More than 50 y of research have provided great insight into the physiology, metabolism, and molecular biology of Salmonella enterica serovar Typhimurium (S. Typhimurium), but important gaps in our ...knowledge remain. It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites (TSSs) has been lacking. We combined three RNA-sequencing techniques and two sequencing platforms to generate a robust picture of transcription in S. Typhimurium. Differential RNA sequencing identified 1,873 TSSs on the chromosome of S. Typhimurium SL1344 and 13% of these TSSs initiated antisense transcripts. Unique findings include the TSSs of the virulence regulators phoP, slyA, and invF. Chromatin immunoprecipitation revealed that RNA polymerase was bound to 70% of the TSSs, and two-thirds of these TSSs were associated with σ70 (including phoP, slyA, and invF) from which we identified the –10 and –35 motifs of σ70-dependent S. Typhimurium gene promoters. Overall, we corrected the location of important genes and discovered 18 times more promoters than identified previously. S. Typhimurium expresses 140 small regulatory RNAs (sRNAs) at early stationary phase, including 60 newly identified sRNAs. Almost half of the experimentally verified sRNAs were found to be unique to the Salmonella genus, and <20% were found throughout the Enterobacteriaceae. This description of the transcriptional map of SL1344 advances our understanding of S. Typhimurium, arguably the most important bacterial infection model.
Although pre-revascularization ischaemia testing is recommended, the interaction between the extent of ischaemia and myocardial scar with performance of revascularization on patient survival is ...unclear.
We identified 13 969 patients who underwent adenosine or exercise stress SPECT myocardial perfusion scintigraphy (MPS). The percent myocardium ischaemic (%I) and fixed (%F) were calculated using 5 point/20-segment MPS scoring. Patients lost to follow-up (2.8%) were excluded leaving 13 555 patients 35% with history (Hx) of known coronary artery disease (CAD), 65% exercise stress, 61% male, age 66 ± 12. Follow-up was performed at 12-18 months for early revascularization and at >7 years for all-cause death (ACD) (mean follow-up 8.7 ± 3.3 years). All-cause death was modelled using Cox proportional hazards modelling adjusting for logistic-based propensity scores, MPS, revascularization, and baseline characteristics. During FU, 3893 ACD (29%, 3.3%/year) and 1226 early revascularizations (9.0%) occurred. After risk-adjustment, a three-way interaction was present between %I, early revascularization, and HxCAD, such that %I identified a survival benefit with early revascularization in patients without prior myocardial infarction (MI), whereas no such benefit was present in patients with prior MI (overall model χ(2)= 3932, P < 0.001; interaction P < 0.021). Further modelling revealed that after excluding patients with scar >10% total myocardium, %I identified a survival benefit in all patients.
In this large observational series with long-term follow-up, patients with significant ischaemia and without extensive scar were likely to realize a survival benefit from early revascularization. In contrast, the survival of patients with minimal ischaemia was superior with medical therapy without early revascularization.
In situ measurements of the mass, mixing state, and optical size of individual black‐carbon (BC) particles in the fine mode (90–600 nm) have been made in fresh emissions from urban and biomass ...burning sources with an airborne single‐particle soot photometer. Contrasts between the two sources are significant and consistent. Urban BC tends to smaller sizes, fewer coated particles, thinner coatings, and less absorption per unit mass than biomass‐burning BC. This suggests that urban BC may have a longer lifetime in the atmosphere and a different impact on BC radiative forcing in the first indirect effect than biomass‐burning BC. These measurements bound the likely variability in the microphysical state of BC emissions from typical continental processes, and provide direct measurements of the size distribution and coating state of fine‐mode BC for use in constraining climate and aerosol models. These results highlight the need for the integration of source‐specific information into such models.
A single-particle soot photometer (SP2) was flown on a NASA WB-57F high-altitude research aircraft in November 2004 from Houston, Texas. The SP2 uses laser-induced incandescence to detect individual ...black carbon (BC) particles in an air sample in the mass range of approx.3-300 fg (approx.0.15-0.7 microns volume equivalent diameter). Scattered light is used to size the remaining non-BC aerosols in the range of approx.0.17-0.7 microns diameter. We present profiles of both aerosol types from the boundary layer to the lower stratosphere from two midlatitude flights. Results for total aerosol amounts in the size range detected by the SP2 are in good agreement with typical particle spectrometer measurements in the same region. All ambient incandescing particles were identified as BC because their incandescence properties matched those of laboratory-generated BC aerosol. Approximately 40% of these BC particles showed evidence of internal mixing (e.g., coating). Throughout profiles between 5 and 18.7 km, BC particles were less than a few percent of total aerosol number, and black carbon aerosol (BCA) mass mixing ratio showed a constant gradient with altitude above 5 km. SP2 data was compared to results from the ECHAM4/MADE and LmDzT-INCA global aerosol models. The comparison will help resolve the important systematic differences in model aerosol processes that determine BCA loadings. Further intercomparisons of models and measurements as presented here will improve the accuracy of the radiative forcing contribution from BCA.
BACKGROUND Whereas studies have revealed that the cryopreservation of human semen increases sperm DNA fragmentation, the mechanisms involved in this type of cryo-injury are largely unknown. ...Elucidation of these mechanisms may provide insight into preventing such injury. METHODS We obtained 60 semen samples from 60 men and conducted experiments to determine the cause of cryopreservation-induced DNA fragmentation using 8-oxo-7,8-dihydro-2′deoxyguanosine (8OHdG) as a biomarker of oxidative stress, percentage caspase positive cells as an indicator of apoptosis, the potential antioxidant genistein and the caspase inhibitor Z-VAD(OMe)-FMK. RESULTS Cryopreservation led to a significant increase in percentage DNA fragmentation, percentage 8OHdG and percentage caspase positive cells (P < 0.001). Percentage DNA fragmentation was positively correlated with percentage 8OHdG before (r = 0.756, P < 0.001) and after cryopreservation (r = 0.528, P = 0.017). The addition of 50 and 100 µM genistein to the cryoprotectant had a significant protective effect on sperm DNA (P < 0.001) although the caspase inhibitor demonstrated no difference to the control. CONCLUSIONS Human sperm DNA fragmentation is associated with an increase in oxidative stress during cryopreservation, rather than the activation of caspases and apoptosis. The estrogenic compound genistein may be useful in reducing this effect but larger trials are needed to confirm this.
We report the results of a search for ν(e) appearance in a ν(μ) beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2 × 10(20) protons on the ...NuMI target at Fermilab, we find that 2 sin(2) (θ(23))sin(2)(2θ(13))<0.12(0.20) at 90% confidence level for δ = 0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin(2) (θ(23))sin(2)(2θ(13)) = 0.041(-0.031)(+0.047) (0.079(-0.053) (+0.071)). The θ(13) = 0 hypothesis is disfavored by the MINOS data at the 89% confidence level.
This article addresses the need for new data on indirect effects of natural and anthropogenic aerosol particles on atmospheric ice clouds. Simultaneous measurements of the concentration and ...composition of tropospheric aerosol particles capable of initiating ice in cold (cirrus) clouds are reported. Measurements support that cirrus formation occurs both by heterogeneous nucleation by insoluble particles and homogeneous (spontaneous) freezing of particles containing solutions. Heterogeneous ice nuclei concentrations in the cirrus regime depend on temperature, relative humidity, and the concentrations and physical and chemical properties of aerosol particles. The cirrus-active concentrations of heterogeneous nuclei measured in November over the western U.S. were$<\!0.03\>cm^{-3}$. Considering previous modeling studies, this result suggests a predominant potential impact of these nuclei on cirrus formed by slow, large-scale lifting or small cooling rates, including subvisual cirrus. The most common heterogeneous ice nuclei were identified as relatively pure mineral dusts and metallic particles, some of which may have origin through anthropogenic processes. Homogeneous freezing of large numbers of particles was detected above a critical relative humidity along with a simultaneous transition in nuclei composition toward that of the sulfate-dominated total aerosol population. The temperature and humidity conditions of the homogeneous nucleation transition were reasonably consistent with expectations based on previous theoretical and laboratory studies but were highly variable. The strong presence of certain organic pollutants was particularly noted to be associated with impedance of homogeneous freezing.
The Particle Analysis by Laser Mass Spectrometry (PALMS) instrument has measured the composition of single particles during a number of airborne and ground‐based campaigns. In the regions studied, ...30% to over 80% of the aerosol mass in the free troposphere was carbonaceous material. Most of this carbonaceous material was probably organic. Although there were variations in their amounts, over 90% of accumulation mode particles away from local sources were internal mixtures of sulfates and carbonaceous material. Within this internal mixing, there was variation in the pattern of carbonaceous peaks in the spectra, especially in peaks related to organic acids. Particles with a biomass burning signature were a significant fraction of accumulation mode particles even far from fires. The accumulation mode near the ocean surface off the coasts of California and New England had significant numbers of carbonaceous‐sulfate particles whereas at Cape Grim, Tasmania, the organic‐sulfate particles were apparently all smaller than 160 nm. Three kinds of nitrate were evident: on mineral particles, on carbonaceous‐sulfate particles when the sulfate was fully neutralized, and at temperatures below about 198 K. Most mineral particles showed evidence of the uptake of nitrates and chloride. A peak that probably represents protonated pyridine appears in some spectra in the free troposphere.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current ...classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.
Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed.
We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA.
The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
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