Shale gas development impacts on surface water quality in Pennsylvania

Concern has been raised in the scientific literature about the environmental implications of extracting natural gas from deep shale formations, and published studies suggest that shale gas development may affect local groundwater quality. The potential for surface water quality degradation has been discussed in prior work, although no empirical analysis of this issue has been published. The potential for large-scale surface water quality degradation has affected regulatory approaches to shale gas development in some US states, despite the dearth of evidence. This paper conducts a large-scale examination of the extent to which shale gas development activities affect surface water quality. Focusing on the Marcellus Shale in Pennsylvania, we estimate the effect of shale gas wells and the release of treated shale gas waste by permitted treatment facilities on observed downstream concentrations of chloride (Cl⁻) and total suspended solids (TSS), controlling for other factors. Results suggest that (i) the treatment of shale gas waste by treatment plants in a watershed raises downstream Cl⁻ concentrations but not TSS concentrations, and (ii) the presence of shale gas wells in a watershed raises downstream TSS concentrations but not Cl⁻ concentrations. These results can inform future voluntary measures taken by shale gas operators and policy approaches taken by regulators to protect surface water quality as the scale of this economically important activity increases.     

Adipokines and proinflammatory cytokines,the key mediators in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The “two-hit“ hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.     

New Drugs on the Block—Emerging Treatments for Nonalcoholic Steatohepatitis

Patients with nonalcoholic steatohepatitis (NASH) are at higher risk of progression to advanced stages of fibrosis, cirrhosis, hepatocellular carcinoma and othe...     

Brain network analysis reveals affected connectome structure in bipolar I disorder

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections—i.e., the connectome—suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected “rich club” organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (?4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (?13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., “rich club” connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central “rich club” system appears not to be particularly affected. Hum Brain Mapp 37:122–134, 2016. © 2015 Wiley Periodicals, Inc.     

Acute effects of a low‐dose atropine/scopolamine mixture as a food contaminant in human volunteers

To verify the assumptions in our previous risk assessment of an atropine/scopolamine mixture in buckwheat flour, we performed a randomized, double‐blind, placebo‐controlled cross‐over study in 20 healthy, adult volunteers. The volunteers ingested a traditional Slovenian buckwheat meal, made of boiled buckwheat flour to which alkaloids were added. In addition to the placebo they ingested 0.12/0.10, 0.37/0.29, 1.22/0.95, 3.58/2.81 and 12.10/9.50 µg kg^–1 body mass (BM) of the atropine/scopolamine mixture. The changes in body temperature, heart rate, salivary and sweat secretion, pupil size, near‐point vision and subjective symptoms were recorded regularly for 4 h after the ingestion. Decreased salivary and sweat secretion, increased heart rate and pupil size and reduced near‐point vision accompanied by characteristic subjective symptoms were observed at 12.10/9.50 µg kg^–1 BM. At doses of 0.37/0.29 and 1.22/0.95 µg kg^–1 BM, a significant decrease in the heart rate was noted, which we consider to be a critical effect of a low‐dose exposure to the atropine/scopolamine mixture. Although this did not have any clinical relevance in our subjects, it may have serious implications if it occurred in people with pre‐existent cardiac conditions or those on medications that may cause bradycardia. No significant changes in the observed end points were noted at 0.12/0.10 µg kg^–1 BM. We estimate that the NOAEL (No Observed Adverse Effect Level) for the atropine/scopolamine mixture lies between the lower two administered doses. Applying the uncertainty factor of 10, we propose a new provisional Acute Reference Doses (ARfDs) of the mixture, i.e. 0.01 µg kg^–1 BM for each alkaloid, and a further refinement using higher‐tier approaches. Copyright © 2012 John Wiley & Sons, Ltd.     

New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation

Mur ligases (MurC–MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC₅₀ values up to 28 μM. Inhibitor 37, with an IC₅₀ of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.     

Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting D-Glu- and diphosphate-binding sites

Mur ligases are involved in cytoplasmic steps of bacterial peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have designed and synthesized a focused chemical library of compounds combining the glutamic acid moiety and the 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2-iminothiazolidin-4-one or imidazolidine-2,4-dione ring connected by a benzylidene group. These compounds were designed to target the d-Glu- and the diphosphate-binding pockets of the MurD active site and were evaluated for inhibition of MurD ligase from Escherichia coli. The most potent compounds (R)-9 and (S)-9 inhibited MurD with IC₅₀ values of 45 μM and 10 μM, respectively. The specific binding mode of (R)-9 in MurD active site was established by high-resolution NMR spectroscopy.