A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Maximum Cardinality Search for Computing Minimal Triangulations of Graphs

We present a new algorithm, called MCS-M, for computing minimal triangulations of graphs. Lex-BFS, a seminal algorithm for recognizing chordal graphs, was the genesis for two other classical algorithms: LEX M and MCS. LEX M extends the fundamental concept used in Lex-BFS, resulting in an algorithm that not only recognizes chordality, but also computes a minimal triangulation of an arbitrary graph. MCS simplifies the fundamental concept used in Lex-BFS, resulting in a simpler algorithm for recognizing chordal graphs. The new algorithm MCS-M combines the extension of LEX M with the simplification of MCS, achieving all the results of LEX M in the same time complexity.     

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

We have studied the inhibitory action of long- and short-chain fatty acids on hepatic glucose utilization in hepatocytes isolated from fasted rats. The rates of hepatic glucose phosphorylation and glycolysis were determined from the tritiated products of [2-3H] and [6-3H]glucose metabolism, respectively. The difference between these was taken as an estimate of the 'cycling' between glucose and glucose-6-phosphate. In the presence of 40 mM glucose this cycling was estimated at 0.68 mumol/min/g wet wt. Glucose phosphorylation was unaffected during palmitate and hexanoate oxidation to ketone bodies but glycolysis was inhibited. The rate of glucose cycling was increased during this phase to 1.25 mumol/min/g. Following the complete metabolism of the fatty acids, glycolysis was reinstated and cycling rates returned to control levels. Hepatic glucose cycling appears to be an important component of the glucose/fatty acid cycle.     

Pathway engineering for the production of aromatic compounds in Escherichia coli

The standard enzymatic assay for quantification of D-sorbitol in plasma was adapted to the automatic analyzer Cobas Mira S. In the assay, NAD (reagent) in the presence of sorbitoldehydrogenase (SDH; start reagent) converts D-sorbitol to fructose with formation of NADH, which was detected automatically as the difference between the first and last readings at 340 nm. The sample blank values for each specimen were subtracted to exclude both endogenous D-sorbitol and sugars, which also react as substrates for SDH. The method is simple, rapid (40 samples/h), precise down to endogenous concentrations (coefficient of variation < 5%; limit of determination: 0.38 mg/L) and linear up to 100 mg/L. Samples with higher D-sorbitol concentrations were estimated after dilution. The method was used to measure disposition curves of sorbitol in volunteers after a single intravenous dose of 0.8 g sorbitol.     

Cement versus cementless fixation in total knee arthroplasty

A prospectively studied group of 55 uncemented Press Fit Condylar total knee arthroplasties was compared retrospectively with a matched group of 51 cemented Press Fit Condylar total knee arthroplasties at a mean of 10 years after operation. For the cemented group, the pain and function scores improved from 32 and 45 preoperatively to 95 and 77, respectively. For the uncemented group the scores improved from 33 and 50 preoperatively to 93 and 60, respectively. There were 10 revisions in the uncemented group for femoral or tibial aseptic loosening or osteolysis compared with two revisions in the cemented group. Exclusive of problems related to patellar metal backing, survival to revision for aseptic failure or radiographic loosening was 72% in the uncemented group and 94% in the cemented group at 10 years. A significantly higher revision rate was found in the uncemented compared with cemented total knee arthroplasty of the Press Fit Condylar design.     

MRI of intramedullary sarcoidosis: follow-up of a case

Significative enhancement of free radical formation (FRO) in vivo is an important feature of hypertensive disorders of pregnancy (HDP), namely preeclampsia (PIH). The latest investigations about the pathology of HDP, showed the contribution of placental circulation to the development and evolution of such disease. The placental bed can be a potential source of FRO or activation of cells that can produce FRO. Glutathione, is an important molecule for cellular protection against damage, is a cofactor of many enzymes, in particular, for the glutathione peroxidase of the placental tissue; this enzyme in the placenta bed prevent the production of thromboxan and lipoperoxides; the latter are potentially damaging to the endothelium cells and can cause vasoconstriction, the most important feature of PIH. The activity of that enzyme is deficient in PIH. We studied, by fluorometric assay, the concentrations of the two states of glutathione in placental homogenates (PLH) from pregnant women without pathology (PWN) and from pregnant women with PIH (PWPIH). The data showed significant low concentrations in the PLH of the two states of glutathione in the PWN against high concentrations of this molecule in the PLH from PWPIH. This feature can result from a deficient user of the glutathione by the cellular mechanism for prevention against oxidative factors. In addition, our study shows a biochemical marker that is suggestive that the placental bed is a potential source of FRO production in PIH.     

Dynamic-mechanical properties of polybutadiene rubbers

The dynamic properties of high-cis (98%) and cis-trans (42% cis) polybutadienes, crosslinked with 0.1 to 1.0% of crosslinking agent, have been studied using a torsion pendulum method over the temperature range ?170 to +20°C. For the high-cis rubber plots of damping factor (tan δ) against temperature showed the expected peak in the glass-transition region with an additional peak in the neighbourhood of 0°C attributable to crystallization. The cis-trans rubber showed two damping maxima in the transition region, separated by 30 to 40°C (depending on the degree of crosslinking), suggesting incipient phase separation of the component structures. The rebound resilience of the high-cis rubber at room temperature exceeded that of the cis-trans, reaching 92% at the highest crosslink density. Plots of resilience versus temperature for both rubbers showed a single minimum in the glass transition region.