Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature ...of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood–brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near‐future strategy.
ABSTRACT The Large Volume Detector (LVD) has been continuously taking data since 1992 at the INFN Gran Sasso National Laboratory. The LVD is sensitive to neutrino bursts from gravitational stellar ...collapses with full detection probability over the Galaxy. We have searched for neutrino bursts in LVD data taken over 7,335 days of operation. No evidence of neutrino signals has been found between 1992 June and 2013 December. The 90% C.L. upper limit on the rate of core collapse and failed supernova explosions out to distances of 25 kpc is found to be 0.114 yr−1.
Current catalogs of brain expression quantitative trait loci (eQTL) are incomplete and the findings do not replicate well across studies. All existing cortical eQTL studies are small and emphasize ...the need for a meta-analysis. We performed a meta-analysis of 424 brain samples across five studies to identify regulatory variants influencing gene expression in human cortex. We identified 3584 genes in autosomes and chromosome X with false discovery rate q<0.05 whose expression was significantly associated with DNA sequence variation. Consistent with previous eQTL studies, local regulatory variants tended to occur symmetrically around transcription start sites and the effect was more evident in studies with large sample sizes. In contrast to random SNPs, we observed that significant eQTLs were more likely to be near 5'-untranslated regions and intersect with regulatory features. Permutation-based enrichment analysis revealed that SNPs associated with schizophrenia and bipolar disorder were enriched among brain eQTLs. Genes with significant eQTL evidence were also strongly associated with diseases from OMIM (Online Mendelian Inheritance in Man) and the NHGRI (National Human Genome Research Institute) genome-wide association study catalog. Surprisingly, we found that a large proportion (28%) of ~1000 autosomal genes encoding proteins needed for mitochondrial structure or function were eQTLs (enrichment P-value=1.3 × 10(-9)), suggesting a potential role for common genetic variation influencing the robustness of energy supply in brain and a possible role in the etiology of some psychiatric disorders. These systematically generated eQTL information should be a valuable resource in determining the functional mechanisms of brain gene expression and the underlying biology of associations with psychiatric disorders.
The purpose of this study was to compare videofluoroscopy (VFS), fiberoptic endoscopic evaluation of swallowing (FEES) and oro-pharyngo- oesophageal scintigraphy (OPES) with regards to premature ...spillage, post-swallowing residue and aspiration to assess the reliability of these tests for detection of oro-pharyngeal dysphagia. Sixty patients affected with dysphagia of various origin were enrolled in the study and submitted to VFS, FEES and OPES using a liquid and semi-solid bolus. As a reference, we used VFS. Both the FEES and the OPES showed good sensitivity with high overall values (≥ 80% and ≥ 90% respectively). The comparison between FEES vs VFS concerning drop before swallowing showed good specificity (84.4% for semi-solids and 86.7% for liquids). In the case of post-swallowing residue, FEES vs VFS revealed good overall validity (75% for semi-solids) with specificity and sensitivity well balanced for the semi-solids. OPES vs. VFS demonstrated good sensitivity (88.6%) and overall validity (76.7%) for liquids. The analysis of FEES vs. VFS for aspiration showed that the overall validity was low (≤ 65%). On the other hand, OPES demonstrated appreciable overall validity (71.7%). VFS, FEES and OPES are capable of detecting oro-pharyngeal dysphagia. FEES gave significant results in the evaluation of post-swallowing residues.
A novel nebulizer (nDS-200) working at sample uptake rates of less than 500 nL min-1 was developed for a sheathless interfacing of nanoHPLC (75-μm column i.d.) with ICPMS. It was based on a hollow ...fused-silica needle of which the tip (i.d. 10 μm, o.d. 20 μm) centered in a 254-μm-i.d. sapphire orifice. The nebulizer, equipped with a 3-cm3 drain-free vaporization chamber, enabled a stable introduction into an ICP of aqueous mobile phases containing up to 95% acetonitrile at eluent flow rates between 50 and 450 nL min-1. The low dead volume of the interface resulted in a peak width of 1.3 s (at half-height) and the entirely preserved chromatographic resolution. An example application of the coupling to the analysis of a tryptic digest of a SIP18 protein containing two to nine selenomethionine residues was described. The absolute detection limit was 25 fg (80Se), which allowed the detection of low-abundant selenopeptides at the femtomole level. In contrast to electrospray MS, the ICPMS detection in nanoHPLC is unaffected by the coeluting matrix and concomitant compounds and offers an elegant method for the detection and quantification of minor heteroelement-containing species prior to or in parallel with ESI MS analysis.
Membranes with molecular recognition properties were obtained by coagulation in the presence of compounds of biotechnological interest or by modification of non-imprinted membranes with the ...introduction of imprinted nanoparticles obtained by polymerisation of a monomer(s) in the presence of a stamp molecule (template). The functional binding performances in aqueous medium towards template molecules (uric acid, theophylline, caffeine or proteins) were investigated.
Membranes of acrylonitrile-acrylic acid copolymer imprinted with uric acid showed satisfactory recognition capacity and selectivity towards the template (rebinding of uric acid resulted 2.4 times higher than that of theophylline). Porous supports of ethylene-
co-vinyl alcohol-dextran blends were obtained using α-amylase as template and selective properties were confirmed by a rebinding of the stamp molecule 1.96 times higher than that of albumin. In some cases, recognition properties of methylmethacrylate-
co-acrylic acid membranes were enhanced by loading on the surface, or inside the membrane, imprinted cross-linked methylmethacrylate-methacrylic acid nanospheres. The different membranes realised are promising solutions for filtration or adsorption applications in biomedical field or for other biotechnological uses where biomimetic behaviour in water media is requested.
In the present study, a surface functionalization of a synthetic polyurethane was carried out by using biofunctional moieties to obtain a material with the appropriate mechanical properties and ...processing conditions and, at the same time, the advantages of a bioactive material. The polyurethane (PU) was synthesised from poly(ε-caprolactone) diol, 1,6-diisocyanatohexane and 1,4-cyclohexane dimethanol as chain extender. PU films were grafted with acrylic acid using argon plasma. The carboxyl groups formed were used to covalently bind model biomimetic/bioactive macromolecules (gelatine and poly (
l-lysine). All characterizations (attenuated total reflection Fourier transform infrared spectroscopy, ATR-FTIR; X-ray photoelectron spectroscopy, XPS; atomic force microscopy, AFM; scanning electron microscopy, SEM) confirmed the surface changes at each stage of treatment, both in morphology and in chemical composition. Besides, achieved treatment allowed to obtain a very thin layer of both PAA and macromolecules. Moreover, preliminary
in vitro tests were performed using NIH-3T3 fibroblasts as cell model. Both materials showed to support cell adhesion and growth, with poly (
l-lysine) performing better in activating cellular processes, as it can be seen by cell shape, which appears elongated on poly (
l-lysine) coating, whereas on gelatine, cells are more spherical and not uniformly distributed on the polymer surface.
Experimental data obtained using three scintillation detectors are analyzed. The characteristics of cosmogenic neutrons in underground experiments their analytic dependences are considered. The ...behavior of background counting rate for the LVD detector for two measuring thresholds (0.5 and 5 MeV) are discussed.
Gelatine was crosslinked by means of an enzymatic treatment using tissue transglutaminase (tTGase) (Sigma) and microbial transglutaminase (mTGase) (Ajinomoto) which catalyses the formation of ...isopeptide bonds between the gamma-carbonyl group of a glutamine residue and the epsilon-amino group of a lysine residue. The reaction is an interesting alternative to the traditional glutaraldehyde crosslinking, which has several drawbacks (e.g., in medical application) due to the toxicity of the chemical reagent. To further investigate the possibility to utilize the modified protein for tissue engineering application, TGase crosslinked gelatine was incorporated in a gellan matrix, a polysaccharide, to enhance the stability in aqueous media. Films obtained by casting were characterized by thermal analysis, chemical imaging, swelling behaviour and cell adhesion.
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