bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness and safety of an institutional aminoglycoside-based regimen as empirical treatment of patients with pyelonephritis
Authors: Elbaz Meital , Zadka Hila , Weiss-Meilik Ahuva , Ben-Ami Ronen 
Published: March 2020

Abstract

Objectives
To determine clinical outcomes associated with aminoglycosides versus other antimicrobial agents as empirical treatment of hospitalized patients with pyelonephritis.

Patients and methods
An institutional programme promoting aminoglycosides as empirical treatment of pyelonephritis was implemented in 2016. We reviewed the hospital records of patients with pyelonephritis from January 2017 to April 2019. The primary outcome was death within 30 days of index culture. Initial treatment with aminoglycoside-based regimens was compared with non-aminoglycoside antibiotics. Propensity score matching was performed to adjust for between-group differences in baseline covariates.

Results
The study cohort included 2026 patients, 715 treated with aminoglycosides and 1311 treated with non-aminoglycoside drugs (ceftriaxone, n = 774; piperacillin/tazobactam, n = 179; carbapenems, n = 161; and fluoroquinolones, n = 133); 589 patients (29%) had bloodstream infections. Treatment with aminoglycosides was associated with a higher likelihood of in vitro activity against clinical isolates (OR = 2.0; P &lt; 0.001). Death at 30 days occurred in 55 (7.6%) versus 145 (11%) patients treated with aminoglycosides and non-aminoglycoside drugs, respectively (adjusted HR = 0.78; P = 0.013). Aminoglycosides were either superior or similar to comparator drugs in all patient subgroups, stratified according to age, glomerular filtration rate, bacteraemia, haemodynamic shock and infection with third-generation cephalosporin-resistant Enterobacteriaceae. The incidence of acute kidney injury was similar for aminoglycosides and comparators (2.5% versus 2.9%, respectively; P = 0.6).

Conclusions
Within the context of an institutional programme, initial empirical treatment of pyelonephritis with aminoglycosides was associated with higher rates of in vitro activity and lower overall mortality compared with non-aminoglycoside drugs, without excess nephrotoxicity.
Low-dose liposomal amphotericin B for antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell transplantation
Authors: Mendoza-Palomar Natalia , Soques Elena , Benitez-Carabante María Isabel , Gonzalez-Amores Miriam , Fernandez-Polo Aurora , Renedo Berta , Martin Maria Teresa , Soler-Palacin Pere , Diaz-de-Heredia Cristina 
Published: March 2020

AbstractBackgroundPrimary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions.ObjectivesTo evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients.Patients and methodsRetrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day −1 to 48 h before discharge) between January 2012 and December 2016.ResultsIn total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2–11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI.ConclusionsThe incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.
Impact of dietary oxidized protein on oxidative status and performance in growing pigs
Authors: Frame Carl A , Johnson Erika , Kilburn Logan , Huff-Lonergan Elisabeth , Kerr Brian J , Serao Mariana Rossoni 
Published: March 2020

Abstract
Rendered products from the meat industry can provide economical quality sources of proteins to the animal and feed industry. Similar to lipids, rendered proteins are susceptible to oxidation, yet the stability of these proteins is unclear. In addition, interest in understanding how oxidative stress can impact efficiency in production animals is increasing. Recent studies show that consumption of oxidized lipids can lead to a change in the oxidative status of the animal as well as decreases in production efficiency. To date, little is known about how consumption of oxidized proteins impacts oxidative status and growth performance. The objectives of this study were to determine if feeding diets high in oxidized protein to growing pigs would: 1) impact growth performance and 2) induce oxidative stress. Thirty pigs (42 d old; initial body weight [BW] 12.49 ± 1.45 kg) were randomly assigned to one of three dietary treatments with increasing levels of oxidized protein. Spray-dried bovine plasma was used as the protein source and was either unheated upon arrival, heated at 45 °C for 4 d, or heated at 100 °C for 3 d. Diets were fed for 19 d and growth performance was measured. Blood plasma (days 0 and 18), jejunum, colon, and liver tissues (day 19) were collected to analyze for markers of oxidative stress (e.g., protein oxidation, lipid oxidation, DNA damage, and glutathione peroxidase activity). Average daily gain (ADG;P &lt; 0.01) and average daily feed intake (ADFI;P &lt; 0.01) had a positive linear relationship to increased protein oxidation, but there was no effect on gain to feed ratio. Furthermore, protein (P = 0.03) and fat (P &lt; 0.01) digestibility were reduced with increased protein oxidation in the diet. Crypt depth showed a positive linear relationship with dietary protein oxidation levels (P = 0.02). A trend was observed in liver samples where pigs fed the plasma heated to 45 °C had increased lipid oxidation compared with pigs fed the plasma either unheated or heated to 100 °C (P = 0.09). DNA damage in the jejunum tended to have a linear relationship with the dietary protein oxidation level (P = 0.07). Even though results suggest dietary oxidized protein did not induce oxidative stress during short-term feeding, differences in performance, gut morphology, and digestibility are likely a result of reduced protein availability.
Germline MBD4 Mutations and Predisposition to Uveal Melanoma
Authors: Derrien Anne-Céline , Rodrigues Manuel , Eeckhoutte Alexandre , Dayot Stéphane , Houy Alexandre , Mobuchon Lenha , Gardrat Sophie , Lequin Delphine , Ballet Stelly , Pierron Gaëlle , Alsafadi Samar , Mariani Odette , El-Marjou Ahmed , Matet Alexandre , Colas Chrystelle , Cassoux Nathalie , Stern Marc-Henri 
Published: March 2020

Abstract

Background
Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is the only known predisposing gene for UM. UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG&gt;TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3).

Methods
We performed MBD4 targeted sequencing on pooled germline (n = 1093) and tumor (n = 192) DNA samples of UM patients. MBD4 variants (n = 28) were validated by Sanger sequencing. We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9). Variants of unknown pathogenicity were further functionally assessed.

Results
We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 × 10–5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations. Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG&gt;TpG hypermutator phenotype.

Conclusions
We demonstrate that MBD4 is a new predisposing gene for UM associated with hypermutated M3 tumors. The tumor spectrum of this predisposing condition will likely expand with the addition of MBD4 to diagnostic panels. Tumors arising in such a context should be recognized because they may respond to immunotherapy.
The Deuteronomistic Endorsement of Sacrificing Errant Individuals as Reflected by the Hebrew Terms Ḥērem and Biʽēr
Authors: Tatlock Jason 
Published: March 2020

Abstract
Despite the efforts of some scholars, biblical denunciations of one form of human sacrifice cannot be taken as condemnations of all types. Thus, while the writers of the Deuteronomistic History clearly regarded the slaying of children at the Jerusalem Tophet adversely, they accepted the legitimacy of sacrificing religiously errant individuals like murderers and others who went against their form of Yahwism. Such an endorsement is particularly represented by the biblical Hebrew ideas of sacrificial dedication (ḥērem) and burning up/consuming contamination (biʽēr). In the wake of Judah's fall and Jerusalem's destruction, the Deuteronomists promoted human sacrifice as a means to maintain or establish the purity of the Israelite community and the land of Canaan while delineating the limits of their version of a Yahwistic group.
KNOX protein KNAT1 regulates fruitlet abscission in litchi by repressing ethylene biosynthetic genes
Authors: Zhao Minglei , Li Caiqin , Ma Xingshuai , Xia Rui , Chen Jianye , Liu Xuncheng , Ying Peiyuan , Peng Manjun , Wang Jun , Shi Chun-Lin , Li Jianguo 
Published: March 2020

AbstractAbscission is triggered by multiple environmental and developmental cues, including endogenous plant hormones. KNOTTED-LIKE HOMEOBOX (KNOX) transcription factors (TFs) play an important role in controlling abscission in plants. However, the underlying molecular mechanism of KNOX TFs in abscission is largely unknown. Here, we identified LcKNAT1, a KNOTTED-LIKE FROM ARABIDOPSIS THALIANA1 (KNAT1)-like protein from litchi, which regulates abscission by modulating ethylene biosynthesis. LcKNAT1 is expressed in the fruit abscission zone and its expression decreases during fruitlet abscission. Furthermore, the expression of the ethylene biosynthetic genes LcACS1, LcACS7, and LcACO2 increases in the fruit abscission zone, in parallel with the emission of ethylene in fruitlets. In vitro and in vivo assays revealed that LcKNAT1 inhibits the expression of LcACS/ACO genes by directly binding to their promoters. Moreover, ectopic expression of LcKNAT1 represses flower abscission in tomatoes. Transgenic plants expressing LcKNAT1 also showed consistently decreased expression of ACS/ACO genes. Collectively, these results indicate that LcKNAT1 represses abscission via the negative regulation of ethylene biosynthesis.
Production and excitation of molecules by dissipation of two-dimensional turbulence
Authors: Lesaffre P , Todorov P , Levrier F , Valdivia V , Dzyurkevich N , Godard B , Tram L N , Gusdorf A , Lehmann A , Falgarone E 
Published: March 2020

ABSTRACT
The interstellar medium (ISM) is typically a hostile environment: cold, dilute and irradiated. Nevertheless, it appears very fertile for molecules. The localized heating resulting from turbulence dissipation is a possible channel to produce and excite molecules. However, large-scale simulations cannot resolve the dissipative scales of the ISM. Here, we present two-dimensional small-scale simulations of decaying hydrodynamic turbulence using the chemses code, with fully resolved viscous dissipation, time-dependent heating, cooling, chemistry and excitation of a few rotational levels of H2. We show that molecules are produced and excited in the wake of strong dissipation ridges. We carefully identify shocks and we assess their statistics and contribution to the molecular yields and excitation. We find that the formation of molecules is strongly linked to increased density as a result of shock compression and to the opening of endothermic chemical routes because of higher temperatures. We identify a new channel for molecule production via H2 excitation, illustrated by CH+ yields in our simulations. Despite low temperatures and the absence of magnetic fields (favouring CH+ production through ion-neutral velocity drifts), the excitation of the first few rotational levels of H2 shrinks the energy gap to form CH+. The present study demonstrates how dissipative chemistry can be modelled by statistical collections of one-dimensional steady-state shocks. Thus, the excitation of higher J levels of H2 is likely to be a direct signature of turbulence dissipation, and an indirect probe for molecule formation. We hope these results will help to bring new tools and ideas for the interpretation of current observations of H2 rotational lines carried out using the Stratospheric Observatory for Infrared Astronomy (SOFIA), and pave the way for a better understanding of the high-resolution mapping of H2 emission by future instruments, such as theJames Webb Space Telescope and the Space Infrared Telescope for Cosmology and Astrophysics.
The age–chemical abundance structure of the Galaxy I: evidence for a late-accretion event in the outer disc at z ∼ 0.6
Authors: Lian Jianhui , Thomas Daniel , Maraston Claudia , Zamora Olga , Tayar Jamie , Pan Kaike , Tissera Patricia , Fernández-Trincado José G , Garcia-Hernandez D A 
Published: March 2020

ABSTRACT
We investigate the age–chemical abundance structure of the outer Galactic disc at a galactocentric distance of r &gt; 10 kpc as recently revealed by the SDSS/APOGEE survey. Two sequences are present in the [α/Fe]–[Fe/H] plane with systematically different stellar ages. Surprisingly, the young sequence is less metal rich, suggesting a recent dilution process by additional gas accretion. As the stars with the lowest iron abundance in the younger sequence also show an enhancement in α-element abundance, the gas accretion event must have involved a burst of star formation. In order to explain these observations, we construct a chemical evolution model. In this model, we include a relatively short episode of gas accretion at late times on top of an underlying secular accretion over long time-scales. Our model is successful at reproducing the observed distribution of stars in the three-dimensional space of [α/Fe]–[Fe/H]–age in the outer disc. We find that a late-time accretion with a delay of $8.2\,$Gyr and a time-scale of 0.7 Gyr best fits the observed data, in particular the presence of the young, metal-poor sequence. Our best-fitting model further implies that the amount of accreted gas in the late-time accretion event needs to be about three times the local gas reservoir in the outer disc at the time of accretion in order to sufficiently dilute the metal abundance. Given this large fraction, we interpret the late-time accretion event as a minor merger presumably with a gas-rich dwarf galaxy with a mass $M_*\lt 10^{9}\, \mathrm{ M}_{\odot }$ and a gas fraction of ∼75 per cent.
Diffusive photospheres in gamma-ray bursts
Authors: Vereshchagin G V , Siutsou I A 
Published: March 2020

ABSTRACTPhotospheric emission may originate from relativistic outflows in two qualitatively different regimes: last scattering of photons inside the outflow at the photospheric radius or radiative diffusion to the boundary of the outflow. In this work, the measurement of temperature and flux of the thermal component in the early afterglows of several gamma-ray bursts along with the total flux in the prompt phase is used to determine initial radii of the outflow as well as its Lorentz factors. Results indicate that in some cases the outflow has relatively low Lorentz factors (Γ &lt; 10), favouring cocoon interpretation, while in other cases Lorentz factors are larger (Γ &gt; 10), indicating diffusive photospheric origin of the thermal component, associated with an ultrarelativistic outflow.
Cosmic magnetic fields with masclet: an application to galaxy clusters
Authors: Quilis Vicent , Martí José-María , Planelles Susana 
Published: March 2020

ABSTRACT
We describe and test a new version of the adaptive mesh refinement cosmological code masclet. The new version of the code includes all the ingredients of its previous version plus a description of the evolution of the magnetic field under the approximation of the ideal magnetohydrodynamics (MHD). To preserve the divergence-free condition of MHD, the original divergence cleaning algorithm of Dedner et al. (2002) is implemented. We present a set of well-known 1D and 2D tests, such as several shock tube problems, the fast rotor, and the Orszag–Tang vortex. The performance of the code in all the tests is excellent with estimated median relative errors of ∇ · B in the 2D tests smaller than 5 × 10−5 for the fast rotor test, and 5 × 10−3 for the Orszag–Tang vortex. As an astrophysical application of the code, we present a simulation of a cosmological box of 40 comoving Mpc side length in which a primordial uniform comoving magnetic field of strength 0.1 nG is seeded. The simulation shows how the magnetic field is channelled along the filaments of gas and is concentrated and amplified within galaxy clusters. Comparison with the values expected from pure compression reveals an additional amplification of the magnetic field caused by turbulence in the central region of the cluster. Values of the order of ∼1µG are obtained in clusters at z ∼ 0 with median relative errors of ∇ · B below 0.4 per cent. The implications of a proper description of the dynamics of the magnetic field and their possible observational counterparts in future facilities are discussed.
Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond
Authors: Liu Ru-Juan , Long Tao , Li Hao , Zhao JingHua , Li Jing , Wang MingZhu , Palencia Andrés , Lin JinZhong , Cusack Stephen , Wang En-Duo 
Published: March 2020

AbstractHuman cytosolic leucyl-tRNA synthetase (hcLRS) is an essential and multifunctional enzyme. Its canonical function is to catalyze the covalent ligation of leucine to tRNALeu, and it may also hydrolyze mischarged tRNAs through an editing mechanism. Together with eight other aminoacyl-tRNA synthetases (AaRSs) and three auxiliary proteins, it forms a large multi-synthetase complex (MSC). Beyond its role in translation, hcLRS has an important moonlight function as a leucine sensor in the rapamycin complex 1 (mTORC1) pathway. Since this pathway is active in cancer development, hcLRS is a potential target for anti-tumor drug development. Moreover, LRS from pathogenic microbes are proven drug targets for developing antibiotics, which however should not inhibit hcLRS. Here we present the crystal structure of hcLRS at a 2.5 Å resolution, the first complete structure of a eukaryotic LRS, and analyze the binding of various compounds that target different sites of hcLRS. We also deduce the assembly mechanism of hcLRS into the MSC through reconstitution of the entire mega complex in vitro. Overall, our study provides the molecular basis for understanding both the multifaceted functions of hcLRS and for drug development targeting these functions.
PHF2 regulates homology-directed DNA repair by controlling the resection of DNA double strand breaks
Authors: Alonso-de Vega Ignacio , Paz-Cabrera Maria Cristina , Rother Magdalena B , Wiegant Wouter W , Checa-Rodríguez Cintia , Hernández-Fernaud Juan Ramón , Huertas Pablo , Freire Raimundo , van Attikum Haico , Smits Veronique A J 
Published: March 2020

Abstract
Post-translational histone modifications and chromatin remodelling play a critical role controlling the integrity of the genome. Here, we identify histone lysine demethylase PHF2 as a novel regulator of the DNA damage response by regulating DNA damage-induced focus formation of 53BP1 and BRCA1, critical factors in the pathway choice for DNA double strand break repair. PHF2 knockdown leads to impaired BRCA1 focus formation and delays the resolution of 53BP1 foci. Moreover, irradiation-induced RPA phosphorylation and focus formation, as well as localization of CtIP, required for DNA end resection, to sites of DNA lesions are affected by depletion of PHF2. These results are indicative of a defective resection of double strand breaks and thereby an impaired homologous recombination upon PHF2 depletion. In accordance with these data, Rad51 focus formation and homology-directed double strand break repair is inhibited in cells depleted for PHF2. Importantly, we demonstrate that PHF2 knockdown decreases CtIP and BRCA1 protein and mRNA levels, an effect that is dependent on the demethylase activity of PHF2. Furthermore, PHF2-depleted cells display genome instability and are mildly sensitive to the inhibition of PARP. Together these results demonstrate that PHF2 promotes DNA repair by homologous recombination by controlling CtIP-dependent resection of double strand breaks.
Systematic in vitro profiling of off-target affinity, cleavage and efficiency for CRISPR enzymes
Authors: Zhang Liyang , Rube H Tomas , Vakulskas Christopher A , Behlke Mark A , Bussemaker Harmen J , Pufall Miles A 
Published: March 2020

AbstractCRISPR RNA-guided endonucleases (RGEs) cut or direct activities to specific genomic loci, yet each has off-target activities that are often unpredictable. We developed a pair of simple in vitro assays to systematically measure the DNA-binding specificity (Spec-seq), catalytic activity specificity (SEAM-seq) and cleavage efficiency of RGEs. By separately quantifying binding and cleavage specificity, Spec/SEAM-seq provides detailed mechanistic insight into off-target activity. Feature-based models generated from Spec/SEAM-seq data for SpCas9 were consistent with previous reports of its in vitro and in vivo specificity, validating the approach. Spec/SEAM-seq is also useful for profiling less-well characterized RGEs. Application to an engineered SpCas9, HiFi-SpCas9, indicated that its enhanced target discrimination can be attributed to cleavage rather than binding specificity. The ortholog ScCas9, on the other hand, derives specificity from binding to an extended PAM. The decreased off-target activity of AsCas12a (Cpf1) appears to be primarily driven by DNA-binding specificity. Finally, we performed the first characterization of CasX specificity, revealing an all-or-nothing mechanism where mismatches can be bound, but not cleaved. Together, these applications establish Spec/SEAM-seq as an accessible method to rapidly and reliably evaluate the specificity of RGEs, Cas::gRNA pairs, and gain insight into the mechanism and thermodynamics of target discrimination.