Tameness and Artinianness of Graded Generalized Local Cohomology Modules

Let $R=\bigoplus_{n\geq 0}R_n$, \fa\supseteq \bigoplus_{n> 0}R_n and $M$ and $N$ be a standard graded ring, an ideal of $R$ and two finitely generated graded $R$-modules, respectively. This paper studies the homogeneous components of graded generalized local cohomology modules. First of all, we show that for all $i\geq 0$, H^i_{\fa}(M, N)_n, the $n$-th graded component of the $i$-th generalized local cohomology module of $M$ and $N$ with respect to \fa, vanishes for all $n\gg 0$. Furthermore, some sufficient conditions are proposed to satisfy the equality \sup\{\en(H^i_{\fa}(M, N))| i\geq 0\}= \sup\{\en(H^i_{R_+}(M, N))| i\geq 0\}. Some sufficient conditions are also proposed for tameness of H^i_{\fa}(M, N) such that i= f_{\fa}^{R_+}(M, N) or i= \cd_{\fa}(M, N), where f_{\fa}^{R_+}(M, N) and \cd_{\fa}(M, N) denote the $R_+$-finiteness dimension and the cohomological dimension of $M$ and $N$ with respect to \fa, respectively. We finally consider the Artinian property of some submodules and quotient modules of H^j_{\fa}(M, N), where $j$ is the first or last non-minimax level of H^i_{\fa}(M, N).Comment: 18pages, with some revisions and correction

Desenvolvimento de nanoemuls?es contendo ?cido retinoico funcionalizadas com ?cido hialur?nico como alternativa para o tratamento de c?ncer

Data de aprova??o ausente.O ?cido retinoico (AR), um derivado da vitamina A, ? um dos exemplos mais bem-sucedidos de f?rmacos usados na terapia de diferencia??o do c?ncer. O AR ? um f?rmaco altamente lipof?lico (log P 4,6) que apresenta baixa solubilidade aquosa, limitando sua utiliza??o parenteral. Dessa forma, sua incorpora??o em nanocarreadores lip?dicos tem sido proposta como uma alternativa promissora para a administra??o desse f?rmaco. O maior direcionamento dos nanossistemas para as c?lulas tumorais pode ser obtido por meio de modifica??es na superf?cie deste, como o revestimento com ?cido hialur?nico (AH), que se liga a receptor CD44 sobre-expresso em alguns tumores. Assim sendo, este trabalho teve por objetivo principal desenvolver, caracterizar e avaliar a atividade antineopl?sica in vitro de nanoemuls?es contendo AR revestidas e n?o revestidas com AH para tratamento de c?ncer de mama. Primeiramente, foi desenvolvido um m?todo espectrofotom?trico, com detec??o do AR em 324 nm, que foi validado em rela??o ? seletividade em rela??o aos componentes de matriz e aos produtos de degrada??o for?ada, linearidade, precis?o, exatid?o e robustez, conforme a legisla??o pertinente. Em seguida, foram desenvolvidas e caracterizadas nanoemuls?es (NE) preparadas por emulsifica??o espont?nea e revestidas eletrostaticamente com AH em diferentes concentra??es. Ap?s o revestimento com 0,5 mg/mL de AH, a NE escolhida apresentou tamanho de 158 ? 5 nm, distribui??o monodispersa e potencial zeta de -19,7 ? 1,20 mV e um teor de encapsula??o de 99,2 ? 0,5%, estando compat?vel com a administra??o parenteral. Al?m disso, as formula??es revestidas permaneceram est?veis ao longo de 60 dias armazenadas a 4?C. O perfil de libera??o do AR a partir dos nanossistemas foi avaliado e observou-se que segue uma cin?tica de primeira ordem, de forma que a taxa de libera??o depende da concentra??o do f?rmaco ainda presente na matriz. Foram, por fim, avaliados os efeitos citot?xicos em linhagens de c?lulas de c?ncer de mama (MCF-7 e MDA-MB-231) e fibroblastos normais (L929) e observou-se que a formula??o revestida promove aumento de atividade antic?ncer do AR, especialmente nas c?lulas que expressam mais os receptores CD44 (MDA-MB-231) e reduzida toxicidade em rela??o ?s c?lulas normais. Desta forma, a encapsula??o do AR em NE revestida por AH pode ser uma abordagem interessante para aumentar a efic?cia e a biodisponibilidade do AR no tratamento do c?ncer de mama e outros tipos de c?ncer que sobre-expressam esse receptor.Disserta??o (Mestrado) ? Programa de P?s-gradua??o em Ci?ncias Farmac?uticas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2016.Retinoids, such as all-trans retinoic acid (RA), are structural molecules derived from vitamin A and play important roles in various cell types, especially on vision, cell proliferation and differentiation. RA is a lipophilic acid (log P 4.6) with low aqueous solubility, which limits its pharmaceutical use. In order to allow its parenteral administration, an interesting alternative could be its incorporation in lipid nanocarrier systems, such as nanoemulsions (NE). On the other hand, it is possible to increase the target to CD44 receptor expressing tumor cells, coating the NE surface with hyaluronic acid (HA). Therefore, the main goal of this study was to develop, characterize and evaluate the in vitro antitumor activity of RA-loaded NE coated with HA for the treatment of breast cancer. First, a spectrophotometric method was developed, with RA detection at 324 nm, which was validated with regard to selectivity to matrix components and forced degradation products, linearity, precision, accuracy and robustness, in accordance with the proper legislation. Then, the NE, prepared by the spontaneous emulsification and electrostatically coated with HA in different concentrations, were developed and characterized. After coating with 0.5 mg/mL, the chosen HA-coated NE presented size of 158 ? 5 nm, monodisperse distribution, zeta potential of -19.7 ? 1.20 mV and encapsulating efficiency of 99.2 ? 0.5%, which is compatible with parenteral administration. Moreover, the coated formulations remained stable over 60 days stored at 4 ?C. The RA release profile from the nanosystems was evaluated and it follows the first order kinetics, so that the release rate depends on the drug concentration still present in the matrix. Finally, the cytotoxic effects were assessed in breast cancer cell lines (MCF-7 and MDA-MB-231) and in normal fibroblasts (L929), and found that the coated formulation promotes increased anticancer activity of RA, especially in cells expressing plus CD44 receptors (MDA-MB-231) and reduced toxicity compared to normal cells. Thus, the encapsulation of RA in HA-coated NE can be an interesting approach to increase the RA efficacy and bioavailability in the treatment of breast cancer and other cancers overexpressing that receptor

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Homogenization Pressure and Temperature Affect Protein Partitioning and Oxidative Stability of Emulsions

The oxidative stability of 10 % fish oil-in-water emulsions was investigated for emulsions prepared under different homogenization conditions. Homogenization was conducted at two different pressures (5 or 22.5 MPa), and at two different temperatures (22 and 72 °C). Milk proteins were used as the emulsifier. Hence, emulsions were prepared with either a combination of α-lactalbumin and β-lactoglobulin or with a combination of sodium caseinate and β-lactoglobulin. Results showed that an increase in pressure increased the oxidative stability of emulsions with caseinate and β-lactoglobulin, whereas it decreased the oxidative stability of emulsions with α-lactalbumin and β-lactoglobulin. For both types of emulsions the partitioning of proteins between the interface and the aqueous phase appeared to be important for the oxidative stability. The effect of pre-heating the aqueous phase with the milk proteins prior to homogenization did not have any clear effect on lipid oxidation in either of the two types of emulsions. (Résumé d'auteur

A Rapid FACS-Based Strategy to Isolate Human Gene Knockin and Knockout Clones

Gene targeting protocols for mammalian cells remain inefficient and labor intensive. Here we describe FASTarget, a rapid, fluorescent cell sorting based strategy to isolate rare gene targeting events in human somatic cells. A fluorescent protein is used as a means for direct selection of targeted clones obviating the need for selection and outgrowth of drug resistant clones. Importantly, the use of a promoter-less, ATG-less construct greatly facilitates the recovery of correctly targeted cells. Using this method we report successful gene targeting in up to 94% of recovered human somatic cell clones. We create functional EYFP-tagged knockin clones in both transformed and non-transformed human somatic cell lines providing a valuable tool for mammalian cell biology. We further demonstrate the use of this technology to create gene knockouts. Using this generally applicable strategy we can recover gene targeted clones within approximately one month from DNA construct delivery to obtaining targeted monoclonal cell lines

Data set on the bioprecipitation of sulfate and trivalent arsenic by acidophilic non-traditional sulfur reducing bacteria.

Data presented here are related to the original paper ?Simultaneous removal of sulfate and arsenic using immobilized non-traditional sulfate reducing bacteria (SRB) mixed culture and alternative low-cost carbon sources ?published by same authors (Matos et al., 2018) [1]. The data set here presented aims to facilitate this paper comprehension by giving readers some additional information. Data set includes a brief description of experimental conditions and the results obtained during both batch and semi-continuous reactors experiments. Data confirmed arsenic and sulfate were simultaneously removed under acidic pH by using a biological treatment based on the activity of a non-traditional sulfur reducing bacteria consortium. This microbial consortium was able to utilize glycerol, powdered chicken feathers as carbon donors, and proved to be resistant to arsenite up to 8.0 mg L?1. Data related to sulfate and arsenic removal efficiencies, residual arsenite and sulfate contents, pH and Eh measurements obtained under different experimental conditions were depicted in graphical format

Oxidative Stability of Polyunsaturated Edible Oils Mixed With Microcrystalline Cellulose

The oxidative stability of mixtures of edible oils containing polyunsaturated fatty acids (PUFA) and microcrystalline cellulose (MCC) was investigated. The mixtures studied consisted of oils of either camelina (CAM), cod liver (CLO), or salmon (SO) mixed with either colloidal or powdered MCC. A 50:50 (w/w) ratio of oil:MCC resulted in an applicable mixture containing high levels of PUFA edible oil and dietary fiber. The oxidative stability of the formulated mixtures and the pure oils was investigated over a period of 28 days. The peroxide value (PV) was assessed as a parameter for primary oxidation products and dynamic headspace gas chromatography mass spectrometry (GC/MS) was used to analyze secondary volatile organic compounds (VOC). CAM and the respective mixtures were oxidatively stable at both 4 and 22 °C during the storage period. The marine oils and the respective mixtures were stable at 4 °C. At 22 °C, an increase in hydroperoxides was found, but no increase in VOC was detected during the time-frame investigated. At 42 °C, prominent increases in PV and VOC were found for all oils and mixtures. Hexanal, a common marker for the degradation of n-6 fatty acids, propanal and 2,4-heptadienal (E,E), common indicators for the degradation of n-3 fatty acids, were among the volatiles detected in the headspace of oils and mixtures. This study showed that a mixture containing a 50:50 ratio of oil:MCC can be obtained by a low-tech procedure that does not induce oxidation when stored at low temperatures during a period of 1 month