Structure-based design and in-parallel synthesis of inhibitors of AmpC beta-lactamase

Background: Group I p-lactamases are a major cause of antibiotic resistance to beta -lactams such as penicillins and cephalosporins. These enzymes are only modestly affected by classic beta -lactam-based inhibitors, such as clavulanic acid. Conversely, small arylboronic acids inhibit these enzymes at sub-micromolar concentrations. Structural studies suggest these inhibitors bind to a well-defined cleft in the group I beta -lactamase AmpC; this cleft binds the ubiquitous R1 side chain of beta -lactams. Intriguingly, much of this cleft is left unoccupied by the small arylboronic acids. Results: To investigate if larger boronic acids might take advantage of this cleft, structure-guided in-parallel synthesis was used to explore new inhibitors of AmpC. Twenty-eight derivatives of the lead compound, 3-aminophenylboronic acid, led to an inhibitor with 80-fold better binding (2; K-i 83 nM). Molecular docking suggested orientations for this compound in the R1 cleft. Based on the docking results, 12 derivatives of 2 were synthesized, leading to inhibitors with iii values of 60 nM and with improved solubility. Several of these inhibitors reversed the resistance of nosocomial Gram-positive bacteria, though they showed little activity against Gram-negative bacteria. The X-ray crystal structure of compound 2 in complex with AmpC was subsequently determined to 2.1 Angstrom resolution. The placement of the proximal two-thirds of the inhibitor in the experimental structure corresponds with the docked structure, but a bond rotation leads to a distinctly different placement of the distal part of the inhibitor. In the experimental structure, the inhibitor interacts with conserved residues in the R1 cleft whose role in recognition has not been previously explored. Conclusions: Combining structure-based design with in-parallel synthesis allowed for the rapid exploration of inhibitor functionality in the R1 cleft of AmpC. The resulting inhibitors differ considerably from beta -lactams but nevertheless inhibit the enzyme well. The crystal structure of 2 (K-i 83 nM) in complex with AmpC may guide exploration of a highly conserved, largely unexplored cleft, providing a template for further design against AmpC beta -lactamase

Carbon dioxide diffuse emission and thermal energy release from hydrothermal systems at Copahue-Caviahue Volcanic Complex (Argentina).

The north-western sector of Caviahue caldera (Argentina), close to the active volcanic system of Copahue, is characterized by the presence of several hydrothermal sites that host numerous fumarolic emissions, anomalous soil diffuse degassing of CO2 and hot soils. In March 2014, measurements of soil CO2 fluxes in 5 of these sites (namely, Las M\ue1quinas, Las Maquinitas I, Las Maquinitas II, Anfiteatro, and Termas de Copahue) allowed an estimation that ~165t of deeply derived CO2 is daily released. The gas source is likely related to a relatively shallow geothermal reservoir containing a single vapor phase as also suggested by both the geochemical data from the 3 deep wells drilled in the 1980s and gas geoindicators applied to the fumarolic discharges. Gas equilibria within the H-C-O gas system indicate the presence of a large, probably unique, single phase vapor zone at 200-210\ub0C feeding the hydrothermal manifestations of Las M\ue1quinas, Las Maquinitas I and II and Termas de Copahue. A natural thermal release of 107MW was computed by using CO2 as a tracer of the original vapor phase. The magmatic signature of the incondensable fumarolic gases, the wide expanse of the hydrothermal areas and the remarkable high amount of gas and heat released by fluid expulsion seem to be compatible with an active magmatic intrusion beneath this portion of the Caviahue caldera

Probing the formation of intermediate- to high-mass stars in protoclusters: A detailed millimeter study of the NGC 2264 clumps

We present the results of dust continuum and molecular line observations of two massive cluster-forming clumps, NGC 2264-C and NGC 2264-D, including extensive mapping performed with the MAMBO bolometer array and the HERA heterodyne array on the IRAM 30m telescope. Both NGC 2264 clumps are located in the Mon OB1 giant molecular cloud complex, adjacent to one another. Twelve and fifteen compact millimeter continuum sources (i.e. MMSs) are identified in clumps C and D, respectively. Evidence for widespread infall motions is found in, e.g., HCO+(3-2) or CS(3-2) in both NGC 2264-C and NGC 2264-D. A sharp velocity discontinuity ~ 2 km/s in amplitude is observed in N_2H+(1-0) and H^{13}CO+(1-0) in the central, innermost part of NGC 2264-C, which we interpret as the signature of a strong dynamical interaction between two MMSs and their possible merging with the central MMS C-MM3. Radiative transfer modelling supports the idea that NGC 2264-C is a highly unstable prolate clump in the process of collapsing along its long axis on a near free-fall dynamical timescale ~ 1.7x10^5 yr. Our model fit of this large-scale collapse suggests a maximum mass inflow rate ~ 3x10^{-3} Msun/yr toward the central protostellar object C-MM3. Such infall rates are sufficiently high to overcome radiation pressure and allow the formation of ~ 20 Msun stars by accretion in ~ 1.7x10^5 yr, i.e., a time similar to the global dynamical timescale of the central part of NGC 2264-C. We conclude that we are likely witnessing the formation of a high-mass (> 10 Msun) protostar in the central part of NGC 2264-C. Our results suggest a picture of massive star formation intermediate between the scenario of stellar mergers of Bonnell et al. (1998) and the massive turbulent core model of McKee & Tan (2003).Comment: 22 pages, 16 figures, accepted for publication in A&A. Most of the Figures have been de-resolved in order to reduce file size

Herschel observations of the hydroxyl radical (OH) in young stellar objects

Water in Star-forming regions with Herschel (WISH) is a Herschel Key Program investigating the water chemistry in young stellar objects (YSOs) during protostellar evolution. Hydroxyl (OH) is one of the reactants in the chemical network most closely linked to the formation and destruction of H2O. High-temperature chemistry connects OH and H2O through the OH + H2 H2O + H reactions. Formation of H2O from OH is efficient in the high-temperature regime found in shocks and the innermost part of protostellar envelopes. Moreover, in the presence of UV photons, OH can be produced from the photo-dissociation of H2O. High-resolution spectroscopy of the OH 163.12 micron triplet towards HH 46 and NGC 1333 IRAS 2A was carried out with the Heterodyne Instrument for the Far Infrared (HIFI) on board Herschel. The low- and intermediate-mass YSOs HH 46, TMR 1, IRAS 15398-3359, DK Cha, NGC 7129 FIRS 2, and NGC 1333 IRAS 2A were observed with the Photodetector Array Camera and Spectrometer (PACS) in four transitions of OH and two [OI] lines. The OH transitions at 79, 84, 119, and 163 micron and [OI] emission at 63 and 145 micron were detected with PACS towards the class I low-mass YSOs as well as the intermediate-mass and class I Herbig Ae sources. No OH emission was detected from the class 0 YSO NGC 1333 IRAS 2A, though the 119 micron was detected in absorption. With HIFI, the 163.12 micron was not detected from HH 46 and only tentatively detected from NGC 1333 IRAS 2A. The combination of the PACS and HIFI results for HH 46 constrains the line width (FWHM > 11 km/s) and indicates that the OH emission likely originates from shocked gas. This scenario is supported by trends of the OH flux increasing with the [OI] flux and the bolometric luminosity. Similar OH line ratios for most sources suggest that OH has comparable excitation temperatures despite the different physical properties of the sources.Comment: Accepted for publication in Astronomy and Astrophysics (Herschel special issue

Age is no barrier: predictors of academic success in older learners

Although predictors of academic success have been identified in young adults, such predictors are unlikely to translate directly to an older student population, where such information is scarce. The current study aimed to examine cognitive, psychosocial, lifetime, and genetic predictors of university-level academic performance in older adults (50–79 years old). Participants were mostly female (71%) and had a greater than high school education level (M = 14.06 years, SD = 2.76), on average. Two multiple linear regression analyses were conducted. The first examined all potential predictors of grade point average (GPA) in the subset of participants who had volunteered samples for genetic analysis (N = 181). Significant predictors of GPA were then re-examined in a second multiple linear regression using the full sample (N = 329). Our data show that the cognitive domains of episodic memory and language processing, in conjunction with midlife engagement in cognitively stimulating activities, have a role in predicting academic performance as measured by GPA in the first year of study. In contrast, it was determined that age, IQ, gender, working memory, psychosocial factors, and common brain gene polymorphisms linked to brain function, plasticity and degeneration (APOE, BDNF, COMT, KIBRA, SERT) did not influence academic performance. These findings demonstrate that ageing does not impede academic achievement, and that discrete cognitive skills as well as lifetime engagement in cognitively stimulating activities can promote academic success in older adults

Relationship between cardiac deformation parameters measured by cardiovascular magnetic resonance and aerobic fitness in endurance athletes

Background: Athletic training leads to remodelling of both left and right ventricles with increased myocardial mass and cavity dilatation. Whether changes in cardiac strain parameters occur in response to training is less well established. In this study we investigated the relationship in trained athletes between cardiovascular magnetic resonance (CMR) derived strain parameters of cardiac function and fitness. Methods: 35 endurance athletes and 35 age and sex matched controls underwent CMR at 3.0T including cine imaging in multiple planes and tissue tagging by spatial modulation of magnetization (SPAMM). CMR data were analysed quantitatively reporting circumferential strain and torsion from tagged images and left and right ventricular longitudinal strain from feature tracking of cine images. Athletes performed a maximal ramp-incremental exercise test to determine the lactate threshold (LT) and maximal oxygen uptake (V̇O2max). Results: LV circumferential strain at all levels, LV twist and torsion, LV late diastolic longitudinal strain rate, RV peak longitudinal strain and RV early and late diastolic longitudinal strain rate were all lower in athletes than controls. On multivariable linear regression only LV torsion (beta=-0.37, P=0.03) had a significant association with LT. Only RV longitudinal late diastolic strain rate (beta=-0.35, P=0.03) had a significant association with V̇O2max. Conclusions: This cohort of endurance athletes had lower LV circumferential strain, LV torsion and biventricular diastolic strain rates than controls. Increased LT, which is a major determinant of performance in endurance athletes, was associated with decreased LV torsion. Further work is needed to understand the mechanisms by which this occurs

Functional Connectivity in Tactile Object Discrimination—A Principal Component Analysis of an Event Related fMRI-Study

BACKGROUND: Tactile object discrimination is an essential human skill that relies on functional connectivity between the neural substrates of motor, somatosensory and supramodal areas. From a theoretical point of view, such distributed networks elude categorical analysis because subtraction methods are univariate. Thus, the aim of this study was to identify the neural networks involved in somatosensory object discrimination using a voxel-based principal component analysis (PCA) of event-related functional magnetic resonance images. METHODOLOGY/PRINCIPAL FINDINGS: Seven healthy, right-handed subjects aged between 22 and 44 years were required to discriminate with their dominant hand the length differences between otherwise identical parallelepipeds in a two-alternative forced-choice paradigm. Of the 34 principal components retained for analysis according to the 'bootstrapped' Kaiser-Guttman criterion, t-tests applied to the subject-condition expression coefficients showed significant mean differences between the object presentation and inter-stimulus phases in PC 1, 3, 26 and 32. Specifically, PC 1 reflected object exploration or manipulation, PC 3 somatosensory and short-term memory processes. PC 26 evinced the perception that certain parallelepipeds could not be distinguished, while PC 32 emerged in those choices when they could be. Among the cerebral regions evident in the PCs are the left posterior parietal lobe and premotor cortex in PC 1, the left superior parietal lobule (SPL) and the right cuneus in PC 3, the medial frontal and orbitofrontal cortex bilaterally in PC 26, and the right intraparietal sulcus, anterior SPL and dorsolateral prefrontal cortex in PC 32. CONCLUSIONS/SIGNIFICANCE: The analysis provides evidence for the concerted action of large-scale cortico-subcortical networks mediating tactile object discrimination. Parallel to activity in nodes processing object-related impulses we found activity in key cerebral regions responsible for subjective assessment and validation

Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health

Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

Background: Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings: We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions: Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages