Palaeoclimatic distribution models predict Pleistocene refuges for the Neotropical harvestman Geraeocormobius sylvarum (Arachnida: Opiliones: Gonyleptidae)

This paper primarily aims to test a Pleistocene refuge-type scenario, as previously proposed for the gonyleptid Geraeocormobius sylvarum, a semi-deciduous forests dweller in subtropical Argentina, Brazil and Paraguay. Palaeodistributional models of this species were built using MaxEnt for two Last Glacial Maximum (LGM = 21,000 years ago) simulations – Community Climate System Model (CCSM) and Model for Interdisciplinary Research on Climate (MIROC) – and for 6000 years ago (?6k = HCO, the Holocene climatic optimum). Both LGM models retrieved a fragmented pattern. For CCSM, range was split into multiple, scattered fragments. MIROC resulted in very few patches, with a decided range reduction because of a strong humidity drop. Models for ?6k recovered a moderate range expansion. No past connection between the core area and the yungas was predicted. Analysis of variables importance showed that two precipitation predictors (bc18, precipitation warmest quarter; bc14, precipitation driest month) and two temperature predictors (bc7, temperature annual range; bc9, mean temperature driest quarter) scored as the most influencing overall. The Limiting Factor analysis recognized them as limiting too, in different parts of the species range. LGM palaeomodels of G. sylvarum are compatible with the refuge hypothesis invoked in previous molecular analyses, to explain the high genetic diversity found in the core area. Additionally, the results reinforced the hypothesis of the recent anthropogenic origin of the yungas disjunct populations.     

Forecasting key US macroeconomic variables with a factor‐augmented Qual VAR

In this paper, we first extract factors from a monthly dataset of 130 macroeconomic and financial variables. These extracted factors are then used to construct a factor‐augmented qualitative vector autoregressive (FA‐Qual VAR) model to forecast industrial production growth, inflation, the Federal funds rate, and the term spread based on a pseudo out‐of‐sample recursive forecasting exercise over an out‐of‐sample period of 1980:1 to 2014:12, using an in‐sample period of 1960:1 to 1979:12. Short‐, medium‐, and long‐run horizons of 1, 6, 12, and 24 months ahead are considered. The forecast from the FA‐Qual VAR is compared with that of a standard VAR model, a Qual VAR model, and a factor‐augmented VAR (FAVAR). In general, we observe that the FA‐Qual VAR tends to perform significantly better than the VAR, Qual VAR and FAVAR (barring some exceptions relative to the latter). In addition, we find that the Qual VARs are also well equipped in forecasting probability of recessions when compared to probit models.     

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC₃, MC₄, and MC₅ receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC₃ PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.     

Melatonin,mitochondria, and the metabolic syndrome

A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.     

Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.     

Diversity in enoyl-acyl carrier protein reductases

The enoyl-acyl carrier protein reductase (ENR) is the last enzyme in the fatty acid elongation cycle. Unlike most enzymes in this essential pathway, ENR displays an unusual diversity among organisms. The growing interest in ENRs is mainly due to the fact that a variety of both synthetic and natural antibacterial compounds are shown to specifically target their activity. The primary anti-tuberculosis drug, isoniazid, and the broadly used antibacterial compound, triclosan, both target this enzyme. In this review, we discuss the diversity of ENRs, and their inhibitors in the light of current research progress. Received 3 November 2008; received after revision 5 December 2008; accepted 8 December 2008     

Digoxin and ouabain increase the synthesis of cholesterol in human liver cells

Digoxin and ouabain are steroid drugs that inhibit the Na⁺/K⁺-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells. Received 10 January 2009; received after revision 11 February 2009; accepted 6 March 2009     

Vaults and the major vault protein: Novel roles in signal pathway regulation and immunity

The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses. Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular signal transduction and immune defence. Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008     

Direct inhibition of phospholipid scrambling activity in erythrocytes by potassium ions

The exposure of phosphatidylserine (PS) at the cell surface plays a critical role in blood coagulation and serves as a macrophage recognition moiety for the engulfment of apoptotic cells. Previous observations have shown that a high extracellular [K⁺] and selective K⁺ channel blockers inhibit PS exposure in platelets and erythrocytes. Here we show that the rate of PS exposure in erythrocytes decreases by ~50% when the intracellular [K⁺] increases from 0 to physiological concentrations. Using resealed erythrocyte membranes, we further show that lipid scrambling is inducible by raising the intracellular [Ca²⁺] and that K⁺ ions have a direct inhibitory effect on this process. Lipid scrambling in resealed ghosts occurs in the absence of cell shrinkage and microvesicle formation, processes that are generally attributed to Ca²⁺-induced lipid scrambling in intact erythrocytes. Thus, opening of Ca²⁺-sensitive K⁺ channels causes loss of intracellular K⁺ that results in reduced intrinsic inhibitory effect of these ions on scramblase activity. Received 11 September 2008; received after revision 17 October 2008; accepted 27 October 2008     

Forecasting VaR models under Different Volatility Processes and Distributions of Return Innovations

This paper provides clear‐cut evidence that the out‐of‐sample VaR (value‐at‐risk) forecasting performance of alternative parametric volatility models, like EGARCH (exponential general autoregressive conditional heteroskedasticity) or GARCH, and Markov regime‐switching models, can be considerably improved if they are combined with skewed distributions of asset return innovations. The performance of these models is found to be similar to that of the EVT (extreme value theory) approach. The performance of the latter approach can also be improved if asset return innovations are assumed to be skewed distributed. The performance of the Markov regime‐switching model is considerably improved if this model allows for EGARCH effects, for all different volatility regimes considered. Copyright © 2014 John Wiley & Sons, Ltd.