The major nutrients available to human colonic Bacteroides species are glycans, exemplified by pectins, a network of covalently linked plant cell wall polysaccharides containing galacturonic acid ...(GalA). Metabolism of complex carbohydrates by the Bacteroides genus is orchestrated by polysaccharide utilization loci (PULs). In Bacteroides thetaiotaomicron, a human colonic bacterium, the PULs activated by different pectin domains have been identified; however, the mechanism by which these loci contribute to the degradation of these GalA-containing polysaccharides is poorly understood. Here we show that each PUL orchestrates the metabolism of specific pectin molecules, recruiting enzymes from two previously unknown glycoside hydrolase families. The apparatus that depolymerizes the backbone of rhamnogalacturonan-I is particularly complex. This system contains several glycoside hydrolases that trim the remnants of other pectin domains attached to rhamnogalacturonan-I, and nine enzymes that contribute to the degradation of the backbone that makes up a rhamnose-GalA repeating unit. The catalytic properties of the pectin-degrading enzymes are optimized to protect the glycan cues that activate the specific PULs ensuring a continuous supply of inducing molecules throughout growth. The contribution of Bacteroides spp. to metabolism of the pectic network is illustrated by cross-feeding between organisms.
Summary Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of ...global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67·2%) occurred from December to March, and the overall case-fatality risk was 483 (53·5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases.
We analyze the kinematics of Andromeda's disk as a function of stellar age by using photometry from the Panchromatic Hubble Andromeda Treasury survey and spectroscopy from the Spectroscopic and ...Photometric Landscape of Andromeda's Stellar Halo survey. We use H i 21 cm and CO ( ) data to examine the difference between the deprojected rotation velocity of the gas and that of the stars. We divide the stars into four stellar age bins, from shortest lived to longest lived: massive main-sequence stars (0.03 Gyr), more luminous intermediate-mass asymptotic giant branch (AGB) stars (0.4 Gyr), less luminous intermediate-mass AGB stars (2 Gyr), and low-mass red giant branch stars (4 Gyr). There is a clear correlation between the offset of the stellar and the gas rotation velocity, or the asymmetric drift: the longer-lived populations lag farther behind the gas than short-lived populations. We also examine possible causes of the substructure in the rotation curves (RCs) and find that the most significant cause of scatter in the RCs comes from the tilted ring model being an imperfect way to account for the multiple warps in Andromeda's disk.
This study answers a critical question facing the energy sector in the United States: how does natural gas compare to coal as a climate change mitigation technique? Although natural gas burns cleaner ...than coal, methane leakage potentially undermines the climate benefits of fuel switching. This study investigates the impact of methane leakage using a novel plant-level lifecycle emissions inventory of greenhouse gas emissions associated with coal mining, transportation, and combustion at 337 existing coal power plants in the United States. Individual plant emissions rates ranged from 901 to more than 2200 kgCO2e/MWh (100-yr GWP); generation-weighted average was 1046 kgCO2e/MWh. Our study finds that the “breakeven” leakage rates for natural gas to have short and long term climate benefits over coal range from 4.4 to 20.9%, depending on the timeframe, plant efficiency, and upstream coal emissions. Emissions benefits can be maximized by replacing highest emitting coal plants with new natural gas plants. Finally, we find fugitive methane emissions can limit carbon reductions from natural gas carbon capture; above 2% leakage, methane leakage reduces CCS benefits by up to half for 20-yr GWP.
•The US coal fleet has large variations in plant-level LCA emissions.•Likely large emissions benefits from replacing with natural gas.•US natural gas plants are relatively efficient.•Methane leakage reduces benefits, depending on efficiency.
We age-date the stellar populations associated with 12 historic nearby core-collapse supernovae (CCSNe) and two supernova impostors; from these ages, we infer their initial masses and associated ...uncertainties. To do this, we have obtained new Hubble Space Telescope imaging covering these CCSNe. Using these images, we measure resolved stellar photometry for the stars surrounding the locations of the SNe. We then fit the color-magnitude distributions of this photometry with stellar evolution models to determine the ages of any young existing populations present. From these age distributions, we infer the most likely progenitor masses for all of the SNe in our sample. We find ages between 4 and 50 Myr, corresponding to masses from 7.5 to 59 solar masses. There were no SNe that lacked a local young population. Our sample contains four SNe Ib/c; their masses have a wide range of values, suggesting that the progenitors of stripped-envelope SNe are binary systems. Both impostors have masses constrained to be 7.5 solar masses. In cases with precursor imaging measurements, we find that age-dating and precursor imaging give consistent progenitor masses. This consistency implies that, although the uncertainties for each technique are significantly different, the results of both are reliable to the measured uncertainties. We combine these new measurements with those from our previous work and find that the distribution of 25 core-collapse SNe progenitor masses is consistent with a standard Salpeter power-law mass function, no upper mass cutoff, and an assumed minimum mass for core-collapse of 7.5 M . The distribution is consistent with a minimum mass <9.5 M .
Abstract
Aim
The long-term prognostic benefit of coronary computed tomographic angiography (CCTA) findings of coronary artery disease (CAD) in asymptomatic populations is unknown.
Methods and results
...From the prospective multicentre international CONFIRM long-term study, we evaluated asymptomatic subjects without known CAD who underwent both coronary artery calcium scoring (CACS) and CCTA (n = 1226). Coronary computed tomographic angiography findings included the severity of coronary artery stenosis, plaque composition, and coronary segment location. Using the C-statistic and likelihood ratio tests, we evaluated the incremental prognostic utility of CCTA findings over a base model that included a panel of traditional risk factors (RFs) as well as CACS to predict long-term all-cause mortality. During a mean follow-up of 5.9 ± 1.2 years, 78 deaths occurred. Compared with the traditional RF alone (C-statistic 0.64), CCTA findings including coronary stenosis severity, plaque composition, and coronary segment location demonstrated improved incremental prognostic utility beyond traditional RF alone (C-statistics range 0.71–0.73, all P < 0.05; incremental χ2 range 20.7–25.5, all P < 0.001). However, no added prognostic benefit was offered by CCTA findings when added to a base model containing both traditional RF and CACS (C-statistics P > 0.05, for all).
Conclusions
Coronary computed tomographic angiography improved prognostication of 6-year all-cause mortality beyond a set of conventional RF alone, although, no further incremental value was offered by CCTA when CCTA findings were added to a model incorporating RF and CACS.
Polyoma virus (Py) and simian virus 40 (SV40) travel from the plasma membrane to the endoplasmic reticulum (ER) from where they enter the cytosol and then the nucleus to initiate infection. Here we ...demonstrate that specific gangliosides can serve as plasma membrane receptors for these viruses, GD1a and GT1b for Py and GM1 for SV40. Binding and flotation assays were used to show that addition of these gangliosides to phospholipid vesicles allowed specific binding of the respective viruses. The crystal structure of polyoma VP1 with a sialic acid‐containing oligosaccharide was used to derive a model of how the two terminal sugars (sialic acid‐α2,3‐galactose) in one branch of GD1a and GT1b are recognized by the virus. A rat cell line deficient in ganglioside synthesis is poorly infectible by polyoma and SV40, but addition of the appropriate gangliosides greatly facilitates virus uptake, transport to the ER and infection. Lipid binding sites for polyoma are shown to be present in rough ER membranes, suggesting that the virus travel with the ganglioside(s) from the plasma membranes to the ER.
Prior evidence observed no predictive utility of coronary CT angiography (CCTA) over the coronary artery calcium score (CACS) and the Framingham risk score (FRS), among asymptomatic individuals. ...Whether the prognostic value of CCTA differs for asymptomatic patients, when stratified by CACS severity, remains unknown.
From a 12-centre, 6-country observational registry, 3217 asymptomatic individuals without known coronary artery disease (CAD) underwent CACS and CCTA. Individuals were categorized by CACS as: 0-10, 11-100, 101-400, 401-1000, >1000. For CCTA analysis, the number of obstructive vessels-as defined by the per-patient presence of a ≥50% luminal stenosis-was used to grade the extent and severity of CAD. The incremental prognostic value of CCTA over and above FRS was measured by the likelihood ratio (LR) χ(2), C-statistic, and continuous net reclassification improvement (NRI) for prediction, discrimination, and reclassification of all-cause mortality and non-fatal myocardial infarction. During a median follow-up of 24 months (25th-75th percentile, 17-30 months), there were 58 composite end-points. The incremental value of CCTA over FRS was demonstrated in individuals with CACS >100 (LRχ(2), 25.34; increment in C-statistic, 0.24; NRI, 0.62, all P < 0.001), but not among those with CACS ≤100 (all P > 0.05). For subgroups with CACS >100, the utility of CCTA for predicting the study end-point was evident among individuals whose CACS ranged from 101 to 400; the observed predictive benefit attenuated with increasing CACS.
Coronary CT angiography provides incremental prognostic utility for prediction of mortality and non-fatal myocardial infarction for asymptomatic individuals with moderately high CACS, but not for lower or higher CACS.
Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung ...pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.
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•Lungs from cystic fibrosis patients were dissected to obtain regional P. aeruginosa•Clonally related P. aeruginosa from different lung regions differed phenotypically•Phylogenetics shows regional bacteria evolve in isolation and mixing is limited•Isolation drives divergent evolution of P. aeruginosa in cystic fibrosis infections
P. aeruginosa genetically diversifies during cystic fibrosis infections. However, the mechanisms producing diversification are unknown. Jorth et al. demonstrate that clonally related P. aeruginosa inhabiting different lung regions differ phenotypically and evolve divergently. Thus, isolation in different organ regions can contribute to pathogen genetic diversification within a human host.
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with ...variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial.
We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation.
A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio HR 0.80 0.65-0.98, P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 0.50-0.85, P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 0.71-1.19, P = .52), including the MGMT methylated subgroup (HR = 0.89 0.63-1.26, P = .51).
Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.
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