Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression

Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated

An Open Logical Framework

The LFP Framework is an extension of the Harper-Honsell-Plotkin's Edinburgh Logical Framework LF with external predicates, hence the name Open Logical Framework. This is accomplished by defining lock type constructors, which are a sort of \u25a1-modality constructors, releasing their argument under the condition that a possibly external predicate is satisfied on an appropriate typed judgement. Lock types are defined using the standard pattern of constructive type theory, i.e. via introduction, elimination and equality rules. Using LFP, one can factor out the complexity of encoding specific features of logical systems, which would otherwise be awkwardly encoded in LF, e.g. side-conditions in the application of rules in Modal Logics, and sub-structural rules, as in non-commutative Linear Logic. The idea of LFP is that these conditions need only to be specified, while their verification can be delegated to an external proof engine, in the style of the Poincar Principle or Deduction Modulo. Indeed such paradigms can be adequately formalized in LFP. We investigate and characterize the meta-theoretical properties of the calculus underpinning LFP: strong normalization, confluence and subject reduction. This latter property holds under the assumption that the predicates are well-behaved, i.e. closed under weakening, permutation, substitution and reduction in the arguments. Moreover, we provide a canonical presentation of LFP, based on a suitable extension of the notion of \u3b2\u3b7-long normal form, allowing for smooth formulations of adequacy statements. \ua9 The Author, 2013

Expanding the Known Repertoire of C-Type Lectin Receptors Binding to Toxoplasma gondii Oocysts Using a Modified High-Resolution Immunofluorescence Assay

The environmental stage of the apicomplexan Toxoplasma gondii oocyst is vital to its life cycle but largely understudied. Because oocysts are excreted only by infected felids, their availability for research is limited. We report the adaptation of an agarose-based method to immobilize minute amounts of oocysts to perform immunofluorescence assays. Agarose embedding allows high-resolution confocal microscopy imaging of antibodies binding to the oocyst surface as well as unprecedented imaging of intracellular sporocyst structures with Maclura pomifera agglutinin after on-slide permeabilization of the immobilized oocysts. To identify new possible molecules binding to the oocyst surface, we used this method to screen a library of C-type lectin receptor (CLR)-human IgG constant region fusion proteins from the group of related CLRs called the Dectin-1 cluster against oocysts. In addition to CLEC7A that was previously reported to decorate T. gondii oocysts, we present experimental evidence for specific binding of three additional CLRs to the surface of this stage. We discuss how these CLRs, known to be expressed on neutrophils, dendritic cells, or macrophages, could be involved in the early immune response by the host, such as oocyst antigen uptake in the intestine. In conclusion, we present a modified immunofluorescence assay technique that allows material-saving immunofluorescence microscopy with T. gondii oocysts in a higher resolution than previously published, which allowed us to describe three additional CLRs binding specifically to the oocyst surface. IMPORTANCE Knowledge of oocyst biology of Toxoplasma gondii is limited, not the least due to its limited availability. We describe a method that permits us to process minute amounts of oocysts for immunofluorescence microscopy without compromising their structural properties. This method allowed us to visualize internal structures of sporocysts by confocal microscopy in unprecedented quality. Moreover, the method can be used as a low- to medium-throughput method to screen for molecules interacting with oocysts, such as antibodies, or compounds causing structural damage to oocysts (i.e., disinfectants). Using this method, we screened a small library of C-type lectin receptors (CLRs) present on certain immune cells and found three CLRs able to decorate the oocyst wall of T. gondii and which were not known before to bind to oocysts. These tools will allow further study into oocyst wall composition and could also provoke experiments regarding immunological recognition of oocysts.Peer Reviewe

Variable Curvature Slab Molecular Dynamics as a Method to Determine Surface Stress

A thin plate or slab, prepared so that opposite faces have different surface stresses, will bend as a result of the stress difference. We have developed a classical molecular dynamics (MD) formulation where (similar in spirit to constant-pressure MD) the curvature of the slab enters as an additional dynamical degree of freedom. The equations of motion of the atoms have been modified according to a variable metric, and an additional equation of motion for the curvature is introduced. We demonstrate the method to Au surfaces, both clean and covered with Pb adsorbates, using many-body glue potentials. Applications to stepped surfaces, deconstruction and other surface phenomena are under study.Comment: 16 pages, 8 figures, REVTeX, submitted to Physical Review

Identification and manipulation of dynamic active site deficiency-induced competing reactions in electrocatalytic oxidation processes

A detrimental competition between the urea oxidation reaction (UOR) and oxygen evolution reaction is identified. Strategies are proposed to alleviate such competition and boost the performance of the UOR and other organic compound oxidation reactions

JWST/NIRCam Coronagraphy of the Young Planet-hosting Debris Disk AU Microscopii

High-contrast imaging of debris disk systems permits us to assess the composition and size distribution of circumstellar dust, to probe recent dynamical histories, and to directly detect and characterize embedded exoplanets. Observations of these systems in the infrared beyond 2--3 $\mu$m promise access to both extremely favorable planet contrasts and numerous scattered-light spectral features -- but have typically been inhibited by the brightness of the sky at these wavelengths. We present coronagraphy of the AU Microscopii (AU Mic) system using JWST's Near Infrared Camera (NIRCam) in two filters spanning 3--5 $\mu$m. These data provide the first images of the system's famous debris disk at these wavelengths and permit additional constraints on its properties and morphology. Conducting a deep search for companions in these data, we do not identify any compelling candidates. However, with sensitivity sufficient to recover planets as small as $\sim 0.1$ Jupiter masses beyond $\sim 2^{\prime\prime}$ ($\sim 20$ au) with $5\sigma$ confidence, these data place significant constraints on any massive companions that might still remain at large separations and provide additional context for the compact, multi-planet system orbiting very close-in. The observations presented here highlight NIRCam's unique capabilities for probing similar disks in this largely unexplored wavelength range, and provide the deepest direct imaging constraints on wide-orbit giant planets in this very well studied benchmark system.Comment: 27 pages, 14 figure

Approaching theoretical performances of electrocatalytic hydrogen peroxide generation by cobalt‐nitrogen moieties

Electrocatalytic oxygen reduction reaction (ORR) has been intensively studied for environmentally benign applications. However, insufficient understanding of ORR 2 e−‐pathway mechanism at the atomic level inhibits rational design of catalysts with both high activity and selectivity, causing concerns including catalyst degradation due to Fenton reaction or poor efficiency of H2O2 electrosynthesis. Herein we show that the generally accepted ORR electrocatalyst design based on a Sabatier volcano plot argument optimises activity but is unable to account for the 2 e−‐pathway selectivity. Through electrochemical and operando spectroscopic studies on a series of CoN x /carbon nanotube hybrids, a construction‐driven approach based on an extended “dynamic active site saturation” model that aims to create the maximum number of 2 e− ORR sites by directing the secondary ORR electron transfer towards the 2 e− intermediate is proven to be attainable by manipulating O2 hydrogenation kinetics

The Near Infrared Imager and Slitless Spectrograph for JWST -- V. Kernel Phase Imaging and Data Analysis

Kernel phase imaging (KPI) enables the direct detection of substellar companions and circumstellar dust close to and below the classical (Rayleigh) diffraction limit. We present a kernel phase analysis of JWST NIRISS full pupil images taken during the instrument commissioning and compare the performance to closely related NIRISS aperture masking interferometry (AMI) observations. For this purpose, we develop and make publicly available the custom "Kpi3Pipeline" enabling the extraction of kernel phase observables from JWST images. The extracted observables are saved into a new and versatile kernel phase FITS file (KPFITS) data exchange format. Furthermore, we present our new and publicly available "fouriever" toolkit which can be used to search for companions and derive detection limits from KPI, AMI, and long-baseline interferometry observations while accounting for correlated uncertainties in the model fitting process. Among the four KPI targets that were observed during NIRISS instrument commissioning, we discover a low-contrast (~1:5) close-in (~1 $\lambda/D$) companion candidate around CPD-66~562 and a new high-contrast (~1:170) detection separated by ~1.5 $\lambda/D$ from 2MASS~J062802.01-663738.0. The 5-$\sigma$ companion detection limits around the other two targets reach ~6.5 mag at ~200 mas and ~7 mag at ~400 mas. Comparing these limits to those obtained from the NIRISS AMI commissioning observations, we find that KPI and AMI perform similar in the same amount of observing time. Due to its 5.6 times higher throughput if compared to AMI, KPI is beneficial for observing faint targets and superior to AMI at separations >325 mas. At very small separations (<100 mas) and between ~250-325 mas, AMI slightly outperforms KPI which suffers from increased photon noise from the core and the first Airy ring of the point-spread function.Comment: 34 pages, 17 figures, accepted for publication in PAS

Spectroscopic and computational insights on catalytic synergy in bimetallic aluminophosphate catalysts

A combined electronic structure computational and X-ray absorption spectroscopy study was used to investigate the nature of the active sites responsible for catalytic synergy in Co-Ti bimetallic nanoporous frameworks. Probing the nature of the molecular species at the atomic level has led to the identification of a unique Co-O-Ti bond, which serves as the loci for the superior performance of the bimetallic catalyst, when compared with its analogous monometallic counterpart. The structural and spectroscopic features associated with this active site have been characterized and contrasted, with a view to affording structure property relationships, in the wider context of designing sustainable catalytic oxidations with porous solids