NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide ...mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.
Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary ...metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .
The December 2019 outbreak of coronavirus has once again thrown the vexed issue of quarantine into the spotlight, with many countries asking their citizens to ‘self-isolate’ if they have potentially ...come into contact with the infection. However, adhering to quarantine is difficult. Decisions on how to apply quarantine should be based on the best available evidence to increase the likelihood of people adhering to protocols. We conducted a rapid review to identify factors associated with adherence to quarantine during infectious disease outbreaks.
The study design is a rapid evidence review.
We searched Medline, PsycINFO and Web of Science for published literature on the reasons for and factors associated with adherence to quarantine during an infectious disease outbreak.
We found 3163 articles and included 14 in the review. Adherence to quarantine ranged from as little as 0 up to 92.8%. The main factors which influenced or were associated with adherence decisions were the knowledge people had about the disease and quarantine procedure, social norms, perceived benefits of quarantine and perceived risk of the disease, as well as practical issues such as running out of supplies or the financial consequences of being out of work.
People vary in their adherence to quarantine during infectious disease outbreaks. To improve this, public health officials should provide a timely, clear rationale for quarantine and information about protocols; emphasise social norms to encourage this altruistic behaviour; increase the perceived benefit that engaging in quarantine will have on public health; and ensure that sufficient supplies of food, medication and other essentials are provided.
•Adherence to quarantine can be difficult, and adherence rates are variable.•Adherence can be affected by perceived risks and social norms.•Knowledge about quarantine protocol is essential.•Public health benefits of quarantine must be made clear.
The purpose of this study was to determine the effects of a 1-h exposure to 2.0 atm abs (202.6 kPa) and 100% oxygen on subsequent maximal O2 consumption (VO2max), ventilation threshold (VT), lactate ...threshold (LT), and muscle oxygenation (%Mox) during incremental exercise to maximum on a cycle ergometer. Two baseline exercise tests (T1 and T2) were performed on separate occasions without prior exposure to hyperbaric oxygen (HBO2) and a third test (T3-HBO2) was performed after (22.5 +/- 5.6 min) HBO2 Near infared spectroscopy was used to monitor oxygenation of the left vastus lateralis muscle during T2 and T3-HBO2. No significant differences were observed between VO2max VT, or LT among any of the exercise tests. There was no significant difference in %Mox between T2 and T3-HBO2 except at 235 W where there was a significant elevation in %Mox during T3-HBO2 relative to T2. These results suggest that prior exposure to HBO2 (100% O2 at 2 atm abs for 1 h) has no ergogenic effect on subsequent incremental exercise performance.
Congenic mouse strains provide a unique resource for genetic dissection and biological characterization of chromosomal regions associated with diabetes progression in the nonobese diabetic (NOD) ...mouse. Idd11, a mouse diabetes susceptibility locus, was previously localized to a region on chromosome 4. Comparison of a panel of subcongenic NOD mouse strains with different intervals derived from the nondiabetic C57BL/6 (B6) strain now maps Idd11 to an approximately 8-Mb interval. B6-derived intervals protected congenic NOD mice from diabetes onset, even though lymphocytic infiltration of pancreatic islets was similar to that found in NOD mice. In addition, neither thymic structural irregularities nor NKT cell deficiencies were ameliorated in diabetes-resistant congenic NOD mice, indicating that Idd11 does not contribute to these abnormalities, which do not need to be corrected to prevent disease.
We present early results from a project to measure the sky-averaged (global), redshifted \(21\,\)cm signal from the Epoch of Reionisation (EoR), using the Murchison Widefield Array (MWA) telescope. ...Because interferometers are not sensitive to a spatially-invariant global average, they cannot be used to detect this signal using standard techniques. However, lunar occultation of the radio sky imprints a spatial structure on the global signal, allowing us to measure the average brightness temperature of the patch of sky immediately surrounding the Moon. In this paper we present one night of Moon observations with the MWA between 72 - 230 MHz and verify our techniques to extract the background sky temperature from measurements of the Moon's flux density. We improve upon previous work using the lunar occultation technique by using a more sophisticated model for reflected `earthshine' and by employing image differencing to remove imaging artefacts. We leave the Moon's (constant) radio brightness temperature as a free parameter in our fit to the data and as a result, measure \(T_{\rm{moon}} = 180 \pm 12 \) K and a Galactic synchrotron spectral index of \(-2.64\pm0.14\), at the position of the Moon. Finally, we evaluate the prospects of the lunar occultation technique for a global EoR detection and map out a way forward for future work with the MWA.
We present new spectroscopy of the z=3.62 gravitationally lensed quasar B1422+117 from the Gemini North GMOS integral field spectrograph. We observe significant differential magnifications between ...the broad emission lines and the continuum, as well as across the velocity structure of the Lyman-alpha line. We take advantage of this differential microlensing to algebraically decompose the quasar spectrum into the absorbed broad emission line and absorbed continuum components. We use the latter to derive the intrinsic Ly-alpha forest absorption spectrum. The proximity effect is clearly detected, with a proximity zone edge of 8.6-17.3 Mpc from the quasar, implying (perhaps intermittent) activity over at least 28 Myrs. The Ly-alpha line profile exhibits a blue excess that is inconsistent with a symmetric fit to the unabsorbed red side. This has important implications for the use of this fitting technique in estimating the absorbed blue Ly-alpha wings of Gunn-Peterson trough quasars.
We report near simultaneous imaging using LMIRCam on the LBTI of the quadruply imaged lensed quasar HS 0810+2554 at wavelengths of 2.16, 3.7 and \(4.78~\mu\)m with a Full Width Half Max (FWHM) ...spatial resolution of \(0^{\prime\prime}\!\!.13\), \(0^{\prime\prime}\!\!.12\) and \(0^{\prime\prime}\!\!.15\) respectively, comparable to HST optical imaging. In the \(\rm{z} = 1.5\) rest frame of the quasar, the observed wavelengths correspond to 0.86, 1.48, and \(1.91~\mu\)m respectively. The two brightest images in the quad, A and B, are clearly resolved from each other with a separation of \(0.187^{\prime\prime}\). The flux ratio of these two images (A/B) trends from 1.79 to 1.23 from 2.16 to \(4.78~\mu\)m. The trend in flux ratio is consistent with the \(2.16~\mu\)m flux originating from a small sized accretion disk in the quasar that experiences only microlensing. The excess flux above the contribution from the accretion disk at the two longer wavelengths originates from a larger sized region that experiences no microlensing. A simple model employing multiplicative factors for image B due to stellar microlensing \((m)\) and sub-structure millilensing \((M)\) is presented. The result is tightly constrained to the product \(m\times M=1.79\). Given the observational errors, the 60\% probability contour for this product stretches from \(m= 2.6\), \(M = 0.69\) to \(m= 1.79\), \(M = 1.0\), where the later is consistent with microlensing only.
We present a climatology of O
3
, CO, and H
2
O for the upper troposphere and lower stratosphere (UTLS), based on a large collection of high‐resolution research aircraft data taken between 1995 and ...2008. To group aircraft observations with sparse horizontal coverage, the UTLS is divided into three regimes: the tropics, subtropics, and the polar region. These regimes are defined using a set of simple criteria based on tropopause height and multiple tropopause conditions. Tropopause‐referenced tracer profiles and tracer‐tracer correlations show distinct characteristics for each regime, which reflect the underlying transport processes. The UTLS climatology derived here shows many features of earlier climatologies. In addition, mixed air masses in the subtropics, identified by O
3
‐CO correlations, show two characteristic modes in the tracer‐tracer space that are a result of mixed air masses in layers above and below the tropopause (TP). A thin layer of mixed air (1–2 km around the tropopause) is identified for all regions and seasons, where tracer gradients across the TP are largest. The most pronounced influence of mixing between the tropical transition layer and the subtropics was found in spring and summer in the region above 380 K potential temperature. The vertical extent of mixed air masses between UT and LS reaches up to 5 km above the TP. The tracer correlations and distributions in the UTLS derived here can serve as a reference for model and satellite data evaluation.
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