The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity.

ObjectiveThe differential effect of GLP-1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite-related behaviours was investigated in women with normal weight compared with women with obesity.MethodsFollowing an 8-h fast, 19 female subjects (11 lean, 8 obese) participated in a 2-d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30-min post subcutaneous injection of 5 μg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug-induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus.ResultsWomen with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese.ConclusionsObesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP-1 analogues in therapeutic interventions

Equações para a estimativa de peso da biomassa aérea da bracatinga (Mimosa scabrella Benth.) na idade de corte.

Este trabalho foi estimulado pela escassez de instrumentos para estimar a produtividade da bracatinga na idade de corte, visando estatísticas locais ou regionais. Foram amostrados cinco sítios, nos municípios de Colombo e Bocaiúva do Sul - PR. Em cada sitio selecionaram-se 40 árvores para a determinação dos pesos das frações lenha, galhos, biomassa verde (folhas e ramos tenros) e da biomassa total. Os pesos reais das frações e do total de cada árvore, mais as variáveis independentes altura total e diâmetro a 1,30 m (DAP) foram introduzidos no programa STATGRAPHICS, versão 4.0, para realizar os ajustes necessários para a obtenção das equações de regressão. Três modelos demonstraram ser adequados para estimar o peso de qualquer fração e da biomassa total, sendo que a mais precisa foi Y = a.DAPb, onde Y = peso; a e b = constantes

Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent

<p>Abstract</p> <p>Background</p> <p>The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-I_M) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice – a model which is most adequately mimicking the clinical setting.</p> <p>Methods and results</p> <p>Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-I_Mor green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic <it>en face </it>analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-I_Mby 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.</p> <p>Conclusion</p> <p>Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-I_Meach significantly reduced atherosclerosis progression to a similar extent.</p

Jueces, nuevo derecho y burocracia

En este ensayo se indagará por la posibilidad de implementar el modelo del juez hermeneuta dentro de una justicia organizada burocráticamente. Para ello repasaremos en primer lugar la discusión histórica que en teoría jurídica ha dado lugar a la noción de juez argumentador. En segundo lugar la lectura que —desde esta perspectiva teórica— se ofrece de la "pasividad" de los jueces, dada tradicionalmente en términos jurídico— ideológicos o en la condición individual del funcionario judicial. Frente a esto, proponemos aquí una explicación sociológica afincada en la idea de la burocracia como forma de organización que implica la maquinización de las relaciones productivas, también en lo jurídico (o, específicamente, en lo judicial). Para ello miraremos brevemente el significado de la organización burocrática dentro del Estado Moderno y su incidencia respecto a un grupo de tareas específicas asignadas al Estado como son las realizadas por las judicaturas. Finalmente se constatará cómo sobre las judicaturas confluyen dos lógicas que resultan a la larga adversas: por un lado, la lógica jurídica, entendiendo por ella un proceso del conocimiento del derecho cada vez más amplio y depurado; de otro lado, la lógica organizacional propiamente burocrática, que implica necesariamente "limitación". El enfrentamiento de estas dos lógicas plantea una tensión irresoluble en medio de la cual se desarrolla la administración de justicia

Study of the presence and environmental risk of organic contaminants policed by the European Union and other organic compounds in the water resources of a region overlapping protected areas: The Guadiaro River basin (southern Spain)

The study presented here is a first qualitative assessment of the occurrence of organic contaminants contemplated and not yet contemplated in European Union environmental legislation in water resources in the little anthropized Guadiaro River basin (70% of its area is covered by natural vegetation), in southern Spain. Water samples were collected from four carbonate aquifers, two detrital aquifers and four surface water courses and were analyzed for (i) 171 organic contaminants, (ii) major ions and (iii) stable isotopes (δ18OH2O, δ2HH2O, δ13CDIC). An environmental risk assessment was conducted through calculation of risk quotients comparing measured concentrations with ecotoxicological data found in the literature. Twenty-five organic contaminants were detected, at least once, including pesticides, pharmaceuticals, drugs of abuse and polycyclic aromatic hydrocarbons (PAHs). Cocaine and its main metabolite were detected in 85% and 95% of water samples, respectively (0.001–0.18 μg/L and 0.004–0.6 μg/L, respectively). Pyrene (PAH) was found in all water samples (0.001–0.015 μg/L) and forest fires were pointed out as a potential diffuse source. Relationship between rivers and aquifers is reflected by the distribution of organic contaminants, essentially the drugs of abuse. Concentration of contaminants were generally higher in groundwater samples, especially from detrital aquifers, potentially due to an accumulation process promoted by irrigation-return flows and by its slow dynamic compared to that of karstic systems. Pyrene concentration was also higher in some springs from karstic aquifers. Hence, calculated risk quotients were in general higher in groundwater, meaning that the threat to surface aquatic systems can grow as aquifers increase their influence on the water courses as the dry season progresses. The relationship between δ13CDIC and most organic contaminants (especially pyrene) reveal the role of the soil as storage media.Funding for open access charge: Universidad de Málaga / CBU

Genome of Mycoplasma haemofelis, unraveling its strategies for survival and persistence

Mycoplasma haemofelis is a mycoplasmal pathogen (hemoplasma) that attaches to the host's erythrocytes. Distributed worldwide, it has a significant impact on the health of cats causing acute disease and, despite treatment, establishing chronic infection. It might also have a role as a zoonotic agent, especially in immunocompromised patients. Whole genome sequencing and analyses of M. haemofelis strain Ohio2 was undertaken as a step toward understanding its survival and persistence. Metabolic pathways are reduced, relying on the host to supply many of the nutrients and metabolites needed for survival. M. haemofelis must import glucose for ATP generation and ribose derivates for RNA/DNA synthesis. Hypoxanthine, adenine, guanine, uracil and CMP are scavenged from the environment to support purine and pyrimidine synthesis. In addition, nicotinamide, amino acids and any vitamins needed for growth, must be acquired from its environment. The core proteome of M. haemofelis contains an abundance of paralogous gene families, corresponding to 70.6% of all the CDSs. This "paralog pool" is a rich source of different antigenic epitopes that can be varied to elude the host's immune system and establish chronic infection. M. haemofelis also appears to be capable of phase variation, which is particularly relevant to the cyclic bacteremia and persistence, characteristics of the infection in the cat. The data generated herein should be of great use for understanding the mechanisms of M. haemofelis infection. Further, it will provide new insights into its pathogenicity and clues needed to formulate media to support the in vitro cultivation of M. haemofelis

Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

Adeno-Assocated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

Heart disease is the leading cause of morbidity and mortality. Cardiac gene transfer may serve as a novel therapeutic approach. This investigation was undertaken to compare cardiac tropisms of adeno-associated virus (AAV) serotypes 1, 6, 7, 8, and 9. Neonatal mice were injected with 2.5 × 1011 genome copies (GC) of AAV serotype 1, 6, 7, 8, or 9 expressing LacZ under the control of the constitutive chicken β-actin promoter with cytomegalovirus enhancer promoter via intrapericardial injection and monitored for up to 1 year. Adult rats were injected with 5 × 1011 GC of the AAV vectors via direct cardiac injection and monitored for 1 month. Cardiac distribution of LacZ expression was assessed by X-Gal histochemistry, and β-galactosidase activity was quantified in a chemiluminescence assay. Cardiac functional data and biodistribution data were also collected in the rat. AAV9 provided global cardiac gene transfer stable for up to 1 year that was superior to other serotypes. LacZ expression was relatively cardiac specific, and cardiac function was unaffected by gene transfer. AAV9 provides high-level, stable expression in the mouse and rat heart and may provide a simple alternative to the creation of cardiac-specific transgenic mice. AAV9 should be used in rodent cardiac studies and may be the vector of choice for clinical trials of cardiac gene transfer

Exceptional lability of a genomic complex in rice and its close relatives revealed by interspecific and intraspecific comparison and population analysis

<p>Abstract</p> <p>Background</p> <p>Extensive DNA rearrangement of genic colinearity, as revealed by comparison of orthologous genomic regions, has been shown to be a general concept describing evolutionary dynamics of plant genomes. However, the nature, timing, lineages and adaptation of local genomic rearrangement in closely related species (<it>e.g</it>., within a genus) and haplotype variation of genomic rearrangement within populations have not been well documented.</p> <p>Results</p> <p>We previously identified a hotspot for genic rearrangement and transposon accumulation in the <it>Orp </it>region of Asian rice (<it>Oryza sativa</it>, AA) by comparison with its orthologous region in sorghum. Here, we report the comparative analysis of this region with its orthologous regions in the wild progenitor species (<it>O. nivara</it>, AA) of Asian rice and African rice (<it>O. glaberrima</it>) using the BB genome <it>Oryza </it>species (<it>O. punctata</it>) as an outgroup, and investigation of transposon insertion sites and a segmental inversion event in the AA genomes at the population level. We found that <it>Orp </it>region was primarily and recently expanded in the Asian rice species <it>O. sativa </it>and <it>O. nivara</it>. LTR-retrotransposons shared by the three AA-genomic regions have been fixed in all the 94 varieties that represent different populations of the AA-genome species/subspecies, indicating their adaptive role in genome differentiation. However, LTR-retrotransposons unique to either <it>O. nivara </it>or <it>O. sativa </it>regions exhibited dramatic haplotype variation regarding their presence or absence between or within populations/subpopulations.</p> <p>Conclusions</p> <p>The LTR-retrotransposon insertion hotspot in the <it>Orp </it>region was formed recently, independently and concurrently in different AA-genome species, and that the genic rearrangements detected in different species appear to be differentially triggered by transposable elements. This region is located near the end of the short arm of chromosome 8 and contains a high proportion of LTR-retrotransposons similar to observed in the centromeric region of this same chromosome, and thus may represent a genomic region that has recently switched from euchromatic to heterochromatic states. The haplotype variation of LTR-retrotransposon insertions within this region reveals substantial admixture among various subpopulations as established by molecular markers at the whole genome level, and can be used to develop retrotransposon junction markers for simple and rapid classification of <it>O. sativa </it>germplasm.</p