Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit ...the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were ...compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant Kd, ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.
Correcting for tropospheric delays is one of the largest challenges facing the interferometric synthetic aperture radar (InSAR) community. Spatial and temporal variations in temperature, pressure, ...and relative humidity create tropospheric signals in InSAR data, masking smaller surface displacements due to tectonic or volcanic deformation. Correction methods using weather model data, GNSS and/or spectrometer data have been applied in the past, but are often limited by the spatial and temporal resolution of the auxiliary data. Alternatively a correction can be estimated from the interferometric phase by assuming a linear or a power-law relationship between the phase and topography. Typically the challenge lies in separating deformation from tropospheric phase signals. In this study we performed a statistical comparison of the state-of-the-art tropospheric corrections estimated from the MERIS and MODIS spectrometers, a low and high spatial-resolution weather model (ERA-I and WRF), and both the conventional linear and new power-law empirical methods. Our test-regions include Southern Mexico, Italy, and El Hierro. We find spectrometers give the largest reduction in tropospheric signal, but are limited to cloud-free and daylight acquisitions. We find a ~10–20% RMSE increase with increasing cloud cover consistent across methods. None of the other tropospheric correction methods consistently reduced tropospheric signals over different regions and times. We have released a new software package called TRAIN (Toolbox for Reducing Atmospheric InSAR Noise), which includes all these state-of-the-art correction methods. We recommend future developments should aim towards combining the different correction methods in an optimal manner.
•When available, spectrometers provide the largest tropospheric noise reduction.•Phase-based methods work well when delays are correlated with topography.•On average global weather models are superior to local high-resolution models.•InSAR tropospheric correction methods perform 10–20% worse in the presence of clouds.
Although there is an emerging consensus that the anterior temporal lobes (ATLs) are involved in semantic memory, it is currently unclear which specific parts of this region are implicated in semantic ...representation. Answers to this question are difficult to glean from the existing literature for 3 reasons: 1) lesions of relevant patient groups tend to encompass the whole ATL region; 2) while local effects of repetitive transcranial magnetic stimulation (rTMS) are spatially more specific, only the lateral aspects of the ATL are available to stimulation; and 3) until recently, functional magnetic resonance imaging (fMRI) studies were hindered by technical limitations such as signal distortion and dropout due to magnetic inhomogeneities and also, in some cases, by methodological factors, including a restricted field of view and the choice of baseline contrast for subtraction analysis. By utilizing the same semantic task across semantic dementia, rTMS, and distortion-corrected fMRI in normal participants, we directly compared the results across the 3 methods for the first time. The findings were highly convergent and indicated that crucial regions within the ATL for semantic representation include the anterior inferior temporal gyrus, anterior fusiform gyrus, and the anterior superior temporal sulcus.
We present a large-scale, volume-limited companion survey of 245 late-K to mid-M (K7-M6) dwarfs within 15 pc. Infrared adaptive optics (AO) data were analysed from the Very Large Telescope, Subaru ...Telescope, Canada–France–Hawaii Telescope, and MMT Observatory to detect close companions to the sample from ∼ 1 to 100 au, while digitized wide-field archival plates were searched for wide companions from ∼ 100 to 10 000 au. With sensitivity to the bottom of the main sequence over a separation range of 3 to 10 000 au, multiple AO and wide-field epochs allow us to confirm candidates with common proper motions, minimize background contamination, and enable a measurement of comprehensive binary statistics. We detected 65 comoving stellar companions and find a companion star fraction of 23.5 ± 3.2 per cent over the 3 au to 10 000 au separation range. The companion separation distribution is observed to rise to a higher frequency at smaller separations, peaking at closer separations than measured for more massive primaries. The mass ratio distribution across the q = 0.2–1.0 range is flat, similar to that of multiple systems with solar-type primaries. The characterization of binary and multiple star frequency for low-mass field stars can provide crucial comparisons with star-forming environments and hold implications for the frequency and evolutionary histories of their associated discs and planets.
Background: Researchers have begun to focus on age and sex differences in concussion outcomes. Results suggest that younger athletes and female athletes may take longer to recover from a concussion. ...However, little is known about the interactive effects of age and sex on symptoms, neurocognitive testing (NCT), and postural stability.
Hypothesis/Purpose: The purpose of the study was to examine sex and age differences in symptoms, NCT, and postural stability following concussion. We hypothesized that high school and female athletes would have worse symptoms, NCT, and postural stability than college and male athletes, respectively.
Study Design: Cohort study; Level of evidence, 2.
Methods: A total of 296 concussed athletes from a multistate, 2-year study were enrolled in this study. Participants completed the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) and Post-Concussion Symptom Scale (PCSS) at baseline and again at 2, 7, and 14 days after concussion. Participants completed the Balance Error Scoring System (BESS) at 1, 2, and 3 days after concussion.
Results: Female athletes performed worse than male athletes on visual memory (mean, 65.1% and 70.1%, respectively; P = .049) and reported more symptoms (mean, 14.4 and 10.1, respectively) after concussion (P = .035). High school athletes performed worse than college athletes on verbal (mean, 78.8% and 82.7%, respectively; P = .001) and visual (mean, 65.8% and 69.4%, respectively; P = .01) memory. High school athletes were still impaired on verbal memory 7 days after concussion compared with collegiate athletes (P = .001). High school male athletes scored worse on the BESS than college male athletes (mean, 18.8 and 13.0, respectively; P = .001). College female athletes scored worse on the BESS than high school female athletes (mean, 21.1 and 16.9, respectively; P = .001).
Conclusion: The results of the current study supported age differences in memory and sex differences in memory and symptoms and an interaction between age and sex on postural stability after concussion that warrant consideration from clinicians and researchers when interpreting symptoms, specific components of NCT, and postural stability tests. Future research should develop and assess interventions tailored to age and sex differences and include younger (<14 years) participants.
The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of approx.40 kilometers for Nix ...and Hydra and approx. 10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of approx. 2. All four moons have high albedos (approx.50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.
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