A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels

One Complete and Seven Draft Genome Sequences of Subdivision 1 and 3 Acidobacteria Isolated from Soil.

We report eight genomes from representatives of the phylum Acidobacteria subdivisions 1 and 3, isolated from soils. The genome sizes range from 4.9 to 6.7 Mb. Genomic analysis reveals putative genes for low- and high-affinity respiratory oxygen reductases, high-affinity hydrogenases, and the capacity to use a diverse collection of carbohydrates

Metatranscriptomic Sequencing of a Cyanobacterial Soil-Surface Consortium with and without a Diverse Underlying Soil Microbiome.

Soil surface consortia are easily observed and sampled, allowing examination of their interactions with soil microbiomes. Here, we present metatranscriptomic sequences from Dark Green 1 (DG1), a cyanobacterium-based soil surface consortium, in the presence and absence of an underlying soil microbiome and/or urea

Dynamics on and of Complex Networks

<p>Networks -- abstract objects composed of \emph{vertices} connected by \emph{edges}, are ubiquitous in the real world. </p><p>Examples such as social networks, the world wide web, and neural networks in the brain</p><p>are constantly evolving in their topology, the state of their vertices, or a combination of the two.</p><p>This dissertation presents a computational and theoretical study of three models of network dynamics, one corresponding to each of these modes of evolution.</p><p>The first study models the disintegration of a social network of voters with binary opinions, who prefer to be connected to others with the same opinion. </p><p>We study two versions of the model: the network evolves by voters in discordant ties choosing to either </p><p>adopt the opinion of their neighbors, or to rewire their ties to some randomly chosen voter of (i) the same, or (ii) any, opinion. </p><p>We examine how the probability of rewiring, and the initial fraction $\rho_{\textrm{i}}$ in the minority, </p><p>determine the final minority fraction $\rho_{\textrm{f}}$, when the network has bifurcated. </p><p>In case (i), there is a critical probability, that is independent of $\rho_{\textrm{i}}$, above which $\rho_{\textrm{f}}$ is unchanged from $\rho_{\textrm{i}}$, </p><p>and below which there is full concensus. </p><p>In case (ii), the behavior above the critical probability, that now depends on $\rho_{\textrm{i}}$, is similar; but </p><p>below it, $\rho_{\textrm{f}}$ matches the result of starting with $\rho_{\textrm{i}} = 1/2$. Using simulations and approximate calculations, we explain why these two nearly identical </p><p>models have such dramatically different behaviors.</p><p>The second model, called the \emph{quadratic contact process} (QCP) involves ``birth'' and ``death'' events on a static network. </p><p>Vertices take on the binary states occupied(1) or vacant(0). </p><p>We consider two versions of the model -- Vertex QCP, and Edge QCP, corresponding to </p><p>birth events $1-0-1 \longrightarrow 1-1-1$ and $1-1-0 \longrightarrow</p><p>1-1-1$ respectively, where `$-$' represents an edge. </p><p>We study the fraction of occupied vertices at steady state as a function of the birth rate, keeping </p><p>the death rate constant. To investigate the effects </p><p>of network topology, we study the QCP on homogeneous networks with a bounded or rapidly decaying degree distribution, </p><p>and those with a heavy tailed degree distribution. </p><p>From our simulation results and mean field calculations, we conclude </p><p>that on the homogeneous networks, there is a discontinuous phase transition with a</p><p>region of bistability, whereas on the heavy tailed networks, the</p><p>transition is continuous. Furthermore, the critical birth rate is positive </p><p>in the former but zero in the latter.</p><p>In the third study, we propose a general scheme for spatial networks evolving in order to reduce their total edge lengths. </p><p>We study the properties of the </p><p>equilbria of two networks from this class, one of which interpolate between two well studied objects: the Erd\H{o}s-R\'{e}nyi random graph, and the random geometric graph. </p><p>The first of our two evolutions can be used as a model for a social network where individuals have fixed opinions about a number of issues and adjust their ties to be connected to people with similar views. </p><p>The second evolution which preserves the connectivity of the network has potential applications in the design of transportation networks and other distribution systems.</p>Dissertatio

Inflammatory Response in Patients With Crohn's Disease Compared With Ulcerative Colitis: Secondary Results of a Prospective Pilot Study

Lay Summary This study showed that patients with Crohn's disease react with more inflammation to surgery than patients with ulcerative colitis. This finding indicates that Crohn's patients may need more preparation before surgery, and more monitoring after it. Background The aim of this study was to compare the inflammatory response (IR) to surgery between patients with Crohn's disease (CD) and patients with ulcerative colitis (UC). Methods This study is a secondary analysis of data collected in a previous study by the authors. We included all adult patients who underwent elective surgery for CD and UC. The primary outcome variable was the difference in postoperative IR as measured by interleukin 6 (IL-6), interleukin 10 (IL-10), C-reactive protein (CRP), and the count of white blood cells (WBCs) in peripheral blood. Two-way repeated-measures analysis of variance with a mixed effect (disease type as the between-patient factor, and time as the within patient factor). Results We included 46 patients in this pilot study. Median age was 42.5 years (IQR 30.5-42.2), 25/46 were females (54.3. Patients with CD had a more marked IR to surgery compared with those with UC as shown by significant differences in levels of IL-6, IL-10, and CRP. Patients with CD were more often treated with postoperative epidural analgesia 17 (53.1 versus 1 (7.1, P = .009. Patients with colonic CD had a more intense IR to surgery than patients with UC after the same surgical resection. This significant trend continued when patients who underwent small bowel resection compared with those with colectomy. The changes in inflammatory markers and WBC counts from baseline to peak value were also higher in patients with CD indicating a more severe IR. However, there was a similar response in patients undergoing laparoscopic compared with open approaches Conclusions The postoperative IR was greater in patients with CD than those with UC. This is important to tackle in preoperative optimization as well as postoperative recovery protocols.Background: The aim of this study was to compare the inflammatory response (IR) to surgery between patients with Crohn's disease (CD) and patients with ulcerative colitis (UC). Methods: This study is a secondary analysis of data collected in a previous study by the authors. We included all adult patients who underwent elective surgery for CD and UC. The primary outcome variable was the difference in postoperative IR as measured by interleukin 6 (IL-6), interleukin 10 (IL-10), C-reactive protein (CRP), and the count of white blood cells (WBCs) in peripheral blood. Two-way repeated-measures analysis of variance with a mixed effect (disease type as the between-patient factor, and time as the within patient factor). Results: We included 46 patients in this pilot study. Median age was 42.5 years (IQR 30.5-42.2), 25/46 were females (54.3%). Patients with CD had a more marked IR to surgery compared with those with UC as shown by significant differences in levels of IL-6, IL-10, and CRP. Patients with CD were more often treated with postoperative epidural analgesia 17 (53.1%) versus 1 (7.1%), P =. 009. Patients with colonic CD had a more intense IR to surgery than patients with UC after the same surgical resection. This significant trend continued when patients who underwent small bowel resection compared with those with colectomy. The changes in inflammatory markers and WBC counts from baseline to peak value were also higher in patients with CD indicating a more severe IR. However, there was a similar response in patients undergoing laparoscopic compared with open approaches Conclusions: The postoperative IR was greater in patients with CD than those with UC. This is important to tackle in preoperative optimization as well as postoperative recovery protocols.</p

An overview of anti-diabetic plants used in Gabon: Pharmacology and Toxicology

© 2017 Elsevier B.V. All rights reserved.Ethnopharmacological relevance: The management of diabetes mellitus management in African communities, especially in Gabon, is not well established as more than 60% of population rely on traditional treatments as primary healthcare. The aim of this review was to collect and present the scientific evidence for the use of medicinal plants that are in currect by Gabonese traditional healers to manage diabetes or hyperglycaemia based here on the pharmacological and toxicological profiles of plants with anti-diabetic activity. There are presented in order to promote their therapeutic value, ensure a safer use by population and provide some bases for further study on high potential plants reviewed. Materials and methods: Ethnobotanical studies were sourced using databases such as Online Wiley library, Pubmed, Google Scholar, PROTA, books and unpublished data including Ph.D. and Master thesis, African and Asian journals. Keywords including ‘Diabetes’ ‘Gabon’ ‘Toxicity’ ‘Constituents’ ‘hyperglycaemia’ were used. Results: A total of 69 plants currently used in Gabon with potential anti-diabetic activity have been identified in the literature, all of which have been used in in vivo or in vitro studies. Most of the plants have been studied in human or animal models for their ability to reduce blood glucose, stimulate insulin secretion or inhibit carbohydrates enzymes. Active substances have been identified in 12 out of 69 plants outlined in this review, these include Allium cepa and Tabernanthe iboga. Only eight plants have their active substances tested for anti-diabetic activity and are suitables for further investigation. Toxicological data is scarce and is dose-related to the functional parameters of major organs such as kidney and liver. Conclusion: An in-depth understanding on the pharmacology and toxicology of Gabonese anti-diabetic plants is lacking yet there is a great scope for new treatments. With further research, the use of Gabonese anti-diabetic plants is important to ensure the safety of the diabetic patients in Gabon.Peer reviewedFinal Accepted Versio

Io'S Atmospheric Freeze-Out Dynamics In The Presence Of A Non-Condensable Species

One dimensional direct simulation Monte Carlo (DSMC) simulations are used to examine the effect of a trace non-condensable species on the freeze-out dynamics of Io's sulfur dioxide sublimation atmosphere during eclipse and egress. Due to finite ballistic times, essentially no collapse occurs during the first 10 minutes of eclipse at altitudes above similar to 100 km, and hence immediately after ingress auroral emission morphology above 100 km should resemble that of the immediate pre-eclipse state. In the absence of a non-condensable species the sublimation SO2 atmosphere will freeze-out (collapse) during eclipse as the surface temperature drops. However, rapid collapse is prevented by the presence of even a small amount of a perfect non-condensable species due to the formation of a static diffusion layer several mean free paths thick near the surface. The higher the non-condensable mole fraction, the longer the collapse time. The effect of a weakly condensable gas species (non-zero sticking/reaction coefficient) was examined since real gas species may not be perfectly non-condensable at realistic surface temperatures. It is found that even a small sticking coefficient dramatically reduces the effect of the diffusion layer on the dynamics. If the sticking coefficient of the non-condensable exceeds similar to 0.25 the collapse dynamics are effectively the same as if there was no non-condensable present. This sensitivity results because the loss of non-condensable to the surface reduces the effective diffusion layer size and the formation of an effective diffusion layer requires that the layer be stationary which does not occur if the surface is a sink. As the surface temperature increases during egress from eclipse the sublimating SO2 gas pushes the non-condensable diffusion layer up to higher altitudes once it becomes dense enough to be collisional. This vertical species stratification should alter the auroral emissions after egress.Aerospace Engineerin