Hydrogen gas is a potential renewable alternative energy carrier that could be used in the future to help supplement humanity’s growing energy needs. Unfortunately, current industrial methods for ...hydrogen production are expensive or environmentally unfriendly. In recent years research has focused on biological mechanisms for hydrogen production and specifically on hydrogenases, the enzyme responsible for catalyzing the reduction of protons to generate hydrogen. In particular, a better understanding of this enzyme might allow us to generate hydrogen that does not use expensive metals, such as platinum, as catalysts. The soluble hydrogenase I (SHI) from the hyperthermophile Pyrococcus furiosus, a member of the euryarchaeota, has been studied extensively and used in various biotechnological applications. This review summarizes the strategies used in engineering and characterizing three different forms of SHI and the properties of the recombinant enzymes. SHI has also been used in in vitro systems for hydrogen production and NADPH generation and these systems are also discussed.
In this study I explore the phonological behavior of the hypocoristic suffix /-oʃ/-/iʃ/ in Turkish. Such a suffix is common to many of the Balkan languages. Turkish differs in its introduction of the ...front vowel variant of the suffix, presumably to satisfy the vowel harmony requirements in Turkish for backness and rounding in high vowels. However, in spite of the potentially alternating suffix allomorphs, collection of naturalistic data as well as of elicited survey data reveals that the majority of nickname outputs are disharmonic. I conclude that the Turkish data provides further evidence for Ito and Mester’s (2009) key insight that different strata of the lexicon may operate according to different rules/constraint rankings. However, the Turkish data is not consistent with their specific faithfulness-based approach. The hypocoristic lexical stratum exhibits a greater number of vowel harmony violations, but not due to more faithfulness to vowel inputs/underlying forms. Rather, the harmony violations in this stratum are gratuitous – I argue, precisely in order to distinguish this stratum from the lexicon at large. An approach such as Pater’s (2010) indexed constraints model better accommodates this type of lexical variation.
Clinical investigations have demonstrated a relationship between the extended use of rofecoxib and the increased risk for atherothrombotic events. This has led to the removal of rofecoxib from the ...market and concern over the cardiovascular safety of other cyclooxygenase (COX)-2 selective agents. Experimental findings from independent laboratories now indicate that the cardiotoxicity of rofecoxib may not be a class effect but because of its intrinsic chemical properties. Specifically, rofecoxib has been shown to increase the susceptibility of human low-density lipoprotein and cellular membrane lipids to oxidative modification, a contributing factor to plaque instability and thrombus formation. Independently of COX-2 inhibition, rofecoxib also promoted the nonenzymatic formation of isoprostanes and reactive aldehydes from biologic lipids. The basis for these observations is that rofecoxib alters lipid structure and readily forms a reactive maleic anhydride in the presence of oxygen. By contrast, other selective (celecoxib, valdecoxib) and nonselective (naproxen, diclofenac) inhibitors did not influence rates of low-density lipoprotein and membrane lipid oxidation. We have now further confirmed these findings by demonstrating that the prooxidant activity of rofecoxib can be blocked by the potent antioxidant astaxanthin in homochiral form (all-trans 3S, 3′S). These findings provide a mechanistic rationale for differences in cardiovascular risk among COX-selective inhibitors because of their intrinsic physicochemical properties.
Turkish belongs to a special and relatively small group of languages worldwide which are known to be used in whistled form. Such whistled speech is acoustically simplified and not comprehensible to ...untrained speakers of the same language. This study investigates the ability of untrained, non-whistling Turkish speakers to distinguish between whistled Turkish and the whistled versions of other languages. Results indicate that they can do this at above chance levels, depending on individual linguistic factors such as native language and degree/type of familiarity with specific other languages. Whistled Turkish represents a novel source of information on a special modality of Turkish and a cultural practice of some Turkish-speaking communities. In addition, we see that just as newborns are able to discriminate between languages without intelligibility, based on the restricted phonetic information available to them while still in the womb, listeners are also able to discriminate between their native language and others based on the relatively restricted acoustic information and novel modality of whistled speech.
Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding ...diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain.
Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. ...Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.
Derivatives of (3-(9-oxo-9H-fluorene-1-carbonyl)-amino-benzoic acid were synthesized to obtain other acceptable inhibitors of edema toxin (EF) catalyzed stimulation of cyclic AMP production in ...monocyte-macrophage cells.
Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3′,5′-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-(9-oxo-9H-fluorene-1-carbonyl)-amino-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure–activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria.
Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus ...fat for 6 days following a 5-day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53 ± 6 g/day of body fat, fat oxidation was unchanged by fat restriction, leading to 89 ± 6 g/day of fat loss, and was significantly greater than carbohydrate restriction (p = 0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.
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•19 adults with obesity were confined to a metabolic ward for two 2-week periods•Cutting carbohydrates increased net fat oxidation, but cutting fat by equal calories had no effect•Cutting fat resulted in more body fat loss as measured by metabolic balance•Mathematical model simulations predicted small long-term differences in body fat
Hall et al. investigated 19 adults with obesity that selectively restricted dietary carbohydrate versus fat. Cutting carbohydrates increased net fat oxidation while equal calorie fat restriction had no effect. However, cutting fat resulted in more body fat loss than cutting carbohydrates. Mathematical model simulations predicted small long-term differences in body fat.
A greater decrease in 24-hour energy expenditure (24hEE) during short-term fasting is indicative of a thrifty phenotype.
As ghrelin and the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) ...axis are implicated in the regulation of energy intake and metabolism, we investigated whether ghrelin, GH, and IGF-1 concentrations mediate the fasting-induced decrease in 24hEE that characterizes thriftiness.
In 47 healthy individuals, 24hEE was measured in a whole-room indirect calorimeter both during 24-hour eucaloric and fasting conditions. Plasma total ghrelin, GH, and IGF-1 concentrations were measured by enzyme-linked immunosorbent assay after an overnight fast the morning before and after each 24-hour session.
During 24-hour fasting, on average 24hEE decreased by 8.0% (P < .001), GH increased by ~5-fold (P < .001), whereas ghrelin (mean +23 pg/mL) and IGF-1 were unchanged (both P ≥ .19) despite a large interindividual variability in ghrelin change (SD 150 pg/mL). Greater fasting-induced increase in ghrelin was associated with a greater decrease in 24hEE during 24-hour fasting (r = -0.42, P = .003), such that individuals who increased ghrelin by 200 pg/mL showed an average decrease in 24hEE by 55 kcal/day.
Short-term fasting induced selective changes in the ghrelin/GH/IGF-1 axis, specifically a ghrelin-independent GH hypersecretion that did not translate into increased IGF-1 concentrations. Greater increase in ghrelin after 24-hour fasting was associated with greater decrease in 24hEE, indicating ghrelin as a novel biomarker of increased energy efficiency of the thrifty phenotype.
BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes ...hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% interquartile range 0.1%-0.5%), in contrast to lipodystrophy (10.6% interquartile range 2.8%-17.1%, P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.
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