The core-periphery model with three regions

We study a 3-region core-periphery model à la Krugman and compare our results with those of the standard 2-region model. The conditions for the stability of the dispersion and concentration configurations are established. Like in the 2-region model, dispersion and concentration can be simultaneously stable. We show that the 2- region (3-region) model favors the dispersion (concentration) of economic activity. Finally, we extend the core-periphery model to the case of n regions and show that stability of concentration with 2 regions implies stability of concentration with any even number of regions.new economic geography, core-periphery

Chemical composition and anti-inflammatory evaluation of essential oils from leaves and stem barks from Drimys brasiliensis Miers (Winteraceae)

The essential oils from leaves and stem barks from Drimys brasiliensis Miers (Winteraceae) were individually obtained by hydrodistillation and their compounds characterized by use of GC/FID and GC/MS. The main identified derivatives were monoterpenes (leaves 4.31% and stem barks 90.02%) and sesquiterpenes (leaves 52.31% and stem barks 6.35%). Additionally, the sesquiterpene polygodial was isolated from hexane extract from stem barks of D. brasiliensis after chromatographic steps and characterized by spectroscopic means, mainly NMR. Aiming the evaluation of anti-inflammatory potential, the crude essential oils and the sesquiterpene polygodial were subjected to bioassays to evaluate the acute toxicity of these compounds as well as the anti-inflammatory and antinociceptive activities induced by carrageenan and formalin in mices. Ours results showed that essential oil obtained from the stem barks significantly reduced the oedema induced by carrageenan. The anti-inflammatory effect induced by stem barks oil (at 200 mg kg-1) was similar to observed for indomethacin (at 10 mg kg-1) and superior for polygodial (at 200 mg kg-1) in 30 and 60 min after the administration of essential oils. The inflammatory response induced by formalin was effective to the stem barks oil (62.5%) in comparison to polygodial (50.0%).Os óleos essenciais das folhas e das cascas do tronco de Drimys brasiliensis Miers (Winteraceae) foram obtidos individualmente por hidrodestilação e suas composições químicas foram determinadas através de análise por CG/DIC e CG/EM. Os principais constituintes identificados foram monoterpenos (folhas 4,31% e cascas do tronco 90,02%) e sesquiterpenos (folhas 52,31% e cascas do tronco 6,35%). Adicionalmente, o sesquiterpeno poligodial foi isolado do extrato em hexano das cascas do tronco de D. brasiliensis após fracionamento cromatográfico e caracterizado por métodos espectroscópicos. Visando a avaliação do potencial anti-inflamatório, os óleos essenciais brutos e o sesquiterpeno poligodial foram submetidos à bioensaios para avaliação da toxicidade aguda destes compostos bem como das atividades anti-inflamatória e antinociceptiva induzidas por carragenina e formalina em ratos. Nossos resultados mostraram que o óleo essencial bruto obtido das cascas do tronco reduziu significativamente o edema induzido por carragenina. O efeito anti-inflamatório induzido pelo óleo das cascas do tronco (a 200 mg kg-1) foi similar ao observado para indometacina (a 10 mg kg-1) e superior ao poligodial (a 200 mg kg-1) em 30 e em 60 min após administração. A resposta inflamatória induzida pela formalina foi efetiva para o óleo das cascas do tronco (62,5%) em comparação ao poligodial (50,0%).Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Departamento de Ciências Exatas e da TerraUniversidade Presbiteriana Mackenzie Departamento de Ciências Exatas e da Terra Centro de Ciências e Humanidades Centro de Ciências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie Centro de Ciências Biológicas e da SaúdeUNIFESP, Depto. de Ciências Exatas e da TerraSciEL

IFN-gamma Plays a Unique Role in Protection against Low Virulent Trypanosoma cruzi Strain

Background: T. cruzi strains have been divided into six discrete typing units (DTUs) according to their genetic background. These groups are designated T. cruzi I to VI. In this context, amastigotes from G strain (T. cruzi I) are highly infective in vitro and show no parasitemia in vivo. Here we aimed to understand why amastigotes from G strain are highly infective in vitro and do not contribute for a patent in vivo infection. Methodology/Principal Findings: Our in vitro studies demonstrated the first evidence that IFN-gamma would be associated to the low virulence of G strain in vivo. After intraperitoneal amastigotes inoculation in wild-type and knockout mice for TNF-alpha, Nod2, Myd88, iNOS, IL-12p40, IL-18, CD4, CD8 and IFN-gamma we found that the latter is crucial for controlling infection by G strain amastigotes. Conclusions/Significance: Our results showed that amastigotes from G strain are highly infective in vitro but did not contribute for a patent infection in vivo due to its susceptibility to IFN-gamma production by host immune cells. These data are useful to understand the mechanisms underlying the contrasting behavior of different T. cruzi groups for in vitro and in vivo infection.CAPES [3038.005295/2011-40]CAPESFAPEMIGFAPEMIG [APQ-00621-11]CNPqCNPqFAPESPFAPESP [10-50959-4

Non-peptidic Cruzain Inhibitors with Trypanocidal Activity Discovered by Virtual Screening and in Vitro Assay

A multi-step cascade strategy using integrated ligand-and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K-i) in the low micromolar range (3-60 mu M) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 mu M), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. in order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. the IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6 +/- 0.1 mu M, tenfold lower than that obtained for benznidazole, which was taken as positive control. in addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ Fed Sao Carlos, Dept Quim, BR-13560 Sao Carlos, SP, BrazilUniv São Paulo, Inst Quim Sao Carlos, Grp Quim Med IQSC USP, Sao Carlos, SP, BrazilUniv Calif San Francisco, Dept Pathol, Ctr Discovery & Innovat Parasit Dis, San Francisco, CA 94140 USAUniv São Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, BR-14049 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilFAPESP: 2011/01893-3,CNPq: 301614/2010-5CAPES: 5985/11-0Web of Scienc

Geo-environmental mapping using physiographic analysis: constraints on the evaluation of land instability and groundwater pollution hazards in the Metropolitan District of Campinas, Brazil

Geo-environmental terrain assessments and territorial zoning are useful tools for the formulation and implementation of environmental management instruments (including policy-making, planning, and enforcement of statutory regulations). They usually involve a set of procedures and techniques for delimitation, characterisation and classification of terrain units. However, terrain assessments and zoning exercises are often costly and time-consuming, particularly when encompassing large areas, which in many cases prevent local agencies in developing countries from properly benefiting from such assessments. In the present paper, a low-cost technique based on the analysis of texture of satellite imagery was used for delimitation of terrain units. The delimited units were further analysed in two test areas situated in Southeast Brazil to provide estimates of land instability and the vulnerability of groundwater to pollution hazards. The implementation incorporated procedures for inferring the influences and potential implications of tectonic fractures and other discontinuities on ground behaviour and local groundwater flow. Terrain attributes such as degree of fracturing, bedrock lithology and weathered materials were explored as indicators of ground properties. The paper also discusses constraints on- and limitations of- the approaches taken

Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca : observation from a randomized controlled trial

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769)

Zika Virus Disrupts Molecular Fingerprinting Of Human Neurospheres

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Zika virus (ZIKV) has been associated with microcephaly and other brain abnormalities; however, the molecular consequences of ZIKV to human brain development are still not fully understood. Here we describe alterations in human neurospheres derived from induced pluripotent stem (iPS) cells infected with the strain of Zika virus that is circulating in Brazil. Combining proteomics and mRNA transcriptional profiling, over 500 proteins and genes associated with the Brazilian ZIKV infection were found to be differentially expressed. These genes and proteins provide an interactome map, which indicates that ZIKV controls the expression of RNA processing bodies, miRNA biogenesis and splicing factors required for self-replication. It also suggests that impairments in the molecular pathways underpinning cell cycle and neuronal differentiation are caused by ZIKV. These results point to biological mechanisms implicated in brain malformations, which are important to further the understanding of ZIKV infection and can be exploited as therapeutic potential targets to mitigate it.7Brazilian Development Bank (BNDES)Funding Authority for Studies and Projects (FINEP)National Council of Scientific and Technological Development (CNPq)Foundation for Research Support in the State of Rio de Janeiro (FAPERJ)Sao Paulo Research Foundation (FAPESP) [14/21035-0, 14/14881-1, 13/08711-3, 14/10068-4]Coordination for the Improvement of Higher Education Personnel (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Macrocalcitonin Is a Novel Pitfall in the Routine of Serum Calcitonin Immunoassay

Context: Calcitonin (CT) is a sensitive marker of medullary thyroid carcinoma (MTC) and is used for primary diagnosis and follow-up after thyroidectomy. However, persistently elevated CT is observed even after complete surgical removal without evidence of a recurrent or persistent tumor. Objective: To investigate the presence of assay interference in the serum CT of MTC patients who are apparently without a structural disease. Patients and Methods: We studied three index MTC cases for CT assay interference and 14 patients with metastatic MTC. The CT level was measured using an immunofluorometric assay. Screening for assay interference was performed by determination of CT levels before and after serum treatment with polyethylene glycol. Additionally, samples were analyzed by chromatography on ultra-performance liquid chromatography and protein A-Sepharose. Results: Patients with biochemical and structural disease showed CT mean recovery of 84.1% after polyethylene glycol treatment, whereas patients suspected of interference showed recovery from 2-7%. The elution profile on UPLC showed that the immunometric CT from these three patients behaved like a high molecular mass aggregate (>300 kDa). Additionally, when these samples were applied to the protein A-Sepharose, CT immunoreactivity was retained on the column and was only released after lowering the pH. Conclusions: For the first time, our results show the presence of a novel pitfall in the CT immunoassay: "macrocalcitonin." Its etiology, frequency, and meaning remain to be defined, but its recognition is of interest and can help clinicians avoid unnecessary diagnostic investigations and treatment during the follow-up of MTC.Sao Paulo State Research Foundation-FAPESPFAPESPFederal Agency of Support and Evaluation of Postgraduate Education (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)National Council for Scientific and Technological DevelopmentUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Thyroid Dis Ctr, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Biochem, Div Mol Biol, BR-04044020 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Thyroid Dis Ctr, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Biochem, Div Mol Biol, BR-04044020 Sao Paulo, SP, BrazilFAPESP: 2006/60402-1FAPESP: 2010/51547-1FAPESP: 2010/19478Web of Scienc

Prenatal toxicity assessment : teratogenicity study of the insecticide pyriproxyfen in Wistar rats

Este estudo investigou a toxicidade pré-natal do inseticida piriproxifeno em ratos Wistar, de forma a detectar possíveis alterações no desenvolvimento fetal da progênie exposta durante o período organogênico. Três doses de piriproxifeno (100, 300 e 500mg.kg-1) foram administradas por via oral às progenitoras, do sexto ao 15º dia de gestação. Os fetos foram submetidos à técnica de diafanização modificada descrita por Taylor e Van Dyke, para avaliação de malformações e alterações esqueléticas. Os resultados não demonstraram a ocorrência de toxicidade materna sistêmica ou alterações nos índices reprodutivos avaliados. Malformações ou alterações teratogênicas não foram detectadas, no entanto alterações esqueléticas sugestivas de retardo no desenvolvimento foram observadas especialmente nas doses mais altas testadas (300mg.kg-1 e 500mg.kg-1). Considerando-se a situação complexa de risco para a saúde humana, mostra-se importante a execução de investigações adicionais, de modo a contribuir para a adequada avaliação de risco do piriproxifeno em água potável.This study investigated the prenatal toxicity of the insecticide pyriproxyfen in Wistar rats to detect the possible changes in the fetal development of the progeny exposed during the organogenic period. Three doses of pyriproxyfen (100, 300, and 500mg.kg-1) were administered orally to the progenitors, from day 6 to 15 of gestation. The fetuses were processed using the Taylor and Van Dyke modified diaphanization technique to evaluate malformations and skeletal changes. The results did not demonstrate the occurrence of systemic maternal toxicity or changes in the reproductive indexes evaluated. Malformations or teratogenic changes were not detected, however, skeletal changes suggestive of developmental delay were observed, especially in the highest doses tested (300 mg.kg-1 and 500 mg.kg-1). Owing to the potentially complex situation regarding its risk to human health, it is important that further studies be performed to contribute to the risk assessment of the addition of pyriproxyfen in drinking water