Redshift distributions of galaxies in the Dark Energy Survey Science Verification shear catalogue and implications for weak lensing

We present photometric redshift estimates for galaxies used in the weak lensing analysis of the Dark Energy Survey Science Verification (DES SV) data. Four model- or machine learning-based photometric redshift methods—ANNZ2, BPZ calibrated against BCC-Ufig simulations, SKYNET, and TPZ—are analyzed. For training, calibration, and testing of these methods, we construct a catalogue of spectroscopically confirmed galaxies matched against DES SV data. The performance of the methods is evaluated against the matched spectroscopic catalogue, focusing on metrics relevant for weak lensing analyses, with additional validation against COSMOS photo-z’s. From the galaxies in the DES SV shear catalogue, which have mean redshift 0.72 0.01 over the range 0.3 < z < 1.3, we construct three tomographic bins with means of z ¼ f0.45; 0.67; 1.00g. These bins each have systematic uncertainties δz ≲ 0.05 in the mean of the fiducial SKYNET photo-z nðzÞ. We propagate the errors in the redshift distributions through to their impact on cosmological parameters estimated with cosmic shear, and find that they cause shifts in the value of σ8 of approximately 3%. This shift is within the one sigma statistical errors on σ8 for the DES SV shear catalogue. We further study the potential impact of systematic differences on the critical surface density, Σcrit, finding levels of bias safely less than the statistical power of DES SV data. We recommend a final Gaussian prior for the photo-z bias in the mean of nðzÞ of width 0.05 for each of the three tomographic bins, and show that this is a sufficient bias model for the corresponding cosmology analysis

Identification of a Potent Inhibitor for the Extended Spectrum Class C Beta-Lactamase, ADC-7

Resistance to b-lactam antibiotics in the pathogenic bacteria, Acinetobacter baumannii, presents one of the greatest challenges to current antimicrobial chemotherapy. Majority of resistance is due to expression of class C β-lactamase enzymes, known as Acinetobacter-Derived Cephalosporinases (ADCs). The enzyme ADC-7 is a broad-spectrum class C b-lactamase, capable of deactivating multiple types of antibiotics. Boronic acid transition state inhibitors (BATSIs) are compounds that bind covalently and reversibly to class C b-lactamases. Enzyme kinetic studies of one BATSI, designated S02030, demonstrated a greater affinity for binding than a common cephalosporin substrate. After expression and purification of ADC-7, the first known X-ray crystal structure of ADC-7 with inhibitor complex was solved at 2.03 Å resolution. The ADC-7/S02030 complex provides insight into ADC enzyme structure and offers a novel starting point for the structure-based optimization of b-lactamase inhibitors

X-ray crystal structure of the extended-spectrum class C ²-lactamase, ADC-7, in apo form and in complex with a boronic acid transition state analog

Resistance to ²-lactam antibiotics in the pathogenic bacteria, Acinetobacter baumannii, presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance derives from the expression of class C ²-lactamase enzymes, known as Acinetobacter-Derived Cephalosporinases (ADCs). In the search for novel therapies for multidrug resistant pathogens, determining the molecular structure of the enzyme active site is an important contribution. Here, we have determined the X-ray crystal structure of the extended-spectrum class C ²-lactamase, ADC-7, at 1.7 Å (P1 space group). In addition, while current ²-lactamase inhibitors are structurally similar to ²-lactam substrates and are not effective inactivators of the class C enzymes, boronic acid transition state inhibitors (BATSIs; chemically dissimilar to ²-lactams) were explored to inhibit ADC enzymes. In this study, we used a chiral, carboxy-aryl cephalothin analog BATSI, and the ADC-7 complex was determined at 2.0 Å resolution (P21 space group). In the complexed enzyme,the boronic acid makes several canonical interactions. The O1 oxygen is bound in the oxyanion hole, and the R1 amide group makes interactions with conserved residues Asn152 and Gln120. The carboxylate group of the inhibitor mimics the C4\u27 carboxylate found in ²-lactams. Asn289, Thr316, and Asn346 commonly comprise the C4\u27 carboxylate recognition residues in class C enzymes. However, in ADC-7, Asn289 is replaced with Glu289 and is pointed out of the active site. Interestingly, in ADC-7 complex, the inhibitor carboxylate group is observed to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme, AmpC. The ADC-7/boronic acid complex provides insight into recognition of non-²-lactam inhibitors by ADC enzymes and offers a novel starting point for the structure-based optimization of this class of novel ²-lactamase inhibitors against a clinically relevant resistance target

Inhibition of Acinetobacter -Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors

Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 (Ki= 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4found in β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c, 3h, and 3j, Ki= 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d (Ki= 224 nM) and the hydroxyamide derivative 3e (Ki= 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic

Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase

Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12 000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is mediated by class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used β-lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. Kivalues ranged from low micromolar to subnanomolar, and circular dichroism (CD) demonstrated that each inhibitor stabilizes the β-lactamase-inhibitor complexes. Additionally, X-ray crystal structures of ADC-7 in complex with five inhibitors were determined (resolutions from 1.80 to 2.09 Å). In the ADC-7/CR192 complex, the BATSI with the lowest Ki(0.45 nM) and greatest ΔTm(+9 °C), a trifluoromethyl substituent, interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. The ADC-7/BATSI complexes determined in this study shed light into the unique recognition sites in ADC enzymes and also offer insight into further structure-based optimization of these inhibitors

Biochemical and Structural Analysis of Inhibitors Targeting the ADC‑7 Cephalosporinase of <i>Acinetobacter baumannii</i>

β-Lactam resistance in <i>Acinetobacter baumannii</i> presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C β-lactamase enzymes, known as <i>Acinetobacter-</i>derived cephalosporinases (ADCs). Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two <u>b</u>oronic <u>a</u>cid <u>t</u>ransition <u>s</u>tate <u>i</u>nhibitors (BATSIs S02030 and SM23) that are chemically distinct from β-lactams were designed and tested for inhibition of ADC enzymes. BATSIs SM23 and S02030 bind with high affinity to ADC-7, a chromosomal cephalosporinase from <i>Acinetobacter baumannii</i> (<i>K</i>_i = 21.1 ± 1.9 nM and 44.5 ± 2.2 nM, respectively). The X-ray crystal structures of ADC-7 were determined in both the apo form (1.73 Å resolution) and in complex with S02030 (2.0 Å resolution). In the complex, S02030 makes several canonical interactions: the O1 oxygen of S02030 is bound in the oxyanion hole, and the R1 amide group makes key interactions with conserved residues Asn152 and Gln120. In addition, the carboxylate group of the inhibitor is meant to mimic the C₃/C₄ carboxylate found in β-lactams. The C₃/C₄ carboxylate recognition site in class C enzymes is comprised of Asn346 and Arg349 (AmpC numbering), and these residues are conserved in ADC-7. Interestingly, in the ADC-7/S02030 complex, the inhibitor carboxylate group is observed to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme AmpC. A thermodynamic analysis suggests that <i>Δ<i>H</i></i> driven compounds may be optimized to generate new lead agents. The ADC-7/BATSI complex provides insight into recognition of non-β-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel β-lactamase inhibitors against a key resistance target

Inhibition of <i>Acinetobacter</i>-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β‑Lactamase Inhibitors

Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound <b>S02030</b> (<i>K</i>_i = 44 nM) proved to be a good lead compound against ADC-7 (<i>Acinetobacter</i>-derived cephalosporinase), one of the most significant resistance determinants in <i>A. baumannii</i>. The atomic structure of the ADC-7/<b>S02030</b> complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C₃/C₄ found in β-lactams, we designed, synthesized, and characterized six derivatives of <b>S02030</b> (<b>3a</b>). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds <b>3a</b>–<b>c</b>, <b>3h</b>, and <b>3j</b>, <i>K</i>_i = 44–115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative <b>3d</b> (<i>K</i>_i = 224 nM) and the hydroxyamide derivative <b>3e</b> (<i>K</i>_i = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds <b>3c</b>, <b>SM23</b>, and <b>EC04</b> were determined. All three compounds share the same structural features as in <b>S02030</b> but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a “carboxylate binding region” rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of <i>A. baumannii</i> and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic

Stellar kinematics and metallicities in the ultra-faint dwarf galaxy Reticulum II

We present Magellan/M2FS, Very Large Telescope/GIRAFFE, and Gemini South/GMOS spectroscopy of the newly discovered Milky Way satellite Reticulum II. Based on the spectra of 25 Ret II member stars selected from Dark Energy Survey imaging, we measure a mean heliocentric velocity of 62.8 0.5 km s-1 and a velocity dispersion of 3.3 0.7 km s-1. The mass-to-light ratio of Ret II within its half-light radius is 470 210 M L, demonstrating that it is a strongly dark matter-dominated system. Despite its spatial proximity to the Magellanic Clouds, the radial velocity of Ret II differs from that of the LMC and SMC by 199 and 83 km s-1, respectively, suggesting that it is not gravitationally bound to the Magellanic system. The likely member stars of Ret II span 1.3 dex in metallicity, with a dispersion of 0.28 ± 0.09 dex, and we identify several extremely metal-poor stars with [Fe/H] < -3. In combination with its luminosity, size, and ellipticity, these results confirm that Ret II is an ultra-faint dwarf galaxy. With a mean metallicity of [Fe/H] = -2.65 0.07, Ret II matches Segue 1 as the most metal-poor galaxy known. Although Ret II is the third-closest dwarf galaxy to the Milky Way, the line-of-sight integral of the dark matter density squared is log10 (J) 18.8 0.6 GeV cm = 2 -5 within 0 ◦. 2, indicating that the predicted gamma-ray flux from dark matter annihilation in Ret II is lower than that of several other dwarf galaxies