Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

Late Winter Biogeochemical Conditions Under Sea Ice in the Canadian High Arctic

With the Arctic summer sea-ice extent in decline, questions are arising as to how changes in sea-ice dynamics might affect biogeochemical cycling and phenomena such as carbon dioxide (CO2) uptake and ocean acidification. Recent field research in these areas has concentrated on biogeochemical and CO2 measurements during spring, summer or autumn, but there are few data for the winter or winter–spring transition, particularly in the High Arctic. Here, we present carbon and nutrient data within and under sea ice measured during the Catlin Arctic Survey, over 40 days in March and April 2010, off Ellef Ringnes Island (78° 43.11′ N, 104° 47.44′ W) in the Canadian High Arctic. Results show relatively low surface water (1–10 m) nitrate (<1.3 µM) and total inorganic carbon concentrations (mean±SD=2015±5.83 µmol kg−1), total alkalinity (mean±SD=2134±11.09 µmol kg−1) and under-ice pCO2sw (mean±SD=286±17 µatm). These surprisingly low wintertime carbon and nutrient conditions suggest that the outer Canadian Arctic Archipelago region is nitrate-limited on account of sluggish mixing among the multi-year ice regions of the High Arctic, which could temper the potential of widespread under-ice and open-water phytoplankton blooms later in the season

The semiology of changing brand image

This article considers the attempted change to the image of an established brand by studying the semiotics within the brand’s historical advertising campaigns. The use of semiotics to study the interpretation of messages is discussed, and the link between interpretation of messages and advertising effectiveness in changing brand image is explored. The authors deconstruct advertisements of a brand to provide a model containing opposing dialectics that may aid managers by highlighting alternative symbolic messages contained in advertisements. Oncwe identified, these alternative symbolic messages may be used to help change brand image and influence advertising effectiveness. Although the study focuses upon a major brand of beer, this is an industry in which there are numerous small firms, and many of those have constrained marketing budgets, and thus need to make sure that their advertising is effective. Equally, entrepreneurial marketing is not to found only in the small firm, and the case study discusses a radical and imaginative brand repositioning of a well established product

Marine diatoms grown in chemostats under silicate or ammonium limitation. III. Cellular chemical composition and morphology of Chaetoceros debilis, Skeletonema costatum , and Thalassiosira gravida

Three marine diatoms, Skeletonema costatum, Chaetoceros debilis , and Thalassiosira gravida were grown under no limitation and ammonium or silicate limitation or starvation. Changes in cell morphology were documented with photomicrographs of ammonium and silicate-limited and non-limited cells, and correlated with observed changes in chemical composition. Cultures grown under silicate starvation or limitation showed an increase in particulate carbon, nitrogen and phosporus and chlorophyll a per unit cell volume compared to non-limited cells; particulate silica per cell volume decreased. Si-starved cells were different from Si-limited cells in that the former contained more particulate carbon and silica per cell volume. The most sensitive indicator of silicate limitation or starvation was the ratio C:Si, being 3 to 5 times higher than the values for non-limited cells. The ratios Si:chlorophyll a and S:P were lower and N:Si was higher than non-limited cells by a factor of 2 to 3. The other ratios, C:N, C:P, C:chlorophyll a , N:chlorophyll a , P:chlorophyll a and N:P were considered not to be sensitive indicators of silicate limitation or starvation. Chlorophyll a , and particulate nitrogen per unit cell volume decreased under ammonium limitation and starvation. NH 4 -starved cells contained more chlorophyll a , carbon, nitrogen, silica, and phosphorus per cell volume than NH 4 -limited cells. N:Si was the most sensitive ratio to ammonium limitation or starvation, being 2 to 3 times lower than non-limited cells. Si:chlorophyll a , P:chlorophyll a and N:P were less sensitive, while the ratios C:N, C:chlorophyll a , N:chlorophyll a , C:Si, C:P and Si:P were the least sensitive. Limited cells had less of the limiting nutrient per unit cell volume than starved cells and more of the non-limiting nutrients (i.e., silica and phosphorus for NH 4 -limited cells). This suggests that nutrient-limited cells rather than nutrient-starved cells should be used along with non-limited cells to measure the full range of potential change in cellular chemical composition for one species under nutrient limitation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46631/1/227_2004_Article_BF00392568.pd

DL5o da bactéria Aeromonas hydrophila para o matrinxã, Brycon amazonicus

In order to determine the lethal dose (96-h LD50) of the bacteria Aeromonas hydrophila to matrinxã, Brycon amazonicus, to be applied in challenge tests, 90 fish (63.23 ± 6.39 g) were divided into five treatments, with different bacterial solutionsT1 - Control (0.9% NaCl saline solution); T2 (4 x 10(11) cells/ mL); T3 (5 x 10(11) cells/ mL); T4 (1.36 x 10(12) cells/ mL) and T5 (3.06 x 10(12) cells/ mL). Fish were previously anesthetized with benzocaine (60 mg L-1), inoculated in the peritoneal cavity with the bacterial suspensions and then distributed into fifteen 80-L test chambers, where the water variables were monitored and fish mortality was observed. The experiment was randomly designed in three replicates and the 96-h LD50 was estimated according to the trimmed Spearman-Karber method. Water quality variables remained within adequate ranges for fish health and performance. Fish mortality rate increased with the bacterial concentrations of A. hydrophila (T1 = 0%; T2 = 16.66%; T3 = 44.44%; T4 = 72.22% and T5 = 100%), and the first mortalities were observed after 57 h, although the signs of the bacterial infection were already observed 24 h after the inoculation. The results indicate that the 96-h LD50 value of A. hydrophila to matrinxã is 6.66 x 10(11) cells/ mL.Para determinar a dose letal (DL50 96-h) da bactéria Aeromonas hydrophila para o matrinxã, Brycon amazonicus, com aplicabilidade para testes de desafio, foram utilizados 90 peixes (63,23 ± 6,39 g), divididos em cinco tratamentos, com diferentes soluções bacterianas: T1 - Controle (solução salina 0,9% NaCl); T2 (4 x 10(11) células/ mL); T3 (5 x 10(11) células/ mL-1); T4 (1,36 x 10(12) células/mL-1) e T5 (3,06 x 10(12) células/ mL-1). Os peixes foram previamente anestesiados com benzocaína (60 mg L-1), inoculados na cavidade peritoneal com as suspensões bacterianas e distribuídos em 15 aquários de vidro de 80 L de capacidade, com aeração constante. O experimento teve duração de 96 h, no qual foram monitoradas a mortalidade e a qualidade da água. O delineamento experimental foi inteiramente casualisado com três réplicas e a DL50 96-h foi estimada de acordo com o método Spearman-Karber. Durante o experimento os parâmetros físico-químicos da água permaneceram dentro das condições consideradas adequadas para o desenvolvimento e saúde dos organismos aquáticos. A mortalidade dos peixes aumentou nas concentrações crescentes de A. hydrophila (T1 = 0%; T2 = 16,66%; T3 = 44,44%; T4 = 72,22% e T5 = 100%), contudo, as primeiras mortalidades ocorreram em 57 h após a inoculação das concentrações bacterianas, sendo observados os primeiros sinais de infecção em 24 h após a inoculação. Os resultados indicam que o valor da DL50 96-h da bactéria A. hydrophila para o matrinxã foi igual a 6,66 x 10(11) células/mL de solução salina

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Register bypassing in an asynchronous superscalar processor

Register bypassing, universally provided in synchronous processors, is more difficult to implement in an asynchronous design. Asynchronous bypassing requires synchronization between the forwarding and receiving units, with the danger that the advantages of synchronization operation may be nullified by reintroducing the lock-step operation of synchronous processors. We present a novel implementation of register bypassing in an asynchronous processor architecture. Our technique of Decoupled Operand Forwarding provides centralized control over the bypassing operation, yet allows multiple execution units to function asynchronously. Our ideas are presented within the context of the development of Hades, a generic asynchronous processor architecture. We employ single-issue and dual-issue simulations of Hades to quantify the benefits of Decoupled Operand Forwarding and conclude that Decoupled Operand Forwarding yields significant speedups because of its success in removing register files from the critical timing path

Hades - towards the design of an asynchronous superscalar processor

Hades is a processor architecture aimed at single and multiple-instruction-issue asynchronous implementations. This paper uses a baseline version of Hades to illustrate some of the difficulties encountered in asynchronous processor design and demonstrates why it is undesirable to design a processor which is simply an asynchronous version of an existing synchronous processor. Particular emphasis is placed on an explicitly declared delayed branch mechanism and a decoupled register forwarding mechanism developed for Hades. Ths branch mechanism allows instruction fetching to proceed while branch instructions are being resolved, while the forwarding mechanism allows the last result of each functional unit to be bypassed to following instructions, yet completely separates bypassing from the register write back operation