Techniques for systematically monitoring protein translation have lagged far behind methods for measuring messenger RNA (mRNA) levels. Here, we present a ribosome-profiling strategy that is based on ...the deep sequencing of ribosome-protected mRNA fragments and enables genome-wide investigation of translation with subcodon resolution. We used this technique to monitor translation in budding yeast under both rich and starvation conditions. These studies defined the protein sequences being translated and found extensive translational control in both determining absolute protein abundance and responding to environmental stress. We also observed distinct phases during translation that involve a large decrease in ribosome density going from early to late peptide elongation as well as widespread regulated initiation at non-adenine-uracil-guanine (AUG) codons. Ribosome profiling is readily adaptable to other organisms, making high-precision investigation of protein translation experimentally accessible.
Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and ...represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.
Ketone bodies as signaling metabolites Newman, John C; Verdin, Eric
Trends in endocrinology and metabolism,
01/2014, Letnik:
25, Številka:
1
Journal Article
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Highlights • Ketone bodies have signaling functions as well as being a mobile source of cellular energy. • Ketone bodies inhibit histone deacetylases and control gene transcription. • Histone ...deacetylase function is implicated in the regulation of aging. • Ketone bodies may link environmental cues such as diet to the regulation of aging.
For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through ...the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.
Abstract The ketone body β-hydroxybutyrate (βOHB) is a convenient carrier of energy from adipocytes to peripheral tissues during fasting or exercise. However, βOHB is more than just a metabolite, ...having important cellular signaling roles as well. βOHB is an endogenous inhibitor of histone deacetylases (HDACs) and a ligand for at least two cell surface receptors. In addition, the downstream products of βOHB metabolism including acetyl-CoA, succinyl-CoA, and NAD+ (nicotinamide adenine dinucleotide) themselves have signaling activities. These regulatory functions of βOHB serve to link the outside environment to cellular function and gene expression, and have important implications for the pathogenesis and treatment of metabolic diseases including type 2 diabetes.
"Zero-price markets," wherein firms set the price of their goods or services at $0, have exploded in quantity and variety. Creative content, software, search functions, social media platforms, mobile ...applications, travel booking, navigation and mapping systems, and myriad other goods and services are now widely distributed at zero prices. But despite the exponential increase in the volume of zero-price products being consumed, antitrust institutions and analysts have failed to provide an adequate response to markets without prices. Modern antitrust law is firmly grounded in neoclassical economics, which is in turn centered on price theory. Steeped in price theory, preeminent antitrust theorists have urged that without prices there can be no markets, and consequently no market power. This heavy methodological dependence on positive prices has led antitrust courts and enforcement agencies to overlook potentially massive welfare harms. Unfortunately, recent empirical research confirms that such harms have already occurred. These failures to conceive of zero-price markets as antitrust "markets" indicate how fundamentally zero prices challenge traditional theories and analytical frameworks. This Article establishes a novel taxonomy of customer-facing costs, distinguishing "market-signaling" from "non-market-signaling" costs. Crucially, it demonstrates that market-signaling costs are present in many zero-price contexts. The absence of positive prices thus does not foreclose antitrust scrutiny; "trade," for purposes of the Sherman and Clayton Acts, encompasses zero-price transactions. To continue ignoring welfare harms in these markets would be both unjust and inefficient. The Article concludes by identifying antitrust law's proper role within—and stance toward—zero-price markets.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A physiological approach to the analysis of hemodynamic data in pulmonary hypertension (PH) has the advantage of reducing the large number (well over 100) of potential causal illnesses into four ...simple mechanisms. A fifth condition is composed of mixtures of the four basic mechanisms. This approach was beautifully described by Paul Wood, the great cardiologist whose name is given to the units of pulmonary vascular resistance (PVR), Wood units. This approach uses well understood physiological contributions to pulmonary vascular pressure. It is powerful, the major uncertainty being in determination of the magnitude of each mechanism in patients that have mixed PH of several causes. It also makes sense of the occasionally awkward clustering of conditions in the clinical classification of the World Symposium, which omits pulmonary vasoconstriction, hyperkinetic states, and the highly prevalent condition of “mixed” PH. This method of analysis is described and demonstrated, much as Wood did in his writings. The method is useful in the office, the ICU, and in consultation. A basic message from this approach is that correct assessment requires measurement of each of the three major inputs, pulmonary arterial pressure (Ppa), pulmonary artery wedge pressure (Pwedge) and cardiac output (CO). Some cases also need left ventricular end diastolic pressure (LVEDP). Other data contributing to analysis will be discussed in each condition. A key to avoiding mistakes is to always remember that PH is simply an elevation in pressure and is not inherently diagnostic of cause.
Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in ...malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie ...metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = −0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this issue of the
Journal
, Humbert et al.
1
report on a new approach to the treatment of pulmonary arterial hypertension, particularly the idiopathic and heritable forms of the disease. The ...treatment, which is given subcutaneously every 3 weeks, is a fusion protein that impairs activation of one limb of the proproliferative transforming growth factor β (TGF-β) pathways. Why would inactivation of a TGF-β pathway be an effective approach? The answer is in the genes. Approximately 70 to 80% of cases of heritable pulmonary arterial hypertension and roughly 20 to 30% of cases of idiopathic pulmonary arterial hypertension are consequences . . .
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