Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

International audienceDuring the development of the cerebral cortex, Cajal-Retzius (CR) cells settle in the preplate and coordinate the precise growth of the neocortex. Indeed, CR cells migrate tangentially from specific proliferative regions of the telencephalon (for example, the cortical hem (CH)) to populate the entire cortical surface. This is a very finely tuned process regulated by an emerging number of factors that has been sequentially revealed in recent years. However, the putative participation of one of the major families of axon guidance molecules in this process, the Semaphorins, was not explored. Here we show that Semaphorin-3E (Sema3E) is a natural negative regulator of the migration of PlexinD1-positive CR cells originating in the CH. Our results also indicate that Sema3E/PlexinD1 signalling controls the motogenic potential of CR cells in vitro and in vivo. Indeed, absence of Sema3E/PlexinD1 signalling increased the migratory properties of CR cells. This modulation implies negative effects on CXCL12/CXCR4 signalling and increased ADF/Cofilin activity

Mutual Antagonism between the Ebola Virus VP35 Protein and the RIG-I Activator PACT Determines Infection Outcome

SummaryThe cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts

Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity

BACKGROUND One injection of corifollitropin alfa replaces the first seven daily FSH injections in controlled ovarian stimulation (COS) cycles. Repeated treatment with therapeutic proteins may cause immune responses or hypersensitivity reactions. We assessed the immunogenicity and safety of corifollitropin alfa treatment in up to three COS cycles. METHODS In this multicentre, phase III uncontrolled trial, patients (>60 kg) started treatment with one injection of 150 µg corifollitropin alfa on cycle Day 2 or 3 of menses and 0.25 mg ganielix on stimulation Day 5 or 6. Primary outcome measures were antibody formation against corifollitropin alfa (using highly sensitive radioimmunoprecipitation assay), hypersensitivity reactions, local tolerance and adverse events (AEs). RESULTS First, second and third COS cycles were started by 682, 375 and 198 patients, respectively. No clinically relevant immunogenicity or drug-related hypersensitivity was observed. For 192 patients undergoing their third cycle a post-treatment blood sample was negative in the anti-corifollitropin antibody assay, resulting in an upper limit of the one-sided 95% confidence interval (CI) of 1.5%. Most frequent AEs were procedural pain (17.7%, 95% CI: 14.9–20.8%), headache (9.1%, 95% CI: 7.0–11.5%) and pelvic pain (7.6%, 95% CI: 5.7–9.9%). Cumulative ongoing pregnancy rate after three cycles, including frozen-thawed embryo transfer cycles and spontaneous pregnancies, was 61% (95% CI: 56–65%) after censoring for patients who discontinued. CONCLUSIONS Treatment with corifollitropin alfa can safely and effectively initiate and sustain ovarian stimulation during the first 7 days of COS in normal responder patients undergoing up to three treatment cycles, without concerns of immunogenicity.Robert J. Norman, Fernando Zegers-Hochschild, Bruno S. Salle, Jolanda Elbers, Esther Heijnen, Maya Marintcheva-Petrova, and Bernadette Mannaerts for the Trust Investigator

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

A model for presenting accelerometer paradata in large studies : ISCOLE

Background: We present a model for reporting accelerometer paradata (process-related data produced from survey administration) collected in the International Study of Childhood Obesity Lifestyle and the Environment (ISCOLE), a multi-national investigation of >7000 children (averaging 10.5 years of age) sampled from 12 different developed and developing countries and five continents. Methods: ISCOLE employed a 24-hr waist worn 7-day protocol using the ActiGraph GT3X+. Checklists, flow charts, and systematic data queries documented accelerometer paradata from enrollment to data collection and treatment. Paradata included counts of consented and eligible participants, accelerometers distributed for initial and additional monitoring (site specific decisions in the face of initial monitoring failure), inadequate data (e.g., lost/malfunction, insufficient wear time), and averages for waking wear time, valid days of data, participants with valid data (>= 4 valid days of data, including 1 weekend day), and minutes with implausibly high values (>= 20,000 activity counts/min). Results: Of 7806 consented participants, 7372 were deemed eligible to participate, 7314 accelerometers were distributed for initial monitoring and another 106 for additional monitoring. 414 accelerometer data files were inadequate (primarily due to insufficient wear time). Only 29 accelerometers were lost during the implementation of ISCOLE worldwide. The final locked data file consisted of 6553 participant files (90.0% relative to number of participants who completed monitoring) with valid waking wear time, averaging 6.5 valid days and 888.4 minutes/day (14.8 hours). We documented 4762 minutes with implausibly high activity count values from 695 unique participants (9.4% of eligible participants and Conclusions: Detailed accelerometer paradata is useful for standardizing communication, facilitating study management, improving the representative qualities of surveys, tracking study endpoint attainment, comparing studies, and ultimately anticipating and controlling costs.Peer reviewe

Surface Plasmon Resonance Reveals a Different Pattern of Proinsulin Autoantibodies Concentration and Affinity in Diabetic Patients

Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10−9 M and 3.50×107 M−1, respectively) than the adults (median 167.4×10−9 M and 0.84×107 M−1, respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction

The use of telepsychiatry within forensic practice: a literature review on the use of videolink: a ten-year follow-up

In the last decade, telepsychiatry – the use of telecommunications technologies to deliver psychiatric services from a distance – has been increasingly utilised in many areas of mental health care. Since the review by Khalifa and colleagues in 2007 the body of literature relevant to the forensic applications of telepsychiatry has grown substantially, albeit not by much in the United Kingdom. In the current review, we aim to provide an update summary of the literature published since 2007 to determine the effectiveness and feasibility of increasing telepsychiatry utilisation in forensic practice. The literature reviewed provides some encouraging evidence that telepsychiatry is a reliable, effective and highly acceptable method for delivering mental health care in forensic settings. There are also a number of papers that indicate the use of telepsychiatry may be cost effective for health providers in the longer term. Further research is required to consider the potential legal and ethical implications of using telepsychiatry in forensic settings

Relationships between Parental Education and Overweight with Childhood Overweight and Physical Activity in 9-11 Year Old Children: Results from a 12-Country Study

Background: Globally, the high prevalence of overweight and low levels of physical activity among children has serious implications for morbidity and premature mortality in adulthood. Various parental factors are associated with childhood overweight and physical activity. The objective of this paper was to investigate relationships between parental education or overweight, and (i) child overweight, (ii) child physical activity, and (iii) explore household coexistence of overweight, in a large international sample. Methods: Data were collected from 4752 children (9-11 years) as part of the International Study of Childhood Obesity, Lifestyle and the Environment in 12 countries around the world. Physical activity of participating children was assessed by accelerometry, and body weight directly measured. Questionnaires were used to collect parents' education level, weight, and height. Results: Maternal and paternal overweight were positively associated with child overweight. Higher household coexistence of parent-child overweight was observed among overweight children compared to the total sample. There was a positive relationship between maternal education and child overweight in Colombia 1.90 (1.23-2.94) [odds ratio (confidence interval)] and Kenya 4.80 (2.21-10.43), and a negative relationship between paternal education and child overweight in Brazil 0.55 (0.33-0.92) and the USA 0.54 (0.33-0.88). Maternal education was negatively associated with children meeting physical activity guidelines in Colombia 0.53 (0.33-0.85), Kenya 0.35 (0.19-0.63), and Portugal 0.54 (0.31-0.96). Conclusions: Results are aligned with previous studies showing positive associations between parental and child overweight in all countries, and positive relationships between parental education and child overweight or negative associations between parental education and child physical activity in lower economic status countries. Relationships between maternal and paternal education and child weight status and physical activity appear to be related to the developmental stage of different countries. Given these varied relationships, it is crucial to further explore familial factors when investigating child overweight and physical activity

IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry

To replicate, viruses must gain access to the host cell's resources. Interferon (IFN) regulates the actions of a large complement of interferon effector genes (IEGs) that prevent viral replication. The interferon inducible transmembrane protein family members, IFITM1, 2 and 3, are IEGs required for inhibition of influenza A virus, dengue virus, and West Nile virus replication in vitro. Here we report that IFN prevents emergence of viral genomes from the endosomal pathway, and that IFITM3 is both necessary and sufficient for this function. Notably, viral pseudoparticles were inhibited from transferring their contents into the host cell cytosol by IFN, and IFITM3 was required and sufficient for this action. We further demonstrate that IFN expands Rab7 and LAMP1-containing structures, and that IFITM3 overexpression is sufficient for this phenotype. Moreover, IFITM3 partially resides in late endosomal and lysosomal structures, placing it in the path of invading viruses. Collectively our data are consistent with the prediction that viruses that fuse in the late endosomes or lysosomes are vulnerable to IFITM3's actions, while viruses that enter at the cell surface or in the early endosomes may avoid inhibition. Multiple viruses enter host cells through the late endocytic pathway, and many of these invaders are attenuated by IFN. Therefore these findings are likely to have significance for the intrinsic immune system's neutralization of a diverse array of threats