Phage display-derived inhibitor of the essential cell wall biosynthesis enzyme MurF

Background To develop antibacterial agents having novel modes of action against bacterial cell wall biosynthesis, we targeted the essential MurF enzyme of the antibiotic resistant pathogen Pseudomonas aeruginosa. MurF catalyzes the formation of a peptide bond between D-Alanyl-D-Alanine (D-Ala-D-Ala) and the cell wall precursor uridine 5'-diphosphoryl N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid (UDP-MurNAc-Ala-Glu-meso-A2pm) with the concomitant hydrolysis of ATP to ADP and inorganic phosphate, yielding UDP-N-acetylmuramyl-pentapeptide. As MurF acts on a dipeptide, we exploited a phage display approach to identify peptide ligands having high binding affinities for the enzyme. Results Screening of a phage display 12-mer library using purified P. aeruginosa MurF yielded to the identification of the MurFp1 peptide. The MurF substrate UDP-MurNAc-Ala-Glumeso-A2pm was synthesized and used to develop a sensitive spectrophotometric assay to quantify MurF kinetics and inhibition. MurFp1 acted as a weak, time-dependent inhibitor of MurF activity but was a potent inhibitor when MurF was pre-incubated with UDP-MurNAc-Ala-Glu-meso-A2pm or ATP. In contrast, adding the substrate D-Ala-D-Ala during the pre-incubation nullified the inhibition. The IC50 value of MurFp1 was evaluated at 250 μM, and the Ki was established at 420 μM with respect to the mixed type of inhibition against D-Ala-D-Ala. Conclusion MurFp1 exerts its inhibitory action by interfering with the utilization of D-Ala-D-Ala by the MurF amide ligase enzyme. We propose that MurFp1 exploits UDP-MurNAc-Ala-Glu-meso-A2pm-induced structural changes for better interaction with the enzyme. We present the first peptide inhibitor of MurF, an enzyme that should be exploited as a target for antimicrobial drug development

Application of diffusion barriers to the refractory fibers of tungsten, columbium, carbon and aluminum oxide

A radio frequency powered ion-plating system was used to plate protective layers of refractory oxides and carbide onto high strength fiber substrates. Subsequent overplating of these combinations with nickel and titanium was made to determine the effectiveness of such barrier layers in preventing diffusion of the overcoat metal into the fibers with consequent loss of fiber strength. Four substrates, five coatings, and two metal matrix materials were employed for a total of forty material combinations. The substrates were tungsten, niobium, NASA-Hough carbon, and Tyco sapphire. The diffusion-barrier coatings were aluminum oxide, yttrium oxide, titanium carbide, tungsten carbide with 14% cobalt addition, and zirconium carbide. The metal matrix materials were IN 600 nickel and Ti 6/4 titanium. Adhesion of the coatings to all substrates was good except for the NASA-Hough carbon, where flaking off of the oxide coatings in particular was observed

Modeling and predicting the shape of the far-infrared to submillimeter emission in ultra-compact HII regions and cold clumps

Dust properties are very likely affected by the environment in which dust grains evolve. For instance, some analyses of cold clumps (7 K- 17 K) indicate that the aggregation process is favored in dense environments. However, studying warm (30 K-40 K) dust emission at long wavelength ($\lambda$$>$300 $\mu$m) has been limited because it is difficult to combine far infared-to-millimeter (FIR-to-mm) spectral coverage and high angular resolution for observations of warm dust grains. Using Herschel data from 70 to 500 $\mu$m, which are part of the Herschel infrared Galactic (Hi-GAL) survey combined with 1.1 mm data from the Bolocam Galactic Plane Survey (BGPS), we compared emission in two types of environments: ultra-compact HII (UCHII) regions, and cold molecular clumps (denoted as cold clumps). With this comparison we tested dust emission models in the FIR-to-mm domain that reproduce emission in the diffuse medium, in these two environments (UCHII regions and cold clumps). We also investigated their ability to predict the dust emission in our Galaxy. We determined the emission spectra in twelve UCHII regions and twelve cold clumps, and derived the dust temperature (T) using the recent two-level system (TLS) model with three sets of parameters and the so-called T-$\beta$ (temperature-dust emissvity index) phenomenological models, with $\beta$ set to 1.5, 2 and 2.5. We tested the applicability of the TLS model in warm regions for the first time. This analysis indicates distinct trends in the dust emission between cold and warm environments that are visible through changes in the dust emissivity index. However, with the use of standard parameters, the TLS model is able to reproduce the spectral behavior observed in cold and warm regions, from the change of the dust temperature alone, whereas a T-$\beta$ model requires $\beta$ to be known.Comment: Accepted for publication in A&A. 19 pages, 8 figures, 7 table

Detection and characterization of a 500 μm dust emissivity excess in the Galactic plane using Herschel/Hi-GAL observations

Context. Past and recent observations have revealed unexpected variations in the far-infrared – millimeter (FIR-mm) dust emissivity in the interstellar medium. In the Herschel spectral range, those are often referred to as a 500 μm emission excess. Several dust emission models have been developed to interpret astrophysical data in the FIR-mm domain. However, these are commonly unable to fully reconcile theoretical predictions with observations. In contrast, the recently revised two level system (TLS) model, based on the disordered internal structure of amorphous dust grains, seems to provide a promising way of interpreting existing data. Aims. The newly available Herschel infrared GALactic (Hi-GAL) data, which covers most of the inner Milky Way, offers a unique opportunity to investigate possible variations in the dust emission properties both with wavelength and environment. The goal of our analysis is to constrain the internal structure of the largest dust grains on Galactic scales, in the framework of the TLS model. Methods. By combining the IRIS (Improved Reprocessing of the IRAS Survey) 100 μm with the Hi-GAL 160, 250, 350, and 500 μm data, we model the dust emission spectra in each pixel of the Hi-GAL maps, using both the TLS model and, for comparison, a single modified black-body fit. The effect of temperature mixing along the line of sight is investigated to test the robustness of our results. Results. We find a slight decrease in the dust temperature with distance from the Galactic center, confirming previous results. We also report the detection of a significant 500 μm emissivity excess in the peripheral regions of the plane (35° < |l| < 70°) of about 13–15% of the emissivity, which can reach up to 20% in some HII regions. We present the spatial distributions of the best-fit values for the two main parameters of the TLS model, i.e. the charge correlation length, lc, used to characterize the disordered charge distribution (DCD) part of the model, and the amplitude A of the TLS processes with respect to the DCD effect. These distributions illustrate the variations in the dust properties with environment, in particular the plausible existence of an overall gradient with distance to the Galactic center. A comparison with previous findings in the solar neighborhood shows that the local value of the excess is less than expected from the Galactic gradient observed here

Correlates of genetic monogamy in socially monogamous mammals: insights from Azara's owl monkeys

Understanding the evolution of mating systems, a central topic in evolutionary biology for more than 50 years, requires examining the genetic consequences of mating and the relationships between social systems and mating systems. Among pair-living mammals, where genetic monogamy is extremely rare, the extent of extra-group paternity rates has been associated withmale participation in infant care, strength of the pair bond and length of the breeding season. This study evaluated the relationship between two of those factors and the genetic mating system of socially monogamous mammals, testing predictions that male care and strength of pair bond would be negatively correlated with rates of extra-pair paternity (EPP). Autosomal microsatellite analyses provide evidence for genetic monogamy in a pair-living primate with bi-parental care, the Azara’s owl monkey (Aotus azarae). A phylogenetically corrected generalized least square analysis was used to relate male care and strength of the pair bond to their genetic mating system (i.e. proportions of EPP) in 15 socially monogamous mammalian species. The intensity of male care was correlated with EPP rates in mammals, while strength of pair bond failed to reach statistical significance. Our analyses showthat, once social monogamy has evolved, paternal care, and potentially also close bonds, may facilitate the evolution of genetic monogamy.German Science Foundation (HU 1746/2-1); Wenner-Gren Foundation; L.S.B. Leakey Foundation;National Geographic Society; National Science Foundation (BCS-0621020, 1219368, and 1232349); the University of Pennsylvania Research Foundation; the Zoological Society of San Dieg

Measure of the path integral in lattice gauge theory

We show how to construct the measure of the path integral in lattice gauge theory. This measure contains a factor beyond the standard Haar measure. Such factor becomes relevant for the calculation of a single transition amplitude (in contrast to the calculation of ratios of amplitudes). Single amplitudes are required for computation of the partition function and the free energy. For U(1) lattice gauge theory, we present a numerical simulation of the transition amplitude comparing the path integral with the evolution in terms of the Hamiltonian, showing good agreement.Comment: 5 pages, 2 figure

Language control and parallel recovery of language in individuals with aphasia

Background: The causal basis of the different patterns of language recovery following stroke in bilingual speakers is not well understood. Our approach distinguishes the representation of language from the mechanisms involved in its control. Previous studies have suggested that difficulties in language control can explain selective aphasia in one language as well as pathological switching between languages. Here we test the hypothesis that difficulties in managing and resolving competition will also be observed in those who are equally impaired in both their languages even in the absence of pathological switching. Aims: To examine difficulties in language control in bilingual individuals with parallel recovery in aphasia and to compare their performance on different types of conflict task. Methods & procedures: Two right-handed, non-native English-speaking participants who showed parallel recovery of two languages after stroke and a group of non-native English-speaking, bilingual controls described a scene in English and in their first language and completed three explicit conflict tasks. Two of these were verbal conflict tasks: a lexical decision task in English, in which individuals distinguished English words from non-words, and a Stroop task, in English and in their first language. The third conflict task was a non-verbal flanker task. Outcomes & Results: Both participants with aphasia were impaired in the picture description task in English and in their first language but showed different patterns of impairment on the conflict tasks. For the participant with left subcortical damage, conflict was abnormally high during the verbal tasks (lexical decision and Stroop) but not during the non-verbal flanker task. In contrast, for the participant with extensive left parietal damage, conflict was less abnormal during the Stroop task than the flanker or lexical decision task. Conclusions: Our data reveal two distinct control impairments associated with parallel recovery. We stress the need to explore the precise nature of control problems and how control is implemented in order to develop fuller causal accounts of language recovery patterns in bilingual aphasia

Continuous process for selective metal extraction with an ionic liquid

This work describes for the first time a continuous process for selective metal extraction with an ionic liquid (IL) at room temperature. The hydrophobic fatty acid based IL tetraoctylphosphonium oleate ([P-8888][oleate]) was specifically chosen for its low viscosity and high selectivity towards transition metals. Applying [P-8888][oleate] for continuous metal ion extraction with 0.1 M sodium oxalate for regeneration resulted in a process with good and stable extraction efficiencies over time. The selectivity of the IL resulted in a process in which cobalt was selectively removed from two mixed salt solutions (Co/Na, Ca/Co/K) to obtain a pure cobalt stream after stripping the IL. The performed experiments showed that the contact time of the IL for extraction and stripping strongly influenced the achieved efficiencies. The stability of the IL was tested and it was shown that the fatty acid based IL was stable for the duration of the experiment. Liposome tests showed that the IL is very hydrophobic, which limits its leakage towards the water phase, but also results in a higher toxicity towards cell membranes. Economic analysis shows that the IL based process is not (yet) economical compared to ion-exchange resins, in case demineralised water is the only product. However, if the recovery of valuable metals is also taken into account and/or if brine disposal is an issue, then continuous IL metal extraction systems must be regarded as promising alternatives. (C) 2016 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.Peer reviewe

Screening for cardiovascular disease risk factors beginning in childhood

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Individual detection and intervention on CVD risk factors and behaviors throughout childhood and adolescence has been advocated as a strategy to reduce CVD risk in adulthood. The U.S. National Heart, Lung, and Blood Institute (NHLBI) has recently recommended universal screening of several risk factors in children and adolescents, at odds with several recommendations of the U.S. Services Task Force and of the U.K. National Screening committee. In the current review, we discuss the goals of screening for CVD risk factors (elevated blood pressure, abnormal blood lipids, diabetes) and behaviors (smoking) in children and appraise critically various screening recommendations. Our review suggests that there is no compelling evidence to recommend universal screening for elevated blood pressure, abnormal blood lipids, abnormal blood glucose, or smoking in children and adolescents. Targeted screening of these risk factors could be useful but specific screening strategies have to be evaluated. Research is needed to identify target populations, screening frequency, intervention, and follow-up. Meanwhile, efforts should rather focus on the primordial prevention of CVD risk factors and at maintaining a lifelong ideal cardiovascular health through environmental, policy, and educational approaches

Screening for cardiovascular disease risk factors beginning in childhood

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Individual detection and intervention on CVD risk factors and behaviors throughout childhood and adolescence has been advocated as a strategy to reduce CVD risk in adulthood. The U.S. National Heart, Lung, and Blood Institute (NHLBI) has recently recommended universal screening of several risk factors in children and adolescents, at odds with several recommendations of the U.S. Services Task Force and of the U.K. National Screening committee. In the current review, we discuss the goals of screening for CVD risk factors (elevated blood pressure, abnormal blood lipids, diabetes) and behaviors (smoking) in children and appraise critically various screening recommendations. Our review suggests that there is no compelling evidence to recommend universal screening for elevated blood pressure, abnormal blood lipids, abnormal blood glucose, or smoking in children and adolescents. Targeted screening of these risk factors could be useful but specific screening strategies have to be evaluated. Research is needed to identify target populations, screening frequency, intervention, and follow-up. Meanwhile, efforts should rather focus on the primordial prevention of CVD risk factors and at maintaining a lifelong ideal cardiovascular health through environmental, policy, and educational approaches