Miracle-dz/UniFAR-FTUs huggingface dataset:
A Phase I, Randomized, Double-Blinded, Placebo- and Moxifloxacin-Controlled, Four-Period Crossover Study To Evaluate the Effect of Gepotidacin on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram in Healthy Volunteers

ABSTRACT Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, crossover thorough QT study in healthy subjects who were administered intravenous (i.v.) gepotidacin as a therapeutic (1,000-mg) dose and supratherapeutic (1,800-mg) dose, placebo, and 400 mg oral moxifloxacin in 4 separate treatment periods. Gepotidacin caused a mild effect on heart rate, with a largest placebo-corrected change-from-baseline heart rate of 7 and 10 beats per minute at the end of the 1,000-mg and 1,800-mg infusion, respectively. Gepotidacin caused an increase of change-from-baseline QTcF (ΔQTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ΔQTcF (ΔΔQTcF) was 12.1 ms (90% confidence interval [CI], 9.5 to 14.8) and 22.2 ms (90% CI, 19.6 to 24.9) after 1,000 mg and 1,800 mg, respectively. ΔΔQTcF rapidly fell after the end of the infusion, with a mean ΔΔQTcF of 6.1 ms 60 min after the 1,800-mg dose. Exposure-response analysis demonstrated a statistically significant positive relationship between gepotidacin plasma levels and ΔΔQTcF, with a slope of 1.45 ms per μg/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ΔΔQTcF can be predicted to be 11 and 20 ms at the observed mean peak plasma concentration after the infusion of gepotidacin at 1,000 mg (7 μg/ml) and 1,800 mg (13 μg/ml), respectively. In conclusion, gepotidacin caused QT prolongation in this thorough QT study, and a mean effect can be predicted to less than 15 ms at the highest expected plasma concentration, 9 μg/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.)
Functional Characterization of the DNA Gyrases in Fluoroquinolone-Resistant Mutants of Francisella novicida

ABSTRACT Fluoroquinolone (FQ) resistance is a major health concern in the treatment of tularemia. Because DNA gyrase has been described as the main target of these compounds, our aim was to clarify the contributions of both GyrA and GyrB mutations found in Francisella novicida clones highly resistant to FQs. Wild-type and mutated GyrA and GyrB subunits were overexpressed so that the in vitro FQ sensitivity of functional reconstituted complexes could be evaluated. The data obtained were compared to the MICs of FQs against bacterial clones harboring the same mutations and were further validated through complementation experiments and structural modeling. Whole-genome sequencing of highly FQ-resistant lineages was also done. Supercoiling and DNA cleavage assays demonstrated that GyrA D87 is a hot spot FQ resistance target in F. novicida and pointed out the role of the GyrA P43H substitution in resistance acquisition. An unusual feature of FQ resistance acquisition in F. novicida is that the first-step mutation occurs in GyrB, with direct or indirect consequences for FQ sensitivity. Insertion of P466 into GyrB leads to a 50% inhibitory concentration (IC50) comparable to that observed for a mutant gyrase carrying the GyrA D87Y substitution, while the D487E-ΔK488 mutation, while not active on its own, contributes to the high level of resistance that occurs following acquisition of the GyrA D87G substitution in double GyrA/GyrB mutants. The involvement of other putative targets is discussed, including that of a ParE mutation that was found to arise in the very late stage of antibiotic exposure. This study provides the first characterization of the molecular mechanisms responsible for FQ resistance in Francisella.
Focal Segmental Glomerulosclerosis in Related Miniature Schnauzer Dogs

Focal segmental glomerulosclerosis (FSGS) recently has been recognized as a common cause of proteinuria in dogs in general, and in Miniature Schnauzer dogs in particular. This study describes the morphologic features present in the kidneys of 8 related proteinuric Miniature Schnauzer dogs. The FSGS, characterized by solidification of portions of the capillary tuft, affected 32% to 49% of examined glomeruli in these dogs. Synechiae, often accompanied by hyalinosis, were present in 13% to 54% of glomeruli and were more prevalent in older dogs. Seven of 8 dogs had arteriolar hyalinosis. Ultrastructurally, all dogs had evidence of a podocytopathy in the absence of electron-dense deposits, glomerular basement membrane splitting, or fibrils. All dogs had multifocal to extensive podocyte foot process effacement. Other podocyte changes included microvillous transformation, the presence of vacuoles or protein resorption droplets, cytoplasmic electron-dense aggregates, and occasional binucleation. Variable amounts of intraglomerular lipid were present in all dogs. All dogs were proteinuric, with measured values for the urine protein-to-creatinine ratio ranging from 1.2 to 6.5. Azotemia was mild to absent and dogs were euthanatized at 5.1 to 14 years of age, in all cases due to nonrenal diseases. The underlying cause of FSGS in these Miniature Schnauzer dogs has yet to be determined, but contributors likely include genetic podocytopathy, lipid abnormalities, and glomerular hypertension.
Novel learning accelerates systems consolidation of a contextual fear memory

After initial encoding memories may undergo a time‐dependent reorganization, becoming progressively independent from the hippocampus (HPC) and dependent on cortical regions such as the anterior cingulate cortex (ACC). Although the mechanisms underlying systems consolidation are somewhat known, the factors determining its temporal dynamics are still poorly understood. Here, we studied the influence of novel learning occurring between training and test sessions on the time‐course of HPC‐ and ACC‐dependency of contextual fear conditioning (CFC) memory expression. We found that muscimol was disruptive when infused into the HPC up to 35 days after training, while the ACC is vulnerable only after 45 days. However, when animals were subjected to a series of additional, distinct tasks to be learned within the first 3 weeks, muscimol became effective sooner. Muscimol had no effect in the HPC at 20 days after training, exactly when the ACC becomes responsive to this treatment. Thus, our data indicates that the encoding of new information generates a tight interplay between distinct memories, accelerating the reorganization of previously stored long term memories between the hippocampal and cortical areas. © 2016 Wiley Periodicals, Inc.
RSGAN: face swapping and editing using face and hair representation in latent spaces

This abstract introduces a generative neural network for face swapping and editing face images. We refer to this network as "region-separative generative adversarial network (RSGAN)". In existing deep generative models such as Variational autoencoder (VAE) and Generative adversarial network (GAN), training data must represent what the generative models synthesize. For example, image inpainting is achieved by training images with and without holes. However, it is difficult or even impossible to prepare a dataset which includes face images both before and after face swapping because faces of real people cannot be swapped without surgical operations. We tackle this problem by training the network so that it synthesizes synthesize a natural face image from an arbitrary pair of face and hair appearances. In addition to face swapping, the proposed network can be applied to other editing applications, such as visual attribute editing and random face parts synthesis.
A COMPARISON BETWEEN BIORID AND HYBRID III HEAD/NECK/TORSO RESPONSE IN MIDDLE SPEED SLED REAR IMPACT TESTS

The most important tool used in testing methods for evaluating the performance of seat-systems in rear-end impacts is a biofidelic crash test dummy. It has been reported that there are differences in response between two kinds of such dummies, BioRID P3 and Hybrid III, in rear-end impacts at delta V=9.2 km/h. The objective of this study is to compare the responses of these two types of dummies, at moderate speeds with HYGE sled tests (delta V=15 km/h, 25 km/h). At delta V=25 km/h or less, the BioRID and HYIII dummies showed clear differences in their response to a rear-end collision, and the BioRID showed higher biofidelity than the HyIII in this condition.
Two Residues in NSP9 Contribute to the Enhanced Replication and Pathogenicity of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus

ABSTRACT Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) possesses greater replicative capacity and pathogenicity than classical PRRSV. However, the factors that lead to enhanced replication and pathogenicity remain unclear. In our study, an alignment of all available full-length sequences of North American-type PRRSVs (n = 204) revealed two consistent amino acid mutations that differed between HP-PRRSV and classical PRRSV and were located at positions 519 and 544 in nonstructural protein 9. Next, a series of mutant viruses with either single or double amino acid replacements were generated from HP-PRRSV HuN4 and classical PRRSV CH-1a infectious cDNA clones. Deletion of either of the amino acids led to a complete loss of virus viability. In both Marc-145 and porcine alveolar macrophages, the replicative efficiencies of mutant viruses based on HuN4 were reduced compared to the parent, whereas the replication level of CH-1a-derived mutant viruses was increased. Plaque growth assays showed clear differences between mutant and parental viruses. In infected piglets, the pathogenicity of HuN4-derived mutant viruses, assessed through clinical symptoms, viral load in sera, histopathology examination, and thymus atrophy, was reduced. Our results indicate that the amino acids at positions 519 and 544 in NSP9 are involved in the replication efficiency of HP-PRRSV and contribute to enhanced pathogenicity. This study is the first to identify specific amino acids involved in PRRSV replication or pathogenicity. These findings will contribute to understanding the molecular mechanisms of PRRSV replication and pathogenicity, leading to better therapeutic and prognostic options to combat the virus. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a significant threat to the global pig industry. Highly pathogenic PRRSV (HP-PRRSV) first emerged in China in 2006 and has subsequently spread across Asia, causing considerable damage to local economies. HP-PRRSV strains possess a greater replication capacity and higher pathogenicity than classical PRRSV strains, although the mechanisms that underlie these characteristics are unclear. In the present study, we identified two mutations in HP-PRRSV strains that distinguish them from classical PRRSV strains. Further experiments that swapped the two mutations in an HP-PRRSV strain and a classical PRRSV strain demonstrated that they are involved in the replication efficiency of the virus and its virulence. Our findings have important implications for understanding the molecular mechanisms of PRRSV replication and pathogenicity and also provide new avenues of research for the study of other viruses.
Metabotropic Glutamate Receptor Type 5 (mGluR5) Cortical Abnormalities in Focal Cortical Dysplasia Identified In Vivo With [11C]ABP688 Positron-Emission Tomography (PET) Imaging

Metabotropic glutamate receptor type 5 (mGluR5) abnormalities have been described in tissue resected from epilepsy patients with focal cortical dysplasia (FCD). To determine if these abnormalities could be identified in vivo, we investigated mGluR5 availability in 10 patients with focal epilepsy and an MRI diagnosis of FCD using positron-emission tomography (PET) and the radioligand [11C]ABP688. Partial volume corrected [11C]ABP688 binding potentials (BPND) were computed using the cerebellum as a reference region. Each patient was compared to homotopic cortical regions in 33 healthy controls using region-of-interest (ROI) and vertex-wise analyses. Reduced [11C]ABP688 BPND in the FCD was seen in 7/10 patients with combined ROI and vertex-wise analyses. Reduced FCD BPND was found in 4/5 operated patients (mean follow-up: 63 months; Engel I), of whom surgical specimens revealed FCD type IIb or IIa, with most balloon cells showing negative or weak mGluR5 immunoreactivity as compared to their respective neuropil and normal neurons at the border of resections. [11C]ABP688 PET shows for the first time in vivo evidence of reduced mGluR5 availability in FCD, indicating focal glutamatergic alterations in malformations of cortical development, which cannot be otherwise clearly demonstrated through resected tissue analyses.
Oxytosis/Ferroptosis—(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System

Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron. Since then there has been a great deal of discussion in the literature about whether these are two distinct pathways or cell type- and insult-dependent variations on the same pathway. In this review, we compare and contrast in detail the commonalities and distinctions between the two pathways concluding that the molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical. Thus, we suggest that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway. In addition, we describe the potential physiological relevance of oxytosis/ferroptosis in multiple neurological diseases.
Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States

Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.
Machining Dynamics: Frequency Response to Improved Productivity

Bargaining with reading habit is no need. Reading is not kind of something sold that you can take or not. It is a thing that will change your life to life better. It is the thing that will give you many things around the world and this universe, in the real world and here after. As what will be given by this machining dynamics frequency response to improved productivity, how can you bargain with the thing that has many benefits for you?
Effects of inorganic mercury exposure on histological structure, antioxidant status and immune response of immune organs in yellow catfish (Pelteobagrus fulvidraco)

Mercury (Hg) is well recognized as a highly toxic substance to fish. Nevertheless, little is known about the toxic effects of Hg on immune organs. In this study, we investigated histology, antioxidant status and immune response of the spleen and head kidney in yellow catfish following 6 weeks of exposure to environmentally relevant concentrations of inorganic Hg (2 and 10 μg l–1 Hg2+). As expected, Hg accumulation and histological injury in both tissues were observed. Meanwhile, Hg2+ exposure induced oxidative stress, which increased antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities, glutathione content, anti‐hydroxyl radical capacity and the expression of genes associated with antioxidant (sod1, cat, gpx1, nrf2 and mt) and stress (hsp70) responses in dose‐ and tissue‐specific manners. In the spleen, the mRNA levels of immune‐related genes (il‐1β, il‐8, tnf‐α, il‐10, tgf‐β, lys and c3) were upregulated by Hg2+ exposure. However, in the head kidney, upregulation of tnf‐α, il‐10 and tgf‐β mRNAs and downregulation of il‐1β and lys expressions were observed, while transcriptions of il‐8 and c3 were remarkably upregulated only in the 2 μg l–1 group. Overall, our study indicated that Hg2+ exposure could result in Hg accumulation and thereby induced histological impairment, oxidative stress and immunotoxicity in immune organs of yellow catfish, but some enzymes and/or genes involved in antioxidant and immune systems would be activated to resist Hg2+‐induced damage.
Macrophage Polarization Favors Epithelial Repair During Acute Respiratory Distress Syndrome*

Objectives: Alveolar macrophage polarization and role on alveolar repair during human acute respiratory distress syndrome remain unclear. This study aimed to determine during human acute respiratory distress syndrome: the alveolar macrophage polarization, the effect of alveolar environment on macrophage polarization, and the role of polarized macrophages on epithelial repair. Design: Experimental ex vivo and in vitro investigations. Setting: Four ICUs in three teaching hospitals. Patients: Thirty-three patients with early moderate-to-severe acute respiratory distress syndrome were enrolled for assessment of the polarization of alveolar macrophages. Interventions: Polarization of acute respiratory distress syndrome macrophages was studied by flow cytometry and quantitative polymerase chain reaction. Modulation of macrophage polarization was studied in vitro using phenotypic and functional readouts. Macrophage effect on repair was studied using alveolar epithelial cells in wound healing models. Measurements and Main Results: Ex vivo, alveolar macrophages from early acute respiratory distress syndrome patients exhibited anti-inflammatory characteristics with high CD163 expression and interleukin-10 production. Accordingly, early acute respiratory distress syndrome-bronchoalveolar lavage fluid drives an acute respiratory distress syndrome–specific anti-inflammatory macrophage polarization in vitro, close to that induced by recombinant interleukin-10. Culture supernatants from macrophages polarized in vitro with acute respiratory distress syndrome-bronchoalveolar lavage fluid or interleukin-10 and ex vivo acute respiratory distress syndrome alveolar macrophages specifically promoted lung epithelial repair. Inhibition of the hepatocyte growth factor pathway in epithelial cells and hepatocyte growth factor production in macrophages both reversed this effect. Finally, hepatocyte growth factor and soluble form of CD163 concentrations expressed relatively to macrophage count were higher in bronchoalveolar lavage fluid from acute respiratory distress syndrome survivors. Conclusions: Early acute respiratory distress syndrome alveolar environment drives an anti-inflammatory macrophage polarization favoring epithelial repair through activation of the hepatocyte growth factor pathway. These results suggest that macrophage polarization may be an important step for epithelial repair and acute respiratory distress syndrome recovery.
Timber-Concrete Composite Structures with Prefabricated FRC Slab

This study relates to the development of innovative composite structures, comprising timber beams and prefabricated concrete slabs, with high prefabrication level, high performance and good durability. For such a purpose completely dry shear connection systems were investigated. Moreover, innovative and very efficient materials, such as fibre reinforced concrete and modified wood were used for the manufacture of the specimens. The investigated shear connectors were; i) shear anchor-key of wood and ii) special inclined steel tubes. In both cases, the connectors are incorporated in the prefabricated concrete slab, which then easily is connected to the timber sub-structure only by means self-tapping screws. Both types of connectors exhibited a great performance, both in terms of strength, stiffness and ductility. The results from this project will allow the use of timber-concrete composite beams more effectively in large-span structures and also contribute to both simple and rapid manufacture and erection.
Optimization Strategies for Responsivity Control of Microgel Assisted Lab-On-Fiber Optrodes

Integrating multi-responsive polymers such as microgels onto optical fiber tips, in a controlled fashion, enables unprecedented functionalities to Lab-on-fiber optrodes. The creation of a uniform microgel monolayer with a specific coverage factor is crucial for enhancing the probes responsivity to a pre-defined target parameter. Here we report a reliable fabrication strategy, based on the dip coating technique, for the controlled realization of microgel monolayer onto unconventional substrates, such as the optical fiber tip. The latter was previously covered by a plasmonic nanostructure to make it sensitive to superficial environment changes. Microgels have been prepared using specific Poly(N-isopropylacrylamide)-based monomers that enable bulky size changes in response to both temperature and pH variations. The formation of the microgel monolayer is efficiently controlled through the selection of suitable operating pH, temperature and concentration of particle dispersions used during the dipping procedure. The effect of each parameter has been evaluated, and the validity of our procedure is confirmed by means of both morphological and optical characterizations. We demonstrate that when the coverage factor exceeds 90%, the probe responsivity to microgels swelling/collapsing is significantly improved. Our study opens new paradigms for the development of engineered microgels assisted Lab-on-Fiber probes for biochemical applications.