Perisaccadic perceptual mislocalization strength depends on the visual appearance of saccade targets.

We normally perceive a stable visual environment despite eye movements. To achieve such stability, visual processing integrates information across a given saccade, and laboratory hallmarks of such integration are robustly observed by presenting brief perisaccadic visual probes. In one classic phenomenon, probe locations are grossly mislocalized.

Evaluation of digital medical devices: How to take into account the specificities of these solutions?

The beginning of the 21st century has seen an increasing number of digital medical devices (DMDs) arrive on the European market, bringing major benefits and changes for society. DMDs are unique in that they bring intelligence to the organisation of care, and generate and collect a wealth of real-life data with ultra-fast life cycles. They have specific requirements, particularly in terms of data security and interoperability.

Sensory tuning in neuronal movement commands.

Movement control is critical for successful interaction with our environment. However, movement does not occur in complete isolation of sensation, and this is particularly true of eye movements. Here, we show that the neuronal eye movement commands emitted by the superior colliculus (SC), a structure classically associated with oculomotor control, encompass a robust visual sensory representation of eye movement targets.

Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models.

Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present study was to assess the predictability of human pharmacokinetics by using biphasic dissolution results obtained with the previously established BiPHa+ assay and PBPK tools. For six commercial drug products, formulated by different enabling technologies, the respective organic partitioning profiles were processed with two PBPK in silico modeling tools, namely PK-Sim and GastroPlus, similar to extended-release dissolution profiles.

Metabolically-incorporated deuterium in myelin localized by neutron diffraction and identified by mass spectrometry.

Myelin is a natural and dynamic multilamellar membrane structure that continues to be of significant biological and neurological interest, especially with respect to its biosynthesis and assembly during its normal formation, maintenance, and pathological breakdown. To explore the usefulness of neutron diffraction in the structural analysis of myelin, we investigated the use of labeling by metabolically incorporating non-toxic levels of deuterium (H; D) via drinking water into a pregnant dam (D-dam) and her developing embryos. All of the mice were sacrificed when the pups (D-pups) were 55 days old.

Target Site Pharmacokinetics of Meropenem: Measurement in Human Explanted Lung Tissue by Bronchoalveolar Lavage, Microdialysis, and Homogenized Lung Tissue.

Pneumonia is one of the most common infections in intensive care patients, and it is often treated with beta-lactam antibiotics. Even if therapeutic drug monitoring in blood is available, it is unclear whether sufficient concentrations are reached at the target site: the lung. The present study was initiated to fill this knowledge gap.

The relevance of supersaturation and solubilization in the gastrointestinal tract for oral bioavailability: An in vitro vs. in vivo approach.

The influence of supersaturation and solubilization on oral absorption was assessed independently from the dissolution process for the non-formulated model drugs celecoxib and telmisartan. In vitro, physicochemical characterization and biphasic dissolution were used to characterize the supersaturation and solubilization effects of three water soluble polymers (copovidone, methylcellulose and Soluplus®) on the drugs. While celecoxib precipitated in a crystalline form resulting in pronounced stabilization of supersaturation, telmisartan precipitated as a highly energetic amorphous form and the potential of the polymers to enhance its solubility was subsequently, limited.

Shared IVIVR for Five Commercial Enabling Formulations Using the BiPHa+ Biphasic Dissolution Assay.

The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. The in vitro partitioning profiles in the organic phase were compared with human pharmacokinetic data obtained from literature.

A Rational Design of a Biphasic DissolutionSetup-Modelling of Biorelevant Kinetics for a Ritonavir Hot-Melt Extruded Amorphous Solid Dispersion.

Biphasic dissolution systems achieved good predictability for the in vivo performance of several formulations of poorly water-soluble drugs by characterizing dissolution, precipitation, re-dissolution, and absorption. To achieve a high degree of predictive performance, acceptor media, aqueous phase composition, and the apparatus type have to be carefully selected. Hence, a combination of 1-decanol and an optimized buffer system are proposed as a new, one-vessel biphasic dissolution method (BiPHa+).

Phosphorylation of Glutamine Synthetase on Threonine 301 Contributes to Its Inactivation During Epilepsy.

The astrocyte-specific enzyme glutamine synthetase (GS), which catalyzes the amidation of glutamate to glutamine, plays an essential role in supporting neurotransmission and in limiting NH toxicity. Accordingly, deficits in GS activity contribute to epilepsy and neurodegeneration. Despite its central role in brain physiology, the mechanisms that regulate GS activity are poorly defined.

Myelin structure in unfixed, single nerve fibers: Scanning X-ray microdiffraction with a beam size of 200nm.

Previous raster-scanning with a 1μm X-ray beam of individual, myelinated fibers from glutaraldehyde-fixed rat sciatic nerve revealed a spatially-dependent variation in the diffraction patterns from single fibers. Analysis indicated differences in the myelin periodicity, membrane separations, distribution of proteins, and orientation of membrane lamellae. As chemical fixation is known to produce structural artifacts, we sought to determine in the current study whether the structural heterogeneity is intrinsic to unfixed myelin.

rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System.

Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD.

Claudin-11 Tight Junctions in Myelin Are a Barrier to Diffusion and Lack Strong Adhesive Properties.

The radial component is a network of interlamellar tight junctions (TJs) unique to central nervous system myelin. Ablation of claudin-11, a TJ protein, results in the absence of the radial component and compromises the passive electrical properties of myelin. Although TJs are known to regulate paracellular diffusion, this barrier function has not been directly demonstrated for the radial component, and some evidence suggests that the radial component may also mediate adhesion between myelin membranes.

Plasmalogen phospholipids protect internodal myelin from oxidative damage.

Reactive oxygen species (ROS) are implicated in a range of degenerative conditions, including aging, neurodegenerative diseases, and neurological disorders. Myelin is a lipid-rich multilamellar sheath that facilitates rapid nerve conduction in vertebrates. Given the high energetic demands and low antioxidant capacity of the cells that elaborate the sheaths, myelin is considered intrinsically vulnerable to oxidative damage, raising the question whether additional mechanisms prevent structural damage.

Neutron scattering from myelin revisited: bilayer asymmetry and water-exchange kinetics.

Rapid nerve conduction in the central and peripheral nervous systems (CNS and PNS, respectively) of higher vertebrates is brought about by the ensheathment of axons with myelin, a lipid-rich, multilamellar assembly of membranes. The ability of myelin to electrically insulate depends on the regular stacking of these plasma membranes and on the presence of a number of specialized membrane-protein assemblies in the sheath, including the radial component, Schmidt-Lanterman incisures and the axo-glial junctions of the paranodal loops. The disruption of this fine-structure is the basis for many demyelinating neuropathies in the CNS and PNS.

A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice.

Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤ 1 month) AspA(-/-) mice, a bona-fide animal model for the severest form of CD.

Environmental occurrence and fate of semifluorinated n-alkanes in snow and soil samples from a ski area.

Semifluorinated n-alkanes (SFAs) with carbon chain lengths of 22 to approximately 36 atoms are present in fluorinated ski waxes to reduce the friction between ski base and snow, resulting in a better glide. Semifluorinated n-alkenes (SFAenes) are byproducts in the production process of SFAs and are also found in ski waxes. Snow and soil samples from a ski area in Sweden were taken after a large skiing competition and after snowmelt, respectively, and analyzed for SFAs and SFAenes.

Decreased sensitivity to changes in the concentration of metal ions as the basis for the hyperactivity of DtxR(E175K).

The metal-ion-activated diphtheria toxin repressor (DtxR) is responsible for the regulation of virulence and other genes in Corynebacterium diphtheriae. A single point mutation in DtxR, DtxR(E175K), causes this mutant repressor to have a hyperactive phenotype. Mice infected with Mycobacterium tuberculosis transformed with plasmids carrying this mutant gene show reduced signs of the tuberculosis infection.

Role of the N-terminal helix in the metal ion-induced activation of the diphtheria toxin repressor DtxR.

The metal ion-regulated transcriptional repressor DtxR has been shown to repress the transcription of the diphtheria toxin and other genes associated with ferrous ion homeostasis in Corynebacterium diphtheriae. In vivo studies of single-alanine mutations located in the N-terminal helix of DtxR show that the activity of the mutants is reduced compared to that of the wild type. The three-dimensional structures of the apo and activated forms of DtxR show conformational changes in the N-terminal helix resulting from metal ion activation.

Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation.

Fibroblast growth factor receptor (FGFR) signaling is essential for nervous system development. We have shown that, in the normal postnatal brain, the spatial and temporal expression pattern of FGFR3 parallels the appearance of differentiated oligodendrocytes and that in culture FGFR3 is expressed maximally at the critical stage in the lineage at which oligodendrocyte late progenitors (Pro-OLs) enter terminal differentiation. Therefore, FGFR3 expression is positioned ideally to have an impact on oligodendrocyte differentiation.

Solution structure of a viral DNA repair polymerase.

DNA polymerase X (Pol X) from the African swine fever virus (ASFV) specifically binds intermediates in the single-nucleotide base-excision repair process, an activity indicative of repair function. In addition, Pol X catalyzes DNA polymerization with low nucleotide-insertion fidelity. The structural mechanisms by which DNA polymerases confer high or low fidelity in DNA polymerization remain to be elucidated.

Characterization of two point mutations in the androgen receptor gene of patients with perineoscrotal hypospadia.

Perineoscrotal hypospadia is a major sign of sexual ambiguity due to inadequate androgen action in genetic and gonadal males. In patients showing these symptoms we have detected two androgen receptor gene mutations. In consequence we characterized the properties of the mutant receptors with respect to hormone-binding, transactivation and DNA-binding.

A mutant androgen receptor from patients with Reifenstein syndrome: identification of the function of a conserved alanine residue in the D box of steroid receptors.

Reifenstein syndrome is an eponymic term that describes partial androgen-insensitive disorders. Androgen receptor isolated from five patients with this syndrome contains a specific mutation in the DNA binding domain of the receptor. This mutation converts an alanine to a threonine at position 596 next to the zinc catenation site at the second finger.