Polynuclear Cu4I4py4 complex loaded in mesoporous silica: Photophysics, theoretical investigation, and highly sensitive oxygen sensing application

The polynuclear Cu4I4py4 complex has been largely studied in solution and in the powder form due to its interesting luminescent properties, which are largely dependent on temperature and pressure. In this work, we present the synthesis of the complex and its wet impregnation in a mesoporous silica host obtained by sol-gel methodology. For optimized guest loadings, the well-dispersed guest molecules exhibit strong interaction with molecular oxygen, resulting in a significant quenching of the luminescence. The process is highly reversible with a Stern-Volmer constant of Ksv = 33.8, which is the largest value found in the literature for similar complexes in the solid state, suggesting that the new material is a promising candidate for high sensitivity oxygen sensing. Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT) calculations reveal a weak intermolecular interaction between two guest complexes in the excited state, suggesting the formation of an excited state complex (excimer). The assumption of triplet excimer formation is confirmed by temperature- and concentration-dependent experiments, which provides a new way to explain the giant Stokes shift observed for the guest complex in different media

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Stochastic Gravity: Theory and Applications

Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein-Langevin equation, which has in addition sources due to the noise kernel.In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime: we compute the two-point correlation functions for the linearized Einstein tensor and for the metric perturbations. Second, we discuss structure formation from the stochastic gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a quasi-static black hole.Comment: 75 pages, no figures, submitted to Living Reviews in Relativit

Proinflammatory genotype is associated with the frailty phenotype in the English Longitudinal Study of Ageing

Background: Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic–pituitary–adrenal axis and heightened chronic systemic inflammation appear to be major contributors. Methods: We used the English Longitudinal Study of Ageing dataset of 3160 individuals over the age of 50 and assessed their frailty status according to the Fried-criteria. We selected single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways and performed linear association analysis using age and sex as covariates. To support the biological plausibility of any genetic associations, we selected biomarker levels for further analyses to act as potential endophenotypes of our chosen genetic loci. Results: The strongest association with frailty was observed in the Tumor Necrosis Factor (TNF) (rs1800629, P = 0.001198, β = 0.0894) and the Protein Tyrosine Phosphatase, Receptor type, J (PTPRJ) (rs1566729, P = 0.001372, β = 0.09397) genes. Rs1800629 was significantly associated with decreased levels of high-density lipoprotein (HDL) (P = 0.00949) and cholesterol levels (P = 0.00315), whereas rs1566729 was associated with increased levels of HDL (P = 0.01943). After correcting for multiple testing none of the associations remained significant. Conclusions: We provide potential evidence for the involvement of a multifunctional proinflammatory cytokine gene (TNF) in the frailty phenotype. The implication of this gene is further supported by association with the endophenotype biomarker results

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

Prova tipográfica (In Press)An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7a-(acetylthio)-3-oxo-17a-pregn- 4-ene,21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7a,17a)-17-Hydroxy-3-oxo-7- propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR

Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

Data-driven inference for the spatial scan statistic

<p>Abstract</p> <p>Background</p> <p>Kulldorff's spatial scan statistic for aggregated area maps searches for clusters of cases without specifying their size (number of areas) or geographic location in advance. Their statistical significance is tested while adjusting for the multiple testing inherent in such a procedure. However, as is shown in this work, this adjustment is not done in an even manner for all possible cluster sizes.</p> <p>Results</p> <p>A modification is proposed to the usual inference test of the spatial scan statistic, incorporating additional information about the size of the most likely cluster found. A new interpretation of the results of the spatial scan statistic is done, posing a modified inference question: what is the probability that the null hypothesis is rejected for the original observed cases map with a most likely cluster of size k, taking into account only those most likely clusters of size k found under null hypothesis for comparison? This question is especially important when the p-value computed by the usual inference process is near the alpha significance level, regarding the correctness of the decision based in this inference.</p> <p>Conclusions</p> <p>A practical procedure is provided to make more accurate inferences about the most likely cluster found by the spatial scan statistic.</p

AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease.

Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. To date, there is no treatment to halt or reverse the course of HD. Lowering of either total or only the mutant HTT expression is expected to have therapeutic benefit. This can be achieved by engineered micro (mi)RNAs targeting HTT transcripts and delivered by an adeno-associated viral (AAV) vector. We have previously showed a miHTT construct to induce total HTT knock-down in Hu128/21 HD mice, while miSNP50T and miSNP67T constructs induced allele-selective HTT knock-down in vitro. In the current preclinical study, the mechanistic efficacy and gene specificity of these selected constructs delivered by an AAV serotype 5 (AAV5) vector was addressed using an acute HD rat model. Our data demonstrated suppression of mutant HTT messenger RNA, which almost completely prevented mutant HTT aggregate formation, and ultimately resulted in suppression of DARPP-32-associated neuronal dysfunction. The AAV5-miHTT construct was found to be the most efficient, although AAV5-miSNP50T demonstrated the anticipated mutant HTT allele selectivity and no passenger strand expression. Ultimately, AAV5-delivered-miRNA-mediated HTT lowering did not cause activation of microglia or astrocytes suggesting no immune response to the AAV5 vector or therapeutic precursor sequences. These preclinical results suggest that using gene therapy to knock-down HTT may provide important therapeutic benefit for HD patients and raised no safety concerns, which supports our ongoing efforts for the development of an RNA interference-based gene therapy product for HD

Chemical Composition and Antifungal Properties of Essential Oil of Origanum vulgare Linnaeus (Lamiaceae) against Sporothrix schenckii and Sporothrix brasiliensis

Purpose: To evaluate the effect of the essential oil of Origanum vulgare Linnaeus (Lamiaceae) on the growth of Sporothrix schenckii and Sporothrix brasiliensis.Methods: The chemical composition of the essential oil was investigated by gas chromatography/flame ionization detector (GC-FID). The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined by broth micro-dilution method. Scanning electron microscopy (SEM) was also performed to reveal morphological alterations in Sporothrix spp. cells.Results: The major components of the essential oil were γ-terpinene (30.5%), carvacrol (15.7 %) and 4-terpineol (13.0 %). γ-Terpinene showed potential antifungal activity with MIC ranging from 62.5 to 500.0 μg mL-1 for S. schenckii, and 125.0 to 250.0 μg mL-1 for S. brasiliensis. SEM micrographs revealed morphological alterations in hyphae and reduction of the adhered conidia numbers.Conclusion: Origanum vulgare Linnaeus essential oil possesses potential antifungal activity, and can, therefore, can be developed as an alternative agent for the treatment of sporotrichosis.Keywords: Antifungal Activity, Essential Oil, Gas Chromatography, Origanum vulgare, Sporotrichosi