Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence

Neuroinflammatory signaling pathways in the central nervous system are of current interest as potential pharmacotherapy targets for alcohol dependence. In this study, we examined the ability of ibudilast, a non-selective phosphodiesterase inhibitor, to reduce alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol-dependent mice at doses which had no effect in non-dependent mice. These findings support the viability of ibudilast as a possible treatment for alcohol dependence

Characterization of organic-rich mineral debris revealed by rapid glacier retreat, Indren Glacier, European Alps

In the summer of 2003 and 2004, characterized by a rapid glacier retreat, a stony surface covered by well-structured organic-rich mineral debris was observed very close to the Indren glacier terminus (Monte Rosa Massif, NW Italy, 3100 m ASL), on an area covered by the glacier tongue till the year before. The origin and type of this organic-rich material were investigated, in order to detect their characteristics, potential sources and fate within the foreland system. The deposits were dated using Carbon-14 and analyzed for the chemical characteristics of the organic component, the elemental composition of the mineral fraction and presence of microbial markers. The material, granular and dark in color, had a total organic carbon (TOC) content ranging between 17.4 ± 0.39 and 28.1 ± 0.63 g kg$^{−1}$ dry weight (dw), significantly higher than the surrounding glacial till (~ 1.4 g kg$^{−1}$ dw), although only 0.33% of it was in water soluble form. Microbial carbon (C) and nitrogen (N) accounted for 10.6% and 3.13% of TOC and total N, respectively. Dissolved nitrogen (N), mainly present as ammonium, represented 2.40% of the total N. The low aromatic component and large presence of nitrogen (N)-derived compounds suggested that most of the organic carbon (OC) in these organic-rich mineral deposits was derived from microbial cells, although the high average radiocarbon age of about 2900 years may also point to the contribution of aeolian depositions of anthropogenic or natural origin. Elemental composition and the crustal enrichment factor of trace elements in the mineral fraction of the aggregates corroborated the hypothesis that most part of the accumulated material derived from ice meltwater. Some indicators of the colonization of these deposits by microbial communities were also reported, from the abundance of DNA and phylogenetic markers, to the presence of bacterial taxa commonly able to thrive in similar habitats. All these elements suggested that such kind of deposits may have a potential role as energy and nutrient sources in recently deglaciated areas, highlighting the necessity to better understand the processes underlying their formation and their evolution

Representation of financial markets in macro-economic transition models-a review and suggestions for extensions

As the energy transition accelerates and renewable energy technologies become cost-competitive with fossil fuels in many countries, the availability of finance could become a bottleneck. Integrated assessment models (IAMs) and other macro-economic transition (MET) models typically do not feature detailed financial markets and do not sufficiently consider financing barriers and opportunities for the transition to carbon neutrality. While progress has been made in the representation of financial markets in macro-models since the financial crisis of 2008 the focus has been on financial (in)stability of the financial sector, not its ability to finance investment projects in the energy transition. Hence, a crucial gap remains, preventing macro model-based analysis of financing barriers and policy interventions that may accelerate the energy transition. In this article we review how state-of-the-art macro-economic models consider the financial sector. From this review we identify what elements are still missing to adequately model the financial dynamics and challenges for the energy transition specifically. Based on a discussion of relevant parts of the finance literature, we then propose four steps to improve the representation of finance in global IAMs and MET models more generally

Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies

In May 2014, Dr. Francis Collins, the director of US National Institutes of Health, and Dr. Janine Clayton, the director of the US National Institutes of Health Office of Research on Women’s Health (ORWH) published a commentary in the journal Nature announcing new policies to ensure that preclinical research funded by the NIH consider both males and females. While these policies are still developing, they have already generated great interest by the scientific community and triggered both criticism and applause. This review provides a description and interpretation of the NIH guidelines and it traces the history that led to their implementation. As expected, this NIH initiative generated some anxiety in the scientific community. The use of female animals in the investigation of basic mechanisms is perceived to increase variability in the results, and the use of both sexes has been claimed to slow the pace of scientific discoveries and to increase the cost at a time characterized by declining research support

Differential stability of 2′F-ANA•RNA and ANA•RNA hybrid duplexes: roles of structure, pseudohydrogen bonding, hydration, ion uptake and flexibility

Hybrids of RNA with arabinonucleic acids 2′F-ANA and ANA have very similar structures but strikingly different thermal stabilities. We now present a thorough study combining NMR and other biophysical methods together with state-of-the-art theoretical calculations on a fully modified 10-mer hybrid duplex. Comparison between the solution structure of 2′F-ANA•RNA and ANA•RNA hybrids indicates that the increased binding affinity of 2′F-ANA is related to several subtle differences, most importantly a favorable pseudohydrogen bond (2′F–purine H8) which contrasts with unfavorable 2′-OH–nucleobase steric interactions in the case of ANA. While both 2′F-ANA and ANA strands maintained conformations in the southern/eastern sugar pucker range, the 2′F-ANA strand’s structure was more compatible with the A-like structure of a hybrid duplex. No dramatic differences are found in terms of relative hydration for the two hybrids, but the ANA•RNA duplex showed lower uptake of counterions than its 2′F-ANA•RNA counterpart. Finally, while the two hybrid duplexes are of similar rigidities, 2′F-ANA single strands may be more suitably preorganized for duplex formation. Thus the dramatically increased stability of 2′F-ANA•RNA and ANA•RNA duplexes is caused by differences in at least four areas, of which structure and pseudohydrogen bonding are the most important

Elucidating the Ticking of an In Vitro Circadian Clockwork

A biochemical oscillator can be reconstituted in vitro with three purified proteins, that displays the salient properties of circadian (daily) rhythms, including self-sustained 24-h periodicity that is temperature compensated. We analyze the biochemical basis of this oscillator by quantifying the time-dependent interactions of the three proteins (KaiA, KaiB, and KaiC) by electron microscopy and native gel electrophoresis to elucidate the timing of the formation of complexes among the Kai proteins. The data are used to derive a dynamic model for the in vitro oscillator that accurately reproduces the rhythms of KaiABC complexes and of KaiC phosphorylation, and is consistent with biophysical observations of individual Kai protein interactions. We use fluorescence resonance energy transfer (FRET) to confirm that monomer exchange among KaiC hexamers occurs. The model demonstrates that the function of this monomer exchange may be to maintain synchrony among the KaiC hexamers in the reaction, thereby sustaining a high-amplitude oscillation. Finally, we apply the first perturbation analyses of an in vitro oscillator by using temperature pulses to reset the phase of the KaiABC oscillator, thereby testing the resetting characteristics of this unique circadian oscillator. This study analyzes a circadian clockwork to an unprecedented level of molecular detail

An intracellular pH gradient in the anammox bacterium Kuenenia stuttgartiensis as evaluated by 31P NMR

The cytoplasm of anaerobic ammonium oxidizing (anammox) bacteria consists of three compartments separated by membranes. It has been suggested that a proton motive force may be generated over the membrane of the innermost compartment, the “anammoxosome”. 31P nuclear magnetic resonance (NMR) spectroscopy was employed to investigate intracellular pH differences in the anammox bacterium Kuenenia stuttgartiensis. With in vivo NMR, spectra were recorded of active, highly concentrated suspensions of K. stuttgartiensis in a wide-bore NMR tube. At different external pH values, two stable and distinct phosphate peaks were apparent in the recorded spectra. These peaks were equivalent with pH values of 7.3 and 6.3 and suggested the presence of a proton motive force over an intracytoplasmic membrane in K. stuttgartiensis. This study provides for the second time—after discovery of acidocalcisome-like compartments in Agrobacterium tumefaciens—evidence for an intracytoplasmic pH gradient in a chemotrophic prokaryotic cell

Syntaxin 5 Is Required for Copper Homeostasis in Drosophila and Mammals

Copper is essential for aerobic life, but many aspects of its cellular uptake and distribution remain to be fully elucidated. A genome-wide screen for copper homeostasis genes in Drosophila melanogaster identified the SNARE gene Syntaxin 5 (Syx5) as playing an important role in copper regulation; flies heterozygous for a null mutation in Syx5 display increased tolerance to high dietary copper. The phenotype is shown here to be due to a decrease in copper accumulation, a mechanism also observed in both Drosophila and human cell lines. Studies in adult Drosophila tissue suggest that very low levels of Syx5 result in neuronal defects and lethality, and increased levels also generate neuronal defects. In contrast, mild suppression generates a phenotype typical of copper-deficiency in viable, fertile flies and is exacerbated by co-suppression of the copper uptake gene Ctr1A. Reduced copper uptake appears to be due to reduced levels at the plasma membrane of the copper uptake transporter, Ctr1. Thus Syx5 plays an essential role in copper homeostasis and is a candidate gene for copper-related disease in humans