New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically ...validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.
Abstract
We investigate whether the sky rate of fast radio bursts (FRBs) depends on Galactic latitude using the first catalog of FRBs detected by the Canadian Hydrogen Intensity Mapping Experiment ...Fast Radio Burst (CHIME/FRB) Project. We first select CHIME/FRB events above a specified sensitivity threshold in consideration of the radiometer equation, and then we compare these detections with the expected cumulative time-weighted exposure using Anderson–Darling and Kolmogorov–Smirnov tests. These tests are consistent with the null hypothesis that FRBs are distributed without Galactic latitude dependence (
p
-values distributed from 0.05 to 0.99, depending on completeness threshold). Additionally, we compare rates in intermediate latitudes (∣
b
∣ < 15°) with high latitudes using a Bayesian framework, treating the question as a biased coin-flipping experiment–again for a range of completeness thresholds. In these tests the isotropic model is significantly favored (Bayes factors ranging from 3.3 to 14.2). Our results are consistent with FRBs originating from an isotropic population of extragalactic sources.
Motivated by the need to develop instrumental techniques for characterizing organic aerosol aging, we report on the performance of the Toronto Photo-Oxidation Tube (TPOT) and Potential Aerosol Mass ...(PAM) flow tube reactors under a variety of experimental conditions. The PAM system was designed with lower surface-area-to-volume (SA/V) ratio to minimize wall effects; the TPOT reactor was designed to study heterogeneous aerosol chemistry where wall loss can be independently measured. The following studies were performed: (1) transmission efficiency measurements for CO2, SO2, and bis(2-ethylhexyl) sebacate (BES) particles, (2) H2SO4 yield measurements from the oxidation of SO2, (3) residence time distribution (RTD) measurements for CO2, SO2, and BES particles, (4) aerosol mass spectra, O/C and H/C ratios, and cloud condensation nuclei (CCN) activity measurements of BES particles exposed to OH radicals, and (5) aerosol mass spectra, O/C and H/C ratios, CCN activity, and yield measurements of secondary organic aerosol (SOA) generated from gas-phase OH oxidation of m-xylene and α-pinene. OH exposures ranged from (2.0 ± 1.0) × 1010 to (1.8 ± 0.3) × 1012 molec cm−3 s. Where applicable, data from the flow tube reactors are compared with published results from the Caltech smog chamber. The TPOT yielded narrower RTDs. However, its transmission efficiency for SO2 was lower than that for the PAM. Transmission efficiency for BES and H2SO4 particles was size-dependent and was similar for the two flow tube designs. Oxidized BES particles had similar O/C and H/C ratios and CCN activity at OH exposures greater than 1011 molec cm−3 s, but different CCN activity at lower OH exposures. The O/C ratio, H/C ratio, and yield of m-xylene and α-pinene SOA was strongly affected by reactor design and operating conditions, with wall interactions seemingly having the strongest influence on SOA yield. At comparable OH exposures, flow tube SOA was more oxidized than smog chamber SOA, possibly because of faster gas-phase oxidation relative to particle nucleation. SOA yields were lower in the TPOT than in the PAM, but CCN activity of flow-tube-generated SOA particles was similar. For comparable OH exposures, α-pinene SOA yields were similar in the PAM and Caltech chambers, but m-xylene SOA yields were much lower in the PAM compared to the Caltech chamber.
Background
Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left‐sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved ...(HFpEF) vs. reduced ejection fraction (HFrEF) is unclear.
Methods and results
Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age‐ and gender‐matched groups of patients with HFpEF left ventricular ejection fraction (LVEF) ≥50%; n=219 and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population‐based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (−26.7 ± 5%, −22.7±6.6% and −18.2 ± 6.7%, respectively) and TAPSE (21.0 ± 3.9, 17.5 ± 5.1 and 14.7 ± 4.7 mm, respectively), whereas PASP increased (26.8 ± 7.1, 34.5 ± 11.9 and 39.3 ± 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (−1.06 ± 0.32, −0.75 ± 0.32 and −0.56 ± 0.36, respectively) and TAPSE/PASP ratios (0.83 ± 0.23, 0.54 ± 0.24 and 0.55 ± 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all‐cause death and HF hospitalization, even after multivariable adjustment hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14–0.74 and HR 3.09; 95% CI 1.52–6.26, respectively, with no difference between HFrEF and HFpEF.
Conclusions
Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular–arterial coupling is prognostically important in HF regardless of LVEF.
Recently, graphical representations of aerosol mass spectrometer (AMS) spectra and elemental composition have been developed to explain the oxidative and aging processes of secondary organic aerosol ...(SOA). It has been shown previously that oxygenated organic aerosol (OOA) components from ambient and laboratory data fall within a triangular region in the f44 vs. f43 space, where f44 and f43 are the ratios of the organic signal at m/z 44 and 43 to the total organic signal in AMS spectra, respectively; we refer to this graphical representation as the "triangle plot." Alternatively, the Van Krevelen diagram has been used to describe the evolution of functional groups in SOA. In this study we investigate the variability of SOA formed in chamber experiments from twelve different precursors in both "triangle plot" and Van Krevelen domains. Spectral and elemental data from the high-resolution Aerodyne aerosol mass spectrometer are compared to offline species identification analysis and FTIR filter analysis to better understand the changes in functional and elemental composition inherent in SOA formation and aging. We find that SOA formed under high- and low-NOx conditions occupy similar areas in the "triangle plot" and Van Krevelen diagram and that SOA generated from already oxidized precursors allows for the exploration of areas higher on the "triangle plot" not easily accessible with non-oxidized precursors. As SOA ages, it migrates toward the top of the triangle along a path largely dependent on the precursor identity, which suggests increasing organic acid content and decreasing mass spectral variability. The most oxidized SOA come from the photooxidation of methoxyphenol precursors which yielded SOA O/C ratios near unity. α-pinene ozonolysis and naphthalene photooxidation SOA systems have had the highest degree of mass closure in previous chemical characterization studies and also show the best agreement between AMS elemental composition measurements and elemental composition of identified species within the uncertainty of the AMS elemental analysis. In general, compared to their respective unsaturated SOA precursors, the elemental composition of chamber SOA follows a slope shallower than −1 on the Van Krevelen diagram, which is indicative of oxidation of the precursor without substantial losss of hydrogen, likely due to the unsaturated nature of the precursors. From the spectra of SOA studied here, we are able to reproduce the triangular region originally constructed with ambient OOA compents with chamber aerosol showing that SOA becomes more chemically similar as it ages. Ambient data in the middle of the triangle represent the ensemble average of many different SOA precursors, ages, and oxidative processes.
The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification ...could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM).
In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24.
Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in
and
compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05).
Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness.
NCT03127696.
Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not ...previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype-environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.
Malignant glioma is a fatal brain tumor whose pathological progression is closely associated with glycolytic reprogramming, leading to the high expression of monocarboxylate transporter 1 (MCT1) and ...its ancillary protein, cluster of differentiation 147 (CD147) for enhancing lactate efflux. In particular, malignant glioma cells (GMs) release tremendous number of exosomes, nanovesicles of 30 to 200 nm in size, promoting tumor progression by the transport of pro-oncogenic molecules to neighboring cells. In the present study, we found that hypoxia-induced malignant GMs strongly enhanced MCT1 and CD147 expression, playing a crucial role in promoting calcium-dependent exosome release. Furthermore, it was first identified that hypoxic GMs-derived exosomes contained significantly high levels of MCT1 and CD147, which could be quantitatively detected by noninvasive localized surface plasmon resonance and atomic force microscopy biosensors, demonstrating that they could be precise surrogate biomarkers for tracking parent GMs' metabolic reprogramming and malignant progression as liquid biopsies.
Active and sports fashion in the high-end market focuses on fit, superior comfort and functional performance for various end-uses. However, the engineering design of sports gloves in relation to hand ...anthropometry measurements remains unclear. In this study, two types of ready-to-wear sport gloves, namely, war-gaming glove and hiking glove were purchased from the market. The glove dimensions, fabrication properties and the effect of glove fit on hand and finger dexterity were investigated. Thirty female individuals (20–29 years old) participated a series of hand performance tests and subjective perception rating assessments towards the gloves. Results indicated that the active range of motion of fingers, finger tactile sensitivity, gripping strength and ability to handle pegs and marbles decreased with the use of gloves compared with bare hands. The perceptions of comfort and ease of hand motions decreased with the increased of wear time. The glove fit in terms of finger length dimensions was significantly correlated with hand grip force. The glove fit in hand, wrist and finger circumference dimensions had significant impact on the ability to handle small objects. It is suggested that hand length, hand circumference, finger circumference and the ratio of finger length to palm length should be considered in the design and development of gloves to improve hand performance and comfort.
•The effects of sports gloves and bare hands on hand performance are compared.•Gripping force and ability to handle small objects are sensitive to glove fit.•Glove fit with respect to hand and finger circumferences is correlated with hand dexterity and comfort.
ABSTRACT
Using commissioning data from the first year of operation of the Canadian Hydrogen Intensity Mapping Experiment’s (CHIME) Pulsar backend system, we conduct a systematic analysis of the ...Faraday Rotation Measure (RM) of the Northern hemisphere pulsars detected by CHIME. We present 55 new RMs as well as obtain improved RM uncertainties for 25 further pulsars. CHIME’s low observing frequency and wide bandwidth between 400 and 800 MHz contribute to the precision of our measurements, whereas the high cadence observation provides extremely high signal-to-noise co-added data. Our results represent a significant increase of the pulsar RM census, particularly regarding the Northern hemisphere. These new RMs are for sources that are located in the Galactic plane out to 10 kpc, as well as off the plane to a scale height of ∼16 kpc. This improved knowledge of the Faraday sky will contribute to future Galactic large-scale magnetic structure and ionosphere modelling.
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