A Solution to the Horizon Problem: A Delayed Big-Bang Singularity

One of the main drawbacks of standard cosmology, known as the horizon problem, was until now thought to be only solvable in an inflationary scenario. A delayed Big-Bang in an inhomogeneous universe is shown to solve this problem while leaving unimpaired the main successful features of the standard model.Comment: 18 LaTeX pages and 2 figures, accepted for publication in Physics Letters

The Natural Antimicrobial Chromogranins/Secretogranins- Derived Peptides – Production, Lytic Activity and Processing by Bacterial Proteases

International audienc

Multifaceted Regulations of the Serotonin Transporter: Impact on Antidepressant Response

Serotonin transporter, SERT (SLC64A for solute carrier family 6, member A4), is a twelve transmembrane domain (TMDs) protein that assumes the uptake of serotonin (5-HT) through dissipation of the Na+ gradient established by the electrogenic pump Na/K ATPase. Abnormalities in 5-HT level and signaling have been associated with various disorders of the central nervous system (CNS) such as depression, obsessive-compulsive disorder, anxiety disorders, and autism spectrum disorder. Since the 50s, SERT has raised a lot of interest as being the target of a class of antidepressants, the Serotonin Selective Reuptake Inhibitors (SSRIs), used in clinics to combat depressive states. Because of the refractoriness of two-third of patients to SSRI treatment, a better understanding of the mechanisms regulating SERT functions is of priority. Here, we review how genetic and epigenetic regulations, post-translational modifications of SERT, and specific interactions between SERT and a set of diverse partners influence SERT expression, trafficking to and away from the plasma membrane and activity, in connection with the neuronal adaptive cell response to SSRI antidepressants

An Outer Membrane Vesicle-Based Permeation Assay (OMPA) for Assessing Bacterial Bioavailability

When searching for new antibiotics against Gram-negative bacterial infections, a better understanding of the permeability across the cell envelope and tools to discriminate high from low bacterial bioavailability compounds are urgently needed. Inspired by the phospholipid vesicle-based permeation assay (PVPA), which is designed to predict non-facilitated permeation across phospholipid membranes, outer membrane vesicles (OMVs) of Escherichia coli either enriched or deficient of porins are employed to coat filter supports for predicting drug uptake across the complex cell envelope. OMVs and the obtained in vitro model are structurally and functionally characterized using cryo-TEM, SEM, CLSM, SAXS, and light scattering techniques. In vitro permeability, obtained from the membrane model for a set of nine antibiotics, correlates with reported in bacterio accumulation data and allows to discriminate high from low accumulating antibiotics. In contrast, the correlation of the same data set generated by liposome-based comparator membranes is poor. This better correlation of the OMV-derived membranes points to the importance of hydrophilic membrane components, such as lipopolysaccharides and porins, since those features are lacking in liposomal comparator membranes. This approach can offer in the future a high throughput screening tool with high predictive capacity or can help to identify compound- and bacteria-specific passive uptake pathways

Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid patients who have complex social and psychological characteristics

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils' time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies

Enjeux et solutions pour la sylviculture intensive de plantations dans un contexte d'aménagement écosystémique

Les plantations forestières représentent un outil sylvicole reconnu pour assurer un approvisionnement en matière ligneuse qui répond aux attentes de la société envers l'aménagement durable des forêts. Toutefois, elles font aussi partie du scénario sylvicole qui a le plus grand potentiel d'artificialisation de la forêt naturelle. Les objectifs de la sylviculture intensive de plantations peuvent alors paraître, de prime abord, en contradiction avec ceux de l'aménagement écosystémique. Nous décrivons le processus par lequel nous avons défini et documenté des enjeux associés aux plantations et proposé des pistes de solutions pour que la sylviculture intensive de plantations puisse s'intégrer à l'aménagement écosystémique. Nous avons identifié des enjeux relatifs à l'ampleur, à la localisation et à l'agencement spatial des plantations, aux attributs clés et à la résilience de la forêt naturelle, à l'acceptabilité sociale, ainsi qu’à la productivité et à la rentabilité des plantations. Nous avons également proposé des pistes de solutions qui permettraient de réaliser les plantations dans un contexte d'aménagement écosystémique, telles que la modulation des traitements sylvicoles pour augmenter la naturalité des plantations, la réalisation des traitements de manière à obtenir la production attendue, ainsi qu'un déploiement dans le paysage qui intègre les préoccupations des parties prenantes et qui considère la naturalité de la matrice forestière. Forest plantations are recognized as a silvicultural tool for ensuring a timber supply that meets public expectations regarding sustainable forest management. However, they are also part of the silvicultural scenario that shows the greatest potential for the artificialization of natural forests. From a firsthand perspective, intensive plantation silviculture objectives may appear antagonistic to those of ecosystem management. Here we describe the process through which we defined and documented plantation issues, then propose potential solutions to allow the integration of intensive plantation silviculture into ecosystem management. We identify issues related to the scale, localization and spatial arrangement of plantations, the key attributes and resilience of natural forests, social acceptability, and the productivity and profitability of plantations. We also propose potential solutions likely to help manage plantations within a context of ecosystem management. These include modulating silvicultural treatments to enhance the naturalness of plantations, conducting treatments to obtain expected production rates, and ensuring that plantations are deployed across the landscape in a manner that integrates stakeholder concerns and considers the naturalness of the forest matrix