Functionalized Dialdehydes as Promising Scaffolds for Access to Heterocycles and beta-Amino Acids: Synthesis of Fluorinated Piperidine and Azepane Derivatives

Functionalized dialdehydes are considered important substrates, which may be transformed into various substituted heterocycles, alicyclic and polysubstituted compounds. Here we report a robust stereocontrolled procedure for the synthesis of novel functionalized trifluoromethyl-containing piperidine and azepane derivatives, based on oxidative ring cleavage of the C=C bond of diversely substituted cycloalkenes, followed by reductive ring closure of the diformyl intermediates in the presence of fluorine-containing amines

Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice

<p>Abstract</p> <p>Background</p> <p>CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin (CCK) are neuromodulators involved in feeding behavior. This study is based on previously found synergistic effect of leptin and CCK on food intake and our hypothesis on a co-operation of the CART peptide and CCK in food intake regulation and Fos activation in their common targets, the nucleus tractus solitarii of the brainstem (NTS), the paraventricular nucleus (PVN), and the dorsomedial nucleus (DMH) of the hypothalamus.</p> <p>Results</p> <p>In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102) in the doses of 0.1 or 0.5 μg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 μg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102) on food intake. After simultaneous administration of 0.1 μg/mouse CART(61-102) and of 4 μg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102) and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test.</p> <p>Conclusion</p> <p>The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.</p

Vibrations of fixed-fixed heterogeneous curved beams loaded by a central force at the crown point

This paper addresses the vibrations of heterogeneous curved beams under the assumption that the load of the beam is a dead one and is perpendicular to the centroidal axis. It is assumed that: (a) the radius of curvature is constant, and (b) Young’s modulus and the Poisson’s number depend on the cross-sectional coordinates. As for the issue of fixed-fixed beams, the objectives are the following: (1) to determine the Green’s function matrices provided that the beam is under radial load; (2) to examine how the load affects the natural frequencies given that the beam is subjected to a vertical force at the crown point; (3) to develop a numerical model which makes it possible to determine how the natural frequencies are related to the load. The computational results are presented graphically

The result of treatment enterovesical fistulas for Crohn's disease

A fístula enterovesical na doença de Crohn é relativamente incomum. O objetivo deste estudo é analisar sua incidência e o resultado do seu tratamento em doentes de Crohn no ambulatório de Doenças Inflamatórias Intestinais do Serviço de Cólon e Reto do Departamento de Gastroenterologia do HCFMUSP. MÉTODOS:Dos 647 pacientes com doença de Crohn , quatorze apresentaram fístula enterovesical no período de 1984 a 2006, tendo sido todos tratados cirurgicamente. RESULTADOS: Dos quatorze pacientes, doze são homens sendo a média de idade do início da doença de Crohn de 28,8 anos. O tempo médio de evolução da doença até o diagnóstico da fístula enterovesical foi de 155,1 meses. Em relação à extensão da doença, sete pacientes tinham Crohn em intestino delgado, cólon e região perianal; cinco apenas no intestino delgado; um em cólon e região perianal e outro com acometimento de intestino delgado e perianal. No total treze pacientes tinham doença de Crohn em intestino delgado. O trajeto da fístula enterovesical mais comum foi de intestino delgado (seis pacientes). Os demais pacientes apresentaram fístula enterovesical em: cólon sigmóide (quatro pacientes), entero-colo-vesical (dois pacientes), colo-vesico-cutânea (um paciente) e outra entero-reto-vesical (um paciente). Todos foram tratados cirurgicamente com ressecção da porção intestinal acometida e sutura da lesão da bexiga, e em um doente foi feito cistectomia parcial. No pós-operatório imediato tivemos duas recorrências da fistula enterovesical, um paciente permanece em tratamento clínico e o outro foi a óbito. No acompanhamento dos demais doentes, observou-se que: oito pacientes apresentam-se sem sintomas e com medicação, três assintomáticos e sem medicação; um paciente com medicação e com sintomas relacionados à doença de Crohn (mas sem queixas ou recorrência de fístula enterovesical). CONCLUSÃO: O índice de fístula enterovesical em doentes com Crohn neste estudo foi de 2,1%. O tratamento cirúrgico da fistula enterovesical com a ressecção do intestino acometido e sutura da lesão da bexiga mostrou-se eficaz.Enterovesical fistula is relatively uncommon in Crohn's disease. The objective of this study is to analyze the incidence and the result of the treatment of patients with Crohn's disease at the Inflammatory Bowel Clinic of Service of Colon and Rectum of Gastroenterology Department (HCFMUSP). METHODS: 14 out of 647 patients with Crohn's disease presented enterovesical fistula between 1984 and 2006, in which all of them were treated with surgical intervention. RESULTS: 12 out of 14 patients were male and the Crohn's symptoms started with a mean age of 28,8 years. The mean age of evolution of Crohn's disease before discovering the enterovesical fistula was 155,1 months. In regard to Crohn's disease extension, there were seven patients with Crohn's disease in the small intestine, colon and perianal region; five with manifestation only in the small intestine; one had colon and perianal disease and other had small intestine and perianal disease. 13 out of 14 patients studied had Crohn's disease in small intestine. The most commonly encountered type of fistula was in the small intestine (six patients). The others patients presented enterovesical fistula in: sigmoid (four patients), entero-colo-vesical (two patients), colo-vesico-cutaneous (one patient) and entero-reto-vesical (one patient). All the patients were treated with surgical intervention involving resection of the affected bowel and closure of the bladder defect and one patient needed partial cystectomy. In the postoperative period there were two enterovesical fistula recurrences: one patient is still being treated with medical therapy and the other died. In the clinical follow-up of the other patients, eight of them are without symptoms and taking medications, three patients are asymptomatic and under no medications, and one patient is taking medications for Crohn's disease but without enterovesical fistula. CONCLUSIONS: the rate of enterovesical fistula of the Crohn's patients was 2.1 per cent. The surgical intervention involving resection of the affected bowel and closure of the bladder defect was efficient

Local understandings of PTSD and complex PTSD among health professionals working with adolescents in violent neighbourhoods of São Paulo city, Brazil

BACKGROUND: Adolescents in low-resource urban settings in Brazil are often exposed to high levels of trauma that can result in post-traumatic stress disorder (PTSD). However, preliminary evidence indicates that PTSD tends to be under-reported in Brazilian health services, despite the high prevalence of trauma. Additionally, little is known about the perceived applicability among clinicians of the new ICD-11 diagnosis of complex PTSD (CPTSD), despite its potential relevance for contexts of chronic trauma. The current study investigated local understandings of PTSD and CPTSD among health professionals working with adolescents in violent neighbourhoods of São Paulo city. METHODS: Semi-structured interviews were conducted with 58 health professionals working at both the primary care and specialized mental health levels in two areas of São Paulo city with high levels of community violence. RESULTS: Most participants knew about PTSD, but most did not know about CPTSD. There were mixed views concerning the commonality of PTSD among adolescents exposed to community violence. Many participants reported having no experience working with patients with the PTSD diagnosis. According to some, community violence was normalized by adolescents and health professionals, and did not result in PTSD. Others highlighted how they did not use psychiatric diagnoses in their practice, had critical perspectives towards psychiatric diagnoses and/or PTSD, or simply knew little about PTSD. Furthermore, many highlighted how the chronic nature of multiple traumas experienced by adolescents often resulted in complex clinical presentations characterised by many symptoms beyond PTSD. The diagnosis of CPTSD was considered appropriate to the context by many participants as it captured the complex traumatic histories and symptom presentations of adolescents exposed to community violence in Brazil. CONCLUSIONS: These findings have important implications for the assessment and treatment of mental health among adolescents exposed to community violence in Brazil

Guanosine effect on cholesterol efflux and apolipoprotein E expression in astrocytes

The main source of cholesterol in the central nervous system (CNS) is represented by glial cells, mainly astrocytes, which also synthesise and secrete apolipoproteins, in particular apolipoprotein E (ApoE), the major apolipoprotein in the brain, thus generating cholesterol-rich high density lipoproteins (HDLs). This cholesterol trafficking, even though still poorly known, is considered to play a key role in different aspects of neuronal plasticity and in the stabilisation of synaptic transmission. Moreover, cell cholesterol depletion has recently been linked to a reduction in amyloid beta formation. Here we demonstrate that guanosine, which we previously reported to exert several neuroprotective effects, was able to increase cholesterol efflux from astrocytes and C6 rat glioma cells in the absence of exogenously added acceptors. In this effect the phosphoinositide 3 kinase/extracellular signal-regulated kinase 1/2 (PI3K/ERK1/2) pathway seems to play a pivotal role. Guanosine was also able to increase the expression of ApoE in astrocytes, whereas it did not modify the levels of ATP-binding cassette protein A1 (ABCA1), considered the main cholesterol transporter in the CNS. Given the emerging role of cholesterol balance in neuronal repair, these effects provide evidence for a role of guanosine as a potential pharmacological tool in the modulation of cholesterol homeostasis in the brain

The Generation and Exploitation of Protein Mutability Landscapes for Enzyme Engineering

The increasing number of enzyme applications in chemical synthesis calls for new engineering methods to develop the biocatalysts of the future. An interesting concept in enzyme engineering is the generation of large-scale mutational data in order to chart protein mutability landscapes. These landscapes allow the important discrimination between beneficial mutations and those that are neutral or detrimental, thus providing detailed insight into sequence-function relationships. As such, mutability landscapes are a powerful tool with which to identify functional hotspots at any place in the amino acid sequence of an enzyme. These hotspots can be used as targets for combinatorial mutagenesis to yield superior enzymes with improved catalytic properties, stability, or even new enzymatic activities. The generation of mutability landscapes for multiple properties of one enzyme provides the exciting opportunity to select mutations that are beneficial either for one or for several of these properties. This review presents an overview of the recent advances in the construction of mutability landscapes and discusses their importance for enzyme engineering

GEO-6 assessment for the pan-European region

Through this assessment, the authors and the United Nations Environment Programme (UNEP) secretariat are providing an objective evaluation and analysis of the pan-European environment designed to support environmental decision-making at multiple scales. In this assessment, the judgement of experts is applied to existing knowledge to provide scientifically credible answers to policy-relevant questions. These questions include, but are not limited to the following:• What is happening to the environment in the pan-European region and why?• What are the consequences for the environment and the human population in the pan-European region?• What is being done and how effective is it?• What are the prospects for the environment in the future?• What actions could be taken to achieve a more sustainable future?<br/

Bringing the margin to the focus: 10 challenges for riparian vegetation science and management

Riparian zones are the paragon of transitional ecosystems, providing critical habitat and ecosystem services that are especially threatened by global change. Following consultation with experts, 10 key challenges were identified to be addressed for riparian vegetation science and management improvement: (1) Create a distinct scientific community by establishing stronger bridges between disciplines; (2) Make riparian vegetation more visible and appreciated in society and policies; (3) Improve knowledge regarding biodiversity—ecosystem functioning links; (4) Manage spatial scale and context-based issues; (5) Improve knowledge on social dimensions of riparian vegetation; (6) Anticipate responses to emergent issues and future trajectories; (7) Enhance tools to quantify and prioritize ecosystem services; (8) Improve numerical modeling and simulation tools; (9) Calibrate methods and increase data availability for better indicators and monitoring practices and transferability; and (10) Undertake scientific validation of best management practices. These challenges are discussed and critiqued here, to guide future research into riparian vegetation

International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database - the quality controlled standard tool for routine identification of human and animal pathogenic fungi

Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens.This study was supported by an National Health and Medical Research Council of Australia (NH&MRC) grant [#APP1031952] to W Meyer, S Chen, V Robert, and D Ellis; CNPq [350338/2000-0] and FAPERJ [E-26/103.157/2011] grants to RM Zancope-Oliveira; CNPq [308011/2010-4] and FAPESP [2007/08575-1] Fundacao de Amparo Pesquisa do Estado de So Paulo (FAPESP) grants to AL Colombo; PEst-OE/BIA/UI4050/2014 from Fundacao para a Ciencia e Tecnologia (FCT) to C Pais; the Belgian Science Policy Office (Belspo) to BCCM/IHEM; the MEXBOL program of CONACyT-Mexico, [ref. number: 1228961 to ML Taylor and [122481] to C Toriello; the Institut Pasteur and Institut de Veil le Sanitaire to F Dromer and D Garcia-Hermoso; and the grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG) to CM de Almeida Soares and JA Parente Rocha. I Arthur would like to thank G Cherian, A Higgins and the staff of the Molecular Diagnostics Laboratory, Division of Microbiology and Infectious Diseases, Path West, QEII Medial Centre. Dromer would like to thank for the technical help of the sequencing facility and specifically that of I, Diancourt, A-S Delannoy-Vieillard, J-M Thiberge (Genotyping of Pathogens and Public Health, Institut Pasteur). RM Zancope-Oliveira would like to thank the Genomic/DNA Sequencing Platform at Fundacao Oswaldo Cruz-PDTIS/FIOCRUZ [RPT01A], Brazil for the sequencing. B Robbertse and CL Schoch acknowledge support from the Intramural Research Program of the NIH, National Library of Medicine. T Sorrell's work is funded by the NH&MRC of Australia; she is a Sydney Medical School Foundation Fellow.info:eu-repo/semantics/publishedVersio