Genome-wide inhibition of pro-atherogenic gene expression by multi-STAT targeting compounds as a novel treatment strategy of CVDs

Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)a and IFN? and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L-F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNa. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L-F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFN? and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFN?+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDsThis publication was supported by grants UMO-2015/17/B/NZ2/00967 (HB) and UMO-2015/16/T/NZ2/00055 (MS) from National Science Centre Poland. This work was supported by the KNOW RNA Research Centre in Poznan (No. 01/KNOW2/2014) and in part by PL-Grid Infrastructure (MS

Corpo, maturação biológica e actividade física: um olhar interactivo em crianças e jovens madeirenses

Cada vez mais a sociedade moderna é olhada através da sua condição física, enquanto factor de bem-estar, saúde, qualidade de vida e longevidade dos seus membros. Os indicadores demográficos actuais da população madeirense apontam no sentido de uma considerável componente juvenil, adolescente e jovem. No entanto, a evolução demográfica prevista, decorrente de um acentuado decréscimo da natalidade, leva a prever um comportamento diverso da pirâmide de idades, assumindo particular ênfase as questões relacionadas com o estudo e a investigação do corpo, a procura de padrões, a descrição normativa, a interpretação das mudanças e o espaço morfológico externo, que se vem enquadrar no território de investigação reservado à somatotipologia

The role of antimicrobial stewardship programmes in children: a systematic review.

The United Nations and the World Health Organization have designated antimicrobial resistance (AMR) as a major health priority and developed action plans to reduce AMR in all healthcare settings. Establishment of institutional antimicrobial stewardship programmes (ASPs) is advocated as a key intervention to reduce antibiotic consumption in hospitals and address high rates of multi-drug resistant (MDR) bacteria. We searched PUBMED and the Cochrane database of systematic reviews (1/2007-3/2017) to identify studies reporting about the effectiveness of ASPs in general paediatric wards and paediatric intensive care units (PICU), on reducing antibiotic consumption, on using broad spectrum/restricted antibiotics, and on antibiotic resistance and healthcare-associated infections (HAIs). Neonatal units and antifungal agents were excluded. Of 2509 titles and abstracts, nine articles were eligible to be included in the final analysis. All studies reported on the reduction of broad spectrum/restricted antibiotics or antibiotic consumption. One study reported on the reduction of HAI in a PICU, and another evaluated bacterial resistance, showing no effect following ASP implementation. Prospective audit on antibiotic use was the most common ASP core component (eight of nine studies). Antibiotic pre-authorisation was described in two articles. Other described interventions were providing guidelines or written information (five of nine articles), and training of healthcare professionals (one article). There is limited evidence about reducing antibiotic consumption and broad-spectrum/restricted agents following ASP implementation, specifically in PICU. Data evaluating the impact of ASPs on HAI and AMR in PICU is lacking. In addition, there is limited information on effective components of a successful ASPs in PICUs

HER Family Receptors are Important Theranostic Biomarkers for Cervical Cancer: Blocking Glucose Metabolism Enhances the Therapeutic Effect of HER Inhibitors

Persistent HPV infection alone is not sufficient for cervical cancer development, which requires additional molecular alterations for tumor progression and metastasis ultimately leading to a lethal disease. In this study, we performed a comprehensive analysis of HER family receptor alterations in cervical adenocarcinoma. We detected overexpression of HER protein, mainly HER2, which was an independent prognostic marker for these patients. By using in vitro and in vivo approaches, we provided evidence that HER inhibitors, allitinib and lapatinib, were effective in reducing cervical cancer aggressiveness. Furthermore, combination of these drugs with glucose uptake blockers could overcome the putative HIF1-a-mediated resistance to HER-targeted therapies. Thus, we propose that the use of HER inhibitors in association with glycolysis blockers can be a potentially effective treatment option for HER-positive cervical cancer patients.FINEP (MCTI/FINEP/MS/SCTIE/DECIT-BIOPLAT (1302/13), Brazil and co-funded by the project “ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000017)” co-funded by Programa Operacional Regional do Norte (ON.2- O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), through Fundo Europeu de Desenvolvimento Regional (FEDER). OM is recipient of a post-doc fellowship (SFRH/BPD/108351/2015) from Fundação para a Ciência e Tecnologia (FCT), Portugal. FC is recipient of a master fellowship (2014/03684-0) from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). VMG is recipient from a PhD fellowship (SFRH/BD/51997/2012) from Fundação para a Ciência e Tecnologia (FCT), Portugalinfo:eu-repo/semantics/publishedVersio

Homogeneous Ziegler-Natta polymerisation: A kinetic approach .2. Transient-state kinetics

An integrated view is presented of several possible mechanisms applicable to the interpretation of homogeneous Ziegler-Natta polymerisation. In this paper, the transient aspects related to the kinetics of Ziegler-Natta polymerisation are investigated. Extensive data are used to construct kinetic profiles (rM vs. t) from a theoretical approach. Special attention is given to the duration of the transient period as a function of the different kinetic parameters. The kinetic models developed are fitted to experimental data, either directly obtained by the authors or published in the literature. These general models have a broad range of application.info:eu-repo/semantics/publishedVersio

A kinetic approach to homogeneous Ziegler type polymerization. Transient state

In this paper we present a kinetic approach to the analysis of transient-state homogeneous Ziegler-Natta polymerization activity data. The main features of the experimental data are discussed and fitted to transient kinetic models.info:eu-repo/semantics/publishedVersio

Polymerization of ethylene using metallocene and aluminoxane systems

This paper describes ethylene polymerization using a number of metal-locene and aluminoxane catalyst systems, Cp2MR2 and methylaluminoxane [M = Zr, W, Nb; R = Cl, CH3]. Two types of methylaluminoxane, MAO (1) and MAO (2), were used as cocatalysts. The polymerization activities of the complexes Cp2WCl2 and Cp2NbCl2 were compared with that of Cp2ZrCl2. The Nb and W complexes were found to be less active than the Zr complex. Polyethylene characterization was also carried out by the following methods: gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR).info:eu-repo/semantics/publishedVersio

Suscetibilidade Magnética Como Indicador De Qualidade Do Solo Em áreas Sob Cultivo De Cana-de-açúcar

Sugarcane management practices (unburned cane - UC and burned cane - BC) interfere with dynamics of soil magnetic properties. This study focused on determining the potential of magnetic susceptibility as soil quality indicator in areas under sugarcane cultivation. The experiment area is on the limit between basalt from São Bento Group, Serra Geral Formation, and sandstone from Bauru Group - Adamantina Formation. Twenty soil samples were collected from two management areas (burned and unburned sugarcane prior to harvest) at a depth range of 0.0-0.2 m. Local soil was classified as eutroferric Red Latosol (Oxisol), with highly clayey texture. Chemical and physical properties, CO2 emissions and magnetic susceptibility (MS) in air-dried fine earth (MSADFE), total sand fraction (MSTS) and clay fraction (MSCF). The magnetic signature from MS was effective in identifying changes of physical, chemical and mineralogical traits in Latosols under burned and unburned sugarcane crop. The information provided here can guide further studies on the genesis of minerals with magnetic expression in environments and exposed to fire burning. © 2016, Universidade Federal Rural do Semi-Arid. All rights reserved.30228729

The cAMP pathway is important for controlling the morphological switch to the pathogenic yeast form of Paracoccidioides brasiliensis

Paracoccidioides brasiliensis is a human pathogenic fungus that switches from a saprobic mycelium to a pathogenic yeast. Consistent with the morphological transition being regulated by the cAMP-signalling pathway, there is an increase in cellular cAMP levels both transiently at the onset ( 120 h) of the transition to the yeast form, and this transition can be modulated by exogenous cAMP. We have cloned the cyr1 gene encoding adenylate cyclase (AC) and established that its transcript levels correlate with cAMP levels. In addition, we have cloned the genes encoding three Gα (Gpa1–3), Gβ (Gpb1) and Gγ (Gpg1) G proteins. Gpa1 and Gpb1 interact with one another and the N-terminus of AC, but neither Gpa2 nor Gpa3 interacted with Gpb1 or AC. The interaction of Gpa1 with Gpb1 was blocked by GTP, but its interaction with AC was independent of bound nucleotide. The transcript levels for gpa1, gpb1 and gpg1 were similar in mycelium, but there was a transient excess of gpb1 during the transition, and an excess of gpa1 in yeast. We have interpreted our findings in terms of a novel signalling mechanism in which the activity of AC is differentially modulated by Gpa1 and Gpb1 to maintain the signal over the 10 days needed for the morphological switch

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health