Le mode de ségrégation alterne est. prépondérant dans notre série de patients avec 73.45% ±8.05 de spermatozoïdes équilibrés (min 50.92%; max 89.99%). Ces résultats sont en accord avec les données de la littérature, toutes translocations confondues et selon le type de translocation (Les différences observées dans les taux d’aneuploïdies entre les translocations der(13;15) et les autres translocations robertsoniennes et entre les porteurs de translocation à spermogramme normal ou altéré, et l’utilité de ces données dans le conseil génétique conduisent à poursuivre l’analyse systématique de la ségrégation méiotique pour les patients porteurs de translocations robertsoniennes et ceci particulièrement pour les translocations rares.

Resume L’impression en 3 dimensions est en plein essor dans le domaine medical. Cette technologie accroit les possibilites de traitement personnalise pour les patients tout en abaissant les couts de fabrication. Dans le cadre des reconstructions de mandibule par lambeau libre de fibula, des societes proposent, a l’heure actuelle, des guides de coupe obtenus par moulage a partir de scanner. Outre les delais de realisation importants i.e. minimum 21 jours, ces guides sont vendus a des couts prohibitifs (2000 a 6000 euros). Conjointement avec le CNRS, des etudiants ingenieurs, une societe biomedicale, les auteurs ont mis au point des guides de coupe et des fantomes de mandibule imprimes en 3 dimensions, livrables en 7 jours et a moindre cout. La nouveaute de ce projet reside dans la rapidite d’elaboration des produits et la reduction importante de leur prix. Les auteurs proposent de decrire dans cette note technique la chaine logistique de realisation des fantomes et des guides de coupe ainsi que les resultats apportes. L’objectif est de permettre dans un avenir proche l’acces a cette technologie pour tous les patients.

Liver progenitor cells (LPCs)/ductular reactions (DRs) are associated with inflammation and implicated in the pathogenesis of chronic liver diseases. However, how inflammation regulates LPCs/DRs remains largely unknown. Identification of inflammatory processes that involve LPC activation and expansion represent a key step in understanding the pathogenesis of liver diseases. In the current study, we found that diverse types of chronic liver diseases are associated with elevation of infiltrated interleukin (IL)-17-positive (+) cells and cytokeratin 19 (CK19)+ LPCs, and both cell types colocalized and their numbers positively correlated with each other. The role of IL-17 in the induction of LPCs was examined in a mouse model fed a choline-deficient and ethionine-supplemented (CDE) diet. Feeding of wild-type mice with the CDE diet markedly elevated CK19+Ki67+ proliferating LPCs and hepatic inflammation. Disruption of the IL-17 gene or IL-27 receptor, alpha subunit (WSX-1) gene abolished CDE diet-induced LPC expansion and inflammation. In vitro treatment with IL-17 promoted proliferation of bipotential murine oval liver cells (a liver progenitor cell line) and markedly up-regulated IL-27 expression in macrophages. Treatment with IL-27 favored the differentiation of bipotential murine oval liver cells and freshly isolated LPCs into hepatocytes. Conclusion: The current data provide evidence for a collaborative role between IL-17 and IL-27 in promoting LPC expansion and differentiation, respectively, thereby contributing to liver regeneration. (Hepatology Communications 2018;2:329-343).

International audience; The role played by microglia has taken the center of the stage in the etiology of Alzheimer's disease (AD). Several genome-wide association studies carried out on large cohorts of patients have indeed revealed a large number of genetic susceptibility factors corresponding to genes involved in neuroinflammation and expressed specifically by microglia in the brain. Among these genes TREM2, a cell surface receptor expressed by microglia, arouses strong interest because its R47H variant confers a risk of developing AD comparable to the ε4 allele of the APOE gene. Since this discovery, a growing number of studies have therefore examined the role played by TREM2 in the evolution of amyloid plaques and neurofibrillary tangles, the two brain lesions characteristic of AD. Many studies report conflicting results, reflecting the complex nature of microglial activation in AD. Here, we investigated the impact of TREM2 deficiency in the THY-Tau22 transgenic line, a well-characterized model of tauopathy. Our study reports an increase in the severity of tauopathy lesions in mice deficient in TREM2 occurring at an advanced stage of the pathology. This exacerbation of pathology was associated with a reduction in microglial activation indicated by typical morphological features and altered expression of specific markers. However, it was not accompanied by any further changes in memory performance. Our longitudinal study confirms that a defect in microglial TREM2 signaling leads to an increase in neuronal tauopathy occurring only at late stages of the disease.

Resume La frequence de l’anaphylaxie par allergie alimentaire (AA) est en constante augmentation. Malgre la mise en place du plan d’accueil individualise (PAI), les anaphylaxies a l’ecole ne sont pas rares et mettent en danger la vie de l’enfant allergique. Dans cet article, a l’aide des donnees du reseau d’allergovigilance (RAV) et de travaux de differents groupes de la Societe francaise d’allergologie (SFA), nous identifions quelques pistes pour prevenir et mieux gerer ces accidents : meilleure formation des medecins a l’anaphylaxie, importance de l’education therapeutique du patient allergique et de son entourage, harmonisation du PI de l’enfant allergique, diffusion des recommandations concernant les indications de mise en place du PAI en France et la prescription des stylos auto-injecteurs d’adrenaline, necessite de formations a l’allergie de toute personne amenee a prendre en charge un enfant allergique alimentaire.

International audience; Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.

Alzheimer’s disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer’s disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes. Electronic supplementary material The online version of this article (10.1186/s40478-019-0771-x) contains supplementary material, which is available to authorized users.

This scientific commentary refers to ‘Increased translation as a novel pathogenic mechanism in Huntington’s disease’, by Jordi Creus-Muncunill et al. (doi:10.1093/brain/awz230).

International audience; Although many studies have demonstrated the superiority of ultra-fast freezing compared with slow freezing, the debate is still ongoing concerning the best type of vitrification method: direct exposure to liquid nitrogen (i.e., open systems), or sterile system without contact with liquid nitrogen (i.e., closed systems). The aims of this study were to share our experience on closed vitrification systems in the framework of our egg donation programme with fully asynchronous cycles, and to identify predictive factors of successful outcome in this context. Logistic regression analysis indicated that the number of vitrified oocytes was the only factor predictive of the oocyte survival rate and of clinical pregnancy. The addition of one vitrified oocyte increased by 15 % the odds of oocyte survival. When the oocyte survival rate was considered as a continuous variable, the following results were obtained: 7 % of clinical pregnancy probability for 50 % survival rate, 15 % for 75 % survival rate, and 32 % for 100 % survival rate. The rates of oocyte survival and fertilization, embryo implantation, and clinical pregnancy were in agreement with the recommended values established by ALPHA Scientists in Reproductive Medicine in 2012. On the basis of these results, and according to the European directives on safety, we validate the routine use of closed oocyte vitrification systems for egg donation programmes. These results must be confirmed in larger samples before extrapolation to all patient types.

Introduction: The Prospective and Retrospective Memory Questionnaire (PRMQ) is one of the most commonly used scales to assess both retrospective memory (RM) and prospective memory (PM) complaints. ...

Context Prokineticin 1 (PROK1) quantification in global follicular fluid (FF) has been recently reported as a predictive biomarker of in vitro fertilization (IVF) outcome. It is now necessary to evaluate its clinical usefulness in individual follicles. Objectives To evaluate the clinical value of PROK1 secretion in individual FF to predict oocyte competence. To determine the impact of follicular size, oocyte maturity, and gonadotropin treatments on PROK1 secretion. Design and setting Prospective cohort study from May 2015 to May 2017 at the University Hospital of Grenoble. Patients A total of 69 infertile couples underwent IVF. Intervention(s) Collection of 298 individual FF from 44 women undergoing IVF; 52 individual cumulus cell (CC) samples and 15 CC primary cultures from 25 women undergoing IVF-intracytoplasmic sperm injection (ICSI). Main Outcome Measure(s) Oocyte competence was defined as the ability to sustain embryo development to the blastocyst stage. Follicular size was measured by 2D-sonography. PROK1 concentration was quantified by ELISA assay. Results PROK1 concentration was correlated to follicular size (r = 0.85, P = 2.2 × 10−16). Normalized PROK1 concentration in FF was predictive of subsequent oocyte competence (AUROC curve = 0.76 [95% CI, 0.69–0.83]; P = 1.7 × 10−9), irrespectively of day-2 embryo morphokinetic parameters. The expression and secretion of PROK1 were increased in FF and CC of mature oocytes (P < 0.01). Follicle Stimulating Hormone and hCG up-regulated PROK1 secretion in CC primary cultures (P < 0.01; P < 0.05), probably through the cAMP pathway (P < 0.01). Conclusions PROK1 quantification in individual FF could constitute a new predictive biomarker of oocyte competence in addition with embryo morphokinetic parameters. Trial registration number none.

Abstract. This work aimed to assess the role of manual laterality in action coding strategies and, subsequently, in environmental features relevant for each hand’s action. Relying on Eder and Hommel’s (2013) proposal, we distinguished stimulus-related and end state-related consequences in a Simon paradigm where right-handed participants were divided into two groups, one responding with gloves and one without. Two objects were presented pictorially: one for which sensory consequences of grasping were negatively valenced (a chestnut burr), and one for which they were positively valenced (an apricot). By these means, stimulus and end-state effects could be assessed separately, along with the relevance of each feature of the experimental settings. Results showed that the use of one’s dominant or non dominant hand gives rise to different repercussions of stimulus-related and end state-related effects on response: Responses made with the right (dominant) hand were based on an elaborated coding (representing features of stimulus-related and end state-related consequences of action). In contrast, responses made with the left (non dominant) hand seemed to be based on a less elaborated coding (not taking into account end-state consequences of an action).

International audience; Reactive astrocytes exhibit hypertrophic morphology and altered metabolism. Deciphering astrocytic status would be of great importance to understand their role and dysregulation in pathologies, but most analytical methods remain highly invasive or destructive. The diffusion of brain metabolites, as non-invasively measured using diffusion-weighted magnetic resonance spectroscopy (DW-MRS) $in\ vivo$, depends on the structure of their micro-environment. Here we perform advanced DW-MRS in a mouse model of reactive astrocytes to determine how cellular compartments confining metabolite diffusion are changing. This reveals myo-inositol as a specific intra-astrocytic marker whose diffusion closely reflects astrocytic morphology, enabling non-invasive detection of astrocyte hypertrophy (subsequently confirmed by confocal microscopy $ex\ vivo$). Furthermore, we measure massive variations of lactate diffusion properties, suggesting that intracellular lactate is predominantly astrocytic under control conditions, but predominantly neuronal in case of astrocyte reactivity. This indicates massive remodeling of lactate metabolism, as lactate compartmentation is tightly linked to the astrocyte-to-neuron lactate shuttle mechanism.

Classically investigated in the context of judgment tasks about achievable actions, affordances have also been investigated in the context of the stimulus-response compatibility paradigm. Earlier work showed that perceptual categorization performance is significantly faster and more accurate when the orientation of the graspable part of a presented object, and the orientation of the participant's response are compatible, suggesting that the main function of affordances is restricted to action preparation. Here, we investigate the potential role of affordances in the categorization of ambiguous stimuli through a stimulus-response compatibility paradigm. In other words, we investigate if in ambiguous situations, such as ones in which a stimulus may give rise to two percepts, affordances would stabilize perception on one of these two and, therefore, helps in the subsequent categorizations. Two experiments were run, based on the forced-choice stimulus-response compatibility (SRC) paradigm, with a progressive series of ambiguous (bistable) lateral-graspable objects. In Experiment 1, subjects responded by pressing horizontally opposite keyboard keys, while in Experiment 2, the keyboard keys were vertically separated. Experiment 1 found that subjects perceived the initial object in a bistable series for longer, and exhibited greater response stability in compatible than incompatible situations. In Experiment 2, none of these modulations were significant. Overall, our results show that affordances operationalized through a SRC paradigm modulated how subjects categorized ambiguous stimuli. We argue that affordances may play a substantial role in ambiguous contexts by reducing the uncertainty of such situations.

The use of high-throughput sequencing techniques has allowed the identification of numerous mutations in genes responsible for severe astheno-teratozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). However, more than half of the analysed cases remain unresolved suggesting that many yet uncharacterised gene defects account for this phenotype. Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype. One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile). The CFAP70 gene encodes a regulator protein of the outer dynein arms (ODA) strongly expressed in the human testis. In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum. Moreover, IF analysis showed the absence of markers for the ODAs and the central pair complex of the axoneme. Interestingly, whereas CFAP70 staining was present in sperm cells from patients with mutations in the three other MMAF-related genes ARMC2, FSIP2 and CFAP43, we observed an absence of staining in sperm cells from patients mutated in the WDR66 gene, suggesting a possible interaction between two different axonemal components. In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF and that ODA-related proteins may be crucial for the assembly and/or stability of the flagellum axoneme in addition to its motility.

ObjectiveSustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α-synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate α-synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.

International audience; The potential value of succinylated soy protein (SPS) as a wall material for the encapsulation of ibuprofen (IBU), a model hydrophobic drug, by spray-drying was investigated. A succinylation rate of 93% was obtained for soy protein isolate, with a molar ratio of 1/1.5 (NH2/succinic anhydride). The solubility profile at 37°C showed that this chemical modification decreased the solubility of the protein below its isoelectric point, whereas solubility increased in alkaline conditions. Various SPS/IBU ratios (90/10, 80/20, and 60/40) were studied and compared with the same ratio of soy protein isolate (SPI/IBU). High encapsulation efficiency was achieved (91–95%). Microparticles were spherical and between 4 and 8 μm in diameter. The spray-drying of protein/IBU solutions appeared to be beneficial, as it resulted in an amorphous solid dispersion of IBU within the microparticles, coupled with an increase in the thermal stability of IBU. In vitro release was evaluated in acidic (pH 1.2 in the presence of pepsin) and neutral (pH 6.8) conditions similar to those in the gastrointestinal (GI) tract. IBU was released significantly more slowly at pH 1.2, for both proteins. However, this slowing was particularly marked for SPS, for which rapid (within 2 h) and complete release was observed at pH 6.8. These results validate the hypothesis that SPS is suitable for use as a coating material for hydrophobic active pharmaceutical ingredients (APIs) due to its pH sensitivity, which should delay IBU release in the gastrointestinal tract.

Birth weight (BW) is higher after frozen embryo transfer (FET) than after fresh embryo replacement. No study has compared the BW of siblings conceived using the same oocyte/embryo cohort. The aim of this study was to determine whether the freezing-thawing procedure is involved in such difference. Multicenter study at Montpellier University Hospital, Clinique Ovo, Canada and Grenoble-Alpes University Hospital. The first cohort (Fresh/FET) included in vitro fertilization (IVF) cycles where the older was born after fresh embryo transfer (n = 158) and the younger after transfer of frozen supernumerary embryos (n = 158). The second cohort (FET/FET) included IVF cycles where older and younger were born after FET of embryos from the same cohort. The mean adjusted BW of the FET group was higher than that of the fresh group (3508.9 ± 452.4 g vs 3237.7 ± 463.3 g; p vs 3337.1 ± 391.9 g; p = 0.3789). Our results strongly suggest that cryopreservation is directly involved in the BW variation. Comparing BW difference between Fresh/FET cohort and FET/FET one, it suggests that parity is not the only responsible, increasing the role of cryopreservation step in BW variation.

Embodied approaches of cognition argue that retrieval involves the re-enactment of both sensory and motor components of the desired remembering. In this study, we investigated the effect of motor action performed to produce the response in a recognition task when this action is compatible with the affordance of the objects that have to be recognised. In our experiment, participants were first asked to learn a list of words referring to graspable objects, and then told to make recognition judgements on pictures. The pictures represented objects where the graspable part was either pointing to the same or to the opposite side of the "Yes" response key. Results show a robust effect of compatibility between objects affordance and response hand. Moreover, this compatibility improves participants' ability of discrimination, suggesting that motor components are relevant cue for memory judgement at the stage of retrieval in a recognition task. More broadly, our data highlight that memory judgements are a function of motor components mappings at the stage of retrieval.

International audience; The concept of motor fluency, defined as the positive marking associated with the easy realisation of a movement, is used to explain the various compatibility effects observed between emotional valence and lateral space. In this work, we propose that these effects arise from the motor fluency simulation induced by emotionally positive stimuli. In a perceptual line bisection task (Landmark task) we primed each trial with an emotionally positive word, negative word, neutral word or no word before asking participants to verbally indicate the side of the vertical mark on the horizontal line (Experiment 1) or to indicate the longest side of the line (Experiment 2). After positive words and for bisected lines, participants’ responses were biased towards their dominant side for both right- and left-handers and similarly under the two different instructions. As movements of the dominant hand or in the dominant hemispace have been described as the most fluent lateral actions, this result supports our hypothesis that positive stimuli induce a mental simulation of fluent lateral movements. Furthermore, the replication of the effect under opposite instructions between the two experiments is in line with an explanation in terms of a bias in response selection rather than variations in perceptual content.

International audience; The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

STUDY QUESTION Does DNAH1 status influence intracytoplasmic sperm injection (ICSI) outcomes for patients with multiple morphological abnormalities of the sperm flagella (MMAF)? SUMMARY ANSWER Despite a highly abnormal morphology, sperm from MMAF patients with DNAH1 mutations have a low aneuploidy rate and good nuclear quality, leading to good embryonic development following ICSI and a high pregnancy rate. WHAT IS KNOWN ALREADY Teratozoospermia represents a heterogeneous group including a wide range of phenotypes. Among all these qualitative defects, a flagellar phenotype called MMAF is characterized by a mosaic of morphological abnormalities of the flagellum, including coiled, bent, irregular, short or/and absent flagella, mainly due to the absence of the axonemal central pair microtubules. We previously demonstrated that homozygous mutations in the DNAH1 gene, encoding an inner arm heavy chain dynein, are frequently found in patients with MMAF (28% of the patients from the initial cohort). Numerous studies have reported an increased rate of aneuploidy and a poor sperm nuclear quality related to sperm flagellar abnormalities, which could impede ICSI outcome. Moreover, success rates after ICSI may be influenced by the type of ultrastructural flagellar defects and/or by the gene defects carried by the patients. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 6 infertile males with MMAF due to deleterious homozygous DNAH1 mutations and their respective spouses, who underwent 9 ISCI cycles, with 16 embryos being transferred. ICSI results were compared with two control populations of 13 MMAF men without DNAH1 mutations and an aged-matched control group of 1431 non-MMAF couples. All ICSI attempts took place between 2000 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Clinical and biological data were collected from patients treated for infertility at the CPSR les Jasmins in Tunis (Tunisia). We compared the ICSI outcomes obtained with couples including DNAH1 mutated and nonmutated patients and non-MMAF couples. For the analysis of the chromosomal status, fluorescence in situ hybridization (FISH) analyses were performed on sperm cells from 3 DNAH1-mutated patients and from 29 fertile control subjects. Sperm chromatin condensation and DNA fragmentation were evaluated using aniline blue staining and TUNEL assays, respectively, on sperm cells from 3 DNAH1-mutated men and 6 fertile controls. MAIN RESULTS AND THE ROLE OF CHANCE There was a significantly increased proportion of disomy XY and 18 in sperm from DNAH1 mutated patients compared with fertile controls (1.52 versus 0.28%, P = 0.0001 and 0.64 versus 0.09%, P = 0.0001). However, there were no statistically significant differences among sperm from the two groups in their frequencies of either 13, 21, XX or YY disomy or diploidy. Measures of DNA compaction and fragmentation demonstrated a good nuclear sperm quality among DNAH1 mutated men. The overall fertilization, pregnancy and delivery rates of couples including DNAH1 mutated men were of 70.8, 50.0 and 37.5%, respectively. There were no statistically significant differences in any of these parameters compared with the two control groups (P > 0.05). LIMITATIONS, REASONS FOR CAUTION A limitation of this study is the small number of DNAH1-mutated patients available and the low number of genes identified in MMAF. Further genetic studies are warranted to identify other MMAF-inducing genes to better characterize the genetic etiology of the MMAF phenotype and to improve the management of patients diagnosed with flagellar defects. WIDER IMPLICATIONS OF THE FINDINGS MMAF patients with DNAH1 mutations have low aneuploidy rates and good nuclear sperm quality, explaining the high pregnancy rate obtained with these patients. Good ICSI results were obtained for both MMAF groups (DNAH1 mutated and nonmutated), suggesting that patients presenting with asthenozoospermia due to flagellar defects have a good ICSI prognosis irrespective of their genotype. The majority of MMAF cases currently remain idiopathic with no genetic cause yet identified. In depth genetic analysis of these patients using next generation sequencing should reveal new causal genes. Subsequent genotype phenotype analyses could improve advice and care provided to MMAF patients. STUDY FUNDING/COMPETING INTERESTS None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)', funded by the program GENOPAT 2009 from the French Research Agency (ANR) and the MAS-Flagella project, financed by the French ANR and the Direction Generale de l'Offre de Soins (DGOS).

International audience; Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD.

International audience; The total PSA testing has been frequently criticized for its effectiveness in the early detection of prostate cancer. These widely resumed in and out of the medical community have led to a decrease in prescriptions. Recommendations against the use of PSA for screening have been issued in France and in most countries. In the US, the significant decline in total PSA use since 2004 has led to an increase in advanced cancer diagnosis, which has led the authorities to back down. The US preventive services task force (USPSTF) now recommends that men between the ages of 55 and 69 make an individual decision about prostate cancer screening with their clinician. The purpose of this work is to summarize the good practices for the use of the total and free PSA with the views of these last data.