George J. Mitchell: Maine\u27s Environmental Senator

The State of Maine is blessed with a history of impressive and respected politicians. Among others, the list includes James Blaine, Margaret Chase Smith, and Edmund S. Muskie. The State now must add the name of George J. Mitchell to these ranks. A native son of Waterville, Maine, he attended Bowdoin College, Georgetown University Law Center, and eventually catapulted himself into one of the most powerful political positions in the United States government when he was elected as majority leader of the United States Senate. During his tenure as majority leader, he helped to redefine the position through his strong work ethic, sense of fairness, and orientation toward results in the Senate. This Comment summarizes some of those results through an environmental lens, focusing on Mitchell\u27s contributions to federal environmental legislation in the late 1980s. As Mitchell served in the Senate for fourteen years, six as the majority leader, he sponsored or cosponsored countless pieces of legislation. Environmental protection, however, always was a focus of his public service. In that vein, this Comment canvasses Senator Mitchell\u27s influence on the provisions of the Water Quality Act of 1987, the Clean Air Act Amendments of 1990, and the Oil Pollution Act of 1990, three major legislative accomplishments aimed at protecting the environment. This Comment analyzes those provisions of each Act for which Senator Mitchell fought most ardently and discusses the different tactics and strategies he employed to secure passage of each of these important bills. Finally, this Comment is a tribute to a Maine native who dedicated his life to public service. This Author recognizes that no one Senator could be solely responsible for any of these three pieces of environmental legislation. Nonetheless, only a few Senators held the key to passage of each of these acts. George J. Mitchell was one of the those Senators. Senator Mitchell\u27s contributions to environmental law can be understood only by viewing his Senate career in context. First, Mitchell served as a Federal District Court Judge for the District of Maine

Contributions of precision engineering to the revision of the SI

All measurements performed in science and industry are based on the International System of Units, the SI. It has been proposed to revise the SI following an approach which was implemented for the redefinition of the unit of length, the metre, namely to define the SI units by fixing the numerical values of so-called defining constants, including c, h, e, k and NA. We will discuss the reasoning behind the revision, which will likely be put into force in 2018. Precision engineering was crucial to achieve the required small measurement uncertainties and agreement of measurement results for the defining constants

QUEnch assiSTed (QUEST) MRI Used as a Novel Approach to Identify Reactive Oxygen Species as a Result of Experimental TBI

Introduction: Traumatic brain injury (TBI) generates reactive oxygen species (ROS), promoting inflammatory processes and impeding TBI recovery. Within the VA population, over 70% of military personnel that sustain a TBI receive opioid-based pain relief, however, opiates may actually exacerbate post-TBI complications through its documented recruitment of oxidative and inflammatory systems. Thus, we hypothesize that TBI and opioid treatment act synergistically to worsen post-TBI oxidative stress. Methods: Mice were exposed to either TBI or sham injury and administered morphine or saline in the acute post-injury period. Afterwards, neuroimaging was conducted using a novel technique, QUEnch assiSTed (QUEST) MRI, which compares standard MRI signals across mice that acutely receive an antioxidant “quench” therapy and those receiving saline as control. Therefore, differential MRI signals between these groups are an index of ROS generation. Changes in hippocampus and cortex signals were measured, as these structures are most commonly affected by TBI. Methylene blue and α-lipoic acid were used as antioxidants in the quenching step as they halt mitochondrial ROS production and scavenge excess ROS, respectively. Results: No significant changes in ROS levels were detected as a result of TBI, opioid exposure or their combination using QUEST MRI in either the cortex or hippocampus. Conclusions and Future Directions: While QUEST imaging did not yield significant changes between experimental groups, future work will include ex-vivo biochemical ROS analyses from harvested tissues, which will provide higher resolution quantification of oxidative processes than that of QUEST MRI

Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens

12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used

Electric field distribution in porous piezoelectric materials during polarization

High piezoelectric coupling coefficients enable the harvesting of more energy or increase the sensitivity of sensors which work using the principle of piezoelectricity. These coefficients depend on the material properties, but the manufacturing process can have a significant impact on the resulting overall coefficients. During the manufacturing process, one of the main steps is the process of polarization where a poling electric field aligns the ferroelectric domains in a similar direction in order to create a transversely isotropic material able to generate electric fields or deformations. The degree of polarization depends on multiple factors and it can strongly influence the final piezoelectric coefficients. In this paper, a study on the electric field distribution on the sensitivity of the main piezoelectric and dielectric coefficients to the polarization process is performed, focusing on porous piezoelectric materials. Different inclusion geometries are considered, namely spherical, ellipsoidal and spheres with cracks. The electric field distribution at the micro scale within a representative volume element is modelled to determine the material polarization level using the finite element method. The results show that the electric field distribution is highly dependent on the inclusion geometries and cracks and it has a noticeable impact on the equivalent piezoelectric coefficients. These results are compared with experimental measurements from published literature. Good agreement is found between the ellipsoidal model and the experimental data

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment. Experimental Design: We investigated the expression of several druggable targets (phospho-S6(S240) ribosomal protein, PTEN, PDGFR-alpha, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6(S240), was tested in patient-derived xenograft (PDX) leiomyosarcoma models. Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6(S240) correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6(S240) expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6(S240) in response prediction to PI3K/mTOR inhibition. Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6(S240) expression is a potential predictive biomarker for response to treatment. (C)2017 AACR.Peer reviewe

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC

An investigation of the effects of lipid-lowering medications: genome-wide linkage analysis of lipids in the HyperGEN study

BACKGROUND: Use of anti-hyperlipidemic medications compromises genetic analysis because of altered lipid profiles. We propose an empirical method to adjust lipid levels for medication effects so that the adjusted lipid values substitute the unmedicated lipid values in the genetic analysis. RESULTS: Published clinical trials were reviewed for HMG-CoA reductase inhibitors and fibric acid derivatives as mono-drug therapy. HMG-CoA reductase inhibitors showed similar effects in African Americans (AA) and non-African Americans (non-AA) for lowering total cholesterol (TC, -50.7 mg/dl), LDL cholesterol (LDL-C, -48.1 mg/dl), and triglycerides (TG, -19.7 mg/dl). Their effect on increasing HDL cholesterol (HDL-C) in AA (+0.4 mg/dl) was lower than in Non-AA (+2.3 mg/dl). The effects of fibric acid derivatives were estimated as -46.1 mg/dl for TC, -40.1 mg/dl for LDL-C, and +5.9 mg/dl for HDL-C in non-AA. The corresponding effects in AA were less extreme (-20.1 mg/dl, -11.4 mg/dl, and +3.1 mg/dl). Similar effect for TG (59.0 mg/dl) was shown in AA and non-AA. The above estimated effects were applied to a multipoint variance components linkage analysis on the lipid levels in 2,403 Whites and 2,214 AA in the HyperGEN study. The familial effects did vary depending on whether the lipids were adjusted for medication use. For example, the heritabilities increased after medication adjustment for TC and LDL-C, but did not change significantly for HDL-C and TG. CONCLUSION: Ethnicity-specific medication adjustments using our empirical method can be employed in epidemiological and genetic analysis of lipids.National Heart, Lung, and Blood Institute (HL554471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515

Genetic Associations and Architecture of Asthma-COPD Overlap

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 x 10(-6)) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 x 10(-8)) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.Peer reviewe