There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of ...known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant
S. aureus
(MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
There is a dire need for new compounds to combat antibiotic resistance: metal complexes might provide the solution. 906 metal complexes were evaluated against dangerous ESKAPE pathogens and found to have a higher hit-rate than organic molecules.
We use the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope (HST) to reduce the uncertainty in the local value of the Hubble constant from 3.3% to 2.4%. The bulk of this improvement comes ...from new near-infrared (NIR) observations of Cepheid variables in 11 host galaxies of recent type Ia supernovae (SNe Ia), more than doubling the sample of reliable SNe Ia having a Cepheid-calibrated distance to a total of 19; these in turn leverage the magnitude-redshift relation based on ~300 SNe Ia at z< 0.15. All 19 hosts as well as the megamaser system NGC 4258 have been observed with WFC3 in the optical and NIR, thus nullifying cross-instrument zeropoint errors in the relative distance estimates from Cepheids. Other noteworthy improvements include a 33% reduction in the systematic uncertainty in the maser distance to NGC 4258, a larger sample of Cepheids in the Large Magellanic Cloud (LMC), a more robust distance to the LMC based on late-type detached eclipsing binaries (DEBs), HST observations of Cepheids in M31, and new HST-based trigonometric parallaxes for Milky Way (MW) Cepheids. We consider four geometric distance calibrations of Cepheids: (i) megamasers in NGC 4258, (ii) 8 DEBs in the LMC, (iii) 15 MW Cepheids with parallaxes measured with HST/FGS, HST/WFC3 spatial scanning and/or Hipparcos, and (iv) 2 DEBs in M31. The Hubble constant from each is 72.25 + or - 2.51, 72.04 + or - 2.67, 76.18 + or - 2.37, and 74.50 + or - 3.27 km s super(-1) Mpc super(-1), respectively. Our best estimate of H sub(0)= 73.24 + or - 1.74 km s super(-1) Mpc super(-1) combines the anchors NGC 4258, MW, and LMC, yielding a 2.4% determination (all quoted uncertainties include fully propagated statistical and systematic components). This value is 3.4sigma higher than 66.93 + or - 0.62 km s super(-1) Mpc super(-1) predicted by LambdaCDM with 3 neutrino flavors having a mass of 0.06 eV and the new Planck data, but the discrepancy reduces to 2.1sigma relative to the prediction of 69.3 + or - 0.7 km s super(-1) Mpc super(-1) based on the comparably precise combination of WMAP+ACT+SPT+BAO observations, suggesting that systematic uncertainties in CMB radiation measurements may play a role in the tension. If we take the conflict between Planck high-redshift measurements and our local determination of H sub(0) at face value, one plausible explanation could involve an additional source of dark radiation in the early universe in the range of DeltaN sub(eff)approximate 0.4-1. We anticipate further significant improvements in H sub(0) from upcoming parallax measurements of long-period MW Cepheids.
ABSTRACT We report evidence for excess blue light from the Type Ia supernova (Sn Ia) SN 2012cg at 15 and 16 days before maximum B-band brightness. The emission is consistent with predictions for the ...impact of the supernova on a non-degenerate binary companion. This is the first evidence for emission from a companion to a normal SN Ia. Sixteen days before maximum light, the color of SN 2012cg is 0.2 mag bluer than for other normal SN Ia. At later times, this supernova has a typical SN Ia light curve, with extinction-corrected mag and . Our data set is extensive, with photometry in seven filters from five independent sources. Early spectra also show the effects of blue light, and high-velocity features are observed at early times. Near maximum, the spectra are normal with a silicon velocity vSi = −10,500 km s−1. Comparing the early data with models by Kasen favors a main-sequence companion of about six solar masses. It is possible that many other SN Ia have main-sequence companions that have eluded detection because the emission from the impact is fleeting and faint.
Different striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) ...of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.
► Identified key elements of fundamentally-important dichotomous organization of GPe ► First correlation of GPe neuron firing in vivo with neurochemistry and structure ► Discovered arkypallidal neurons that massively and specifically innervate striatum ► Defined new factors for widespread and excessive beta oscillations in Parkinson's disease
By rigorously defining the neurochemical and structural properties of individual neurons recorded in vivo, Mallet et al. reveal the foundations of a striking functional dichotomy in the external globus pallidus, including a novel cell type that exclusively targets striatum.
The very nearby Type Ia supernova 2014J in M82 offers a rare opportunity to study the physics of thermonuclear supernovae at extremely late phases ( 800 days). Using the Hubble Space Telescope, we ...obtained 6 epochs of high-precision photometry for SN 2014J from 277 days to 1181 days past the B-band maximum light. The reprocessing of electrons and X-rays emitted by the radioactive decay chain is needed to explain the significant flattening of both the F606W-band and the pseudo-bolometric light curves. The flattening confirms previous predictions that the late-time evolution of type Ia supernova luminosities requires additional energy input from the decay of 57Co. By assuming the F606W-band luminosity scales with the bolometric luminosity at ∼500 days after the B-band maximum light, a mass ratio is required. This mass ratio is roughly ∼3 times the solar ratio and favors a progenitor white dwarf with a mass near the Chandrasekhar limit. A similar fit using the constructed pseudo-bolometric luminosity gives a mass ratio . Astrometric tests based on the multi-epoch HST ACS/WFC images reveal no significant circumstellar light echoes in between 0.3 and 100 pc from the supernova.
Natural disasters frequently affected medieval populations. This book explores what happened when meteorological hazards struck how medieval communities reacted and what steps they took to protect ...themselves against future risks. Through archaeological and historical sources of evidence, the diverse impacts unleashed by disasters on medieval society are traced to provide a well-rounded understanding of catastrophes in the medieval past.
Context:
In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or ...occult thyroid failure.
Methods:
We measured serum TSH, free T4, thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469.
Results:
At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter 95% confidence interval (CI) 0.27, 0.38, P < 0.001, whereas mean free T4 concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype.
Conclusions:
Aging is associated with increased serum TSH concentrations, with no change in free T4 concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.
ABSTRACT We present multiple-epoch measurements of the size and surface brightness of the light echoes from supernova (SN) 2014J in the nearby starburst galaxy M82. Hubble Space Telescope (HST) ...ACS/WFC images were taken ∼277 and ∼416 days after B-band maximum in the filters F475W, F606W, and F775W. Observations with HST WFC3/UVIS images at epochs ∼216 and ∼365 days are included for a more complete analysis. The images reveal the temporal evolution of at least two major light-echo components. The first one exhibits a filled ring structure with position-angle-dependent intensity. This radially extended, diffuse echo indicates the presence of an inhomogeneous interstellar dust cloud ranging from ∼100 to ∼500 pc in the foreground of the SN. The second echo component appears as an unresolved luminous quarter-circle arc centered on the SN. The wavelength dependence of scattering measured in different dust components suggests that the dust producing the luminous arc favors smaller grain sizes, while that causing the diffuse light echo may have sizes similar to those of the Milky Way dust. Smaller grains can produce an optical depth consistent with that along the supernova-Earth line of sight measured by previous studies around maximum light. Therefore, it is possible that the dust slab from which the luminous arc arises is also responsible for most of the extinction toward SN 2014J. The optical depths determined from the Milky Way-like dust in the scattering matters are lower than the optical depth produced by the dust slab.
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