The chemistry and pharmacology of hydrotrichlorothiazide

Zusammenfassung In der Reihe der Dihydro-benzothiadiazine wurde mit Hydrotrichlorthiazid (III) ein neues, ausserordentlich stark wirksames Diuretikum gefunden. Herstellung und pharmakologische Evaluation werden kurz beschrieben. Im Vergleich zu Hydrochlorthiazid (I) ist III beim Hundper os bis zu 20mal stärker diuretisch wirksam.     

EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.     

Production of dimethylfuran for liquid fuels from biomass-derived carbohydrates

Diminishing fossil fuel reserves and growing concerns about global warming indicate that sustainable sources of energy are needed in the near future. For fuels to be useful in the transportation sector, they must have specific physical properties that allow for efficient distribution, storage and combustion; these properties are currently fulfilled by non-renewable petroleum-derived liquid fuels. Ethanol, the only renewable liquid fuel currently produced in large quantities, suffers from several limitations, including low energy density, high volatility, and contamination by the absorption of water from the atmosphere. Here we present a catalytic strategy for the production of 2,5-dimethylfuran from fructose (a carbohydrate obtained directly from biomass or by the isomerization of glucose) for use as a liquid transportation fuel. Compared to ethanol, 2,5-dimethylfuran has a higher energy density (by 40 per cent), a higher boiling point (by 20 K), and is not soluble in water. This catalytic strategy creates a route for transforming abundant renewable biomass resources into a liquid fuel suitable for the transportation sector, and may diminish our reliance on petroleum.     

The efficacy of a novel compound, (E)-1-(4′-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene againstTrypanosoma cruzi in mice

Summary The biological properties of a novel compound 353C with high activity againstTrypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C had a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.     

Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.     

Censusing bobcats using remote cameras

We estimated bobcat ( Lynx rufus ) density for 3 different locations in northern California using active infrared-triggered cameras. Using differences in pelage pattern as well as other physical characteristics, we identified individual bobcats from photographs, and used mark-recapture techniques to estimate population density. Camera density affected the precision of population estimates. The same population was estimated using camera densities of 0.5, 1, 2, 4, 6, and 8 cameras ? km–2. Higher camera densities resulted in more captures and recaptures of bobcats and, consequently, in more precise density estimates. Similarly, the number of photo-captures and recaptures increased with increasing study duration. Increasing the area sampled resulted in the capture of more individuals but did not increase the percentage of recaptures. While some locations captured multiple bobcat photographs (e.g., 15 at 1 station), these photos tended to be recaptures of the same individual. There were no more than 2 individuals photo-captured at any 1 camera location. Bobcat density varied among habitat types as predicted. We estimated density as 0.27 bobcats ? km –2 ( s = 0.16) overall in an area in the northern Sacramento River Valley and as 0.35 bobcats ? km –2 ( s = 0.56) in a steep and rocky canyon within the area. At a 3rd site in the Coast Range, the estimate was 0.39 bobcats ? km –2 ( s = 1.44). Bobcats were more diurnal where human activity was less common. In addition, photo-capture was significantly higher along roads and trails without an attractant than it was off-trail with an attractant.     

Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)).     

Catalase in free-living and parasitic platyhelminths

Summary Catalase was found in all of the free-living species of platyhelminths studied, but could not be detected in any of the parasitic species (trematodes or cestodes). This work was supported by NATO research grant 1681.