Aims. We aim to characterize the multiwavelength emission from Markarian 501 (Mrk 501), quantify the energy-dependent variability, study the potential multiband correlations, and describe the ...temporal evolution of the broadband emission within leptonic theoretical scenarios. Methods. We organized a multiwavelength campaign to take place between March and July of 2012. Excellent temporal coverage was obtained with more than 25 instruments, including the MAGIC, FACT and VERITAS Cherenkov telescopes, the instruments on board the Swift and Fermi spacecraft, and the telescopes operated by the GASP-WEBT collaboration. Results. Mrk 501 showed a very high energy (VHE) gamma-ray flux above 0.2 TeV of ∼0.5 times the Crab Nebula flux (CU) for most of the campaign. The highest activity occurred on 2012 June 9, when the VHE flux was ∼3 CU, and the peak of the high-energy spectral component was found to be at ∼2 TeV. Both the X-ray and VHE gamma-ray spectral slopes were measured to be extremely hard, with spectral indices < 2 during most of the observing campaign, regardless of the X-ray and VHE flux. This study reports the hardest Mrk 501 VHE spectra measured to date. The fractional variability was found to increase with energy, with the highest variability occurring at VHE. Using the complete data set, we found correlation between the X-ray and VHE bands; however, if the June 9 flare is excluded, the correlation disappears (significance < 3σ) despite the existence of substantial variability in the X-ray and VHE bands throughout the campaign. Conclusions. The unprecedentedly hard X-ray and VHE spectra measured imply that their low- and high-energy components peaked above 5 keV and 0.5 TeV, respectively, during a large fraction of the observing campaign, and hence that Mrk 501 behaved like an extreme high-frequency-peaked blazar (EHBL) throughout the 2012 observing season. This suggests that being an EHBL may not be a permanent characteristic of a blazar, but rather a state which may change over time. The data set acquired shows that the broadband spectral energy distribution (SED) of Mrk 501, and its transient evolution, is very complex, requiring, within the framework of synchrotron self-Compton (SSC) models, various emission regions for a satisfactory description. Nevertheless the one-zone SSC scenario can successfully describe the segments of the SED where most energy is emitted, with a significant correlation between the electron energy density and the VHE gamma-ray activity, suggesting that most of the variability may be explained by the injection of high-energy electrons. The one-zone SSC scenario used reproduces the behavior seen between the measured X-ray and VHE gamma-ray fluxes, and predicts that the correlation becomes stronger with increasing energy of the X-rays.
Little is known about emissions and exposure potential from vat polymerization additive manufacturing, a process that uses light-activated polymerization of a resin to build an object. Five vat ...polymerization printers (three stereolithography (SLA) and two digital light processing (DLP) were evaluated individually in a 12.85 m
3
chamber. Aerosols (number, size) and total volatile organic compounds (TVOC) were measured using real-time monitors. Carbonyl vapors and particulate matter were collected for offline analysis using impingers and filters, respectively. During printing, particle emission yields (#/g printed) ranged from 1.3 ± 0.3 to 2.8 ± 2.6 x 10
8
(SLA printers) and from 3.3 ± 1.5 to 9.2 ± 3.0 x 10
8
(DLP printers). Yields for number of particles with sizes 5.6 to 560 nm (#/g printed) were 0.8 ± 0.1 to 2.1 ± 0.9 x 10
10
and from 1.1 ± 0.3 to 4.0 ± 1.2 x 10
10
for SLA and DLP printers, respectively. TVOC yield values (µg/g printed) ranged from 161 ± 47 to 322 ± 229 (SLA printers) and from 1281 ± 313 to 1931 ± 234 (DLP printers). Geometric mean mobility particle sizes were 41.1-45.1 nm for SLA printers and 15.3-28.8 nm for DLP printers. Mean particle and TVOC yields were statistically significantly higher and mean particle sizes were significantly smaller for DLP printers compared with SLA printers (p < 0.05). Energy dispersive X-ray analysis of individual particles qualitatively identified potential occupational carcinogens (chromium, nickel) as well as reactive metals implicated in generation of reactive oxygen species (iron, zinc). Lung deposition modeling indicates that about 15-37% of emitted particles would deposit in the pulmonary region (alveoli). Benzaldehyde (1.0-2.3 ppb) and acetone (0.7-18.0 ppb) were quantified in emissions from four of the printers and 4-oxopentanal (0.07 ppb) was detectable in the emissions from one printer. Vat polymerization printers emitted nanoscale particles that contained potential carcinogens, sensitizers, and reactive metals as well as carbonyl compound vapors. Differences in emissions between SLA and DLP printers indicate that the underlying technology is an important factor when considering exposure reduction strategies such as engineering controls.
Objective
Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified ...as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP.
Methods
Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations.
Results
Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS‐RP). Patients with VEXAS‐RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS‐RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS‐RP than in RP (23% versus 4%; P = 0.029). Elevated acute‐phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS‐RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103/μl differentiated VEXAS‐RP from RP with 100% sensitivity and 96% specificity.
Conclusion
Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.
The Swift Gamma-Ray Burst Mission Gehrels, N; Chincarini, G; Giommi, P ...
The Astrophysical journal,
08/2004, Letnik:
611, Številka:
2
Journal Article
Recenzirano
The Swift mission, scheduled for launch in 2004, is a multiwavelength observatory for gamma-ray burst (GRB) astronomy. It is a first-of-its-kind autonomous rapid-slewing satellite for transient ...astronomy and pioneers the way for future rapid-reaction and multiwavelength missions. It will be far more powerful than any previous GRB mission, observing more than 100 bursts yr super(-1) and performing detailed X-ray and UV/optical afterglow observations spanning timescales from 1 minute to several days after the burst. The objectives are to (1) determine the origin of GRBs, (2) classify GRBs and search for new types, (3) study the interaction of the ultrarelativistic outflows of GRBs with their surrounding medium, and (4) use GRBs to study the early universe out to z > 10. The mission is being developed by a NASA-led international collaboration. It will carry three instruments: a new-generation wide-field gamma-ray (15-150 keV) detector that will detect bursts, calculate 1arcmin-4arcmin positions, and trigger autonomous spacecraft slews; a narrow-field X-ray telescope that will give 5arc sec positions and perform spectroscopy in the 0.2-10 keV band; and a narrow-field UV/optical telescope that will operate in the 170-600 nm band and provide 0!!3 positions and optical finding charts. Redshift determinations will be made for most bursts. In addition to the primary GRB science, the mission will perform a hard X-ray survey to a sensitivity of approx1 mcrab (approx2 x 10 super(-11) ergs cm super(-2) s super(-1) in the 15-150 keV band), more than an order of magnitude better than HEAO 1 A-4. A flexible data and operations system will allow rapid follow-up observations of all types of high-energy transients, with rapid data downlink and uplink available through the NASA TDRSS system. Swift transient data will be rapidly distributed to the astronomical community, and all interested observers are encouraged to participate in follow- up measurements. A Guest Investigator program for the mission will provide funding for community involvement. Innovations from the Swift program applicable to the future include (1) a large-area gamma-ray detector using the new CdZnTe detectors, (2) an autonomous rapid-slewing spacecraft, (3) a multiwavelength payload combining optical, X-ray, and gamma-ray instruments, (4) an observing program coordinated with other ground-based and space-based observatories, and (5) immediate multiwavelength data flow to the community. The mission is currently funded for 2 yr of operations, and the spacecraft will have a lifetime to orbital decay of approx8 yr.
End-ischemic ex situ normothermic machine perfusion (NMP) enables assessment of donor livers prior to transplantation. The objective of this study was to provide support for bile composition as a ...marker of biliary viability and to investigate whether bile ducts of high-risk human donor livers already undergo repair during NMP.
Forty-two livers that were initially declined for transplantation were included in our NMP clinical trial. After NMP, livers were either secondary declined (n = 17) or accepted for transplantation (n = 25) based on the chemical composition of bile and perfusate samples. Bile duct biopsies were taken before and after NMP and assessed using an established histological injury severity scoring system and a comprehensive immunohistochemical assessment focusing on peribiliary glands (PBGs), vascular damage, and regeneration.
Bile ducts of livers that were transplanted after viability testing during NMP showed better preservation of PBGs, (micro)vasculature, and increased cholangiocyte proliferation, compared with declined livers. Biliary bicarbonate, glucose, and pH were confirmed as accurate biomarkers of bile duct vitality. In addition, we found evidence of PBG-based progenitor cell differentiation toward mature cholangiocytes during NMP.
Favorable bile chemistry during NMP correlates well with better-preserved biliary microvasculature and PBGs, with a preserved capacity for biliary regeneration. During NMP, biliary tree progenitor cells start to differentiate toward mature cholangiocytes, facilitating restoration of the ischemically damaged surface epithelium.
Anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) favorably affects diabetic retinopathy (DR) improvement and worsening. It is unknown whether these effects ...differ across anti-VEGF agents.
To compare changes in DR severity during aflibercept, bevacizumab, or ranibizumab treatment for DME.
Preplanned secondary analysis of data from a comparative effectiveness trial for center-involved DME was conducted in 650 participants receiving aflibercept, bevacizumab, or ranibizumab. Retinopathy improvement and worsening were determined during 2 years of treatment. Participants were randomized in 2012 through 2013, and the trial concluded on September 23, 2015.
Random assignment to aflibercept, 2.0 mg; bevacizumab, 1.25 mg; ranibizumab, 0.3 mg, up to every 4 weeks through 2 years following a retreatment protocol.
Percentages with retinopathy improvement at 1 and 2 years and cumulative probabilities for retinopathy worsening through 2-year without adjustment for multiple outcomes.
A total of 650 participants (495 76.2% nonproliferative DR NPDR, 155 proliferative DR PDR) were analyzed; 302 (46.5%) were women and mean (SD) age was 61 (10) years; 425 (65.4%) were white. At 1 year, among 423 NPDR eyes, 44 of 141 (31.2%) treated with aflibercept, 29 of 131 (22.1%) with bevacizumab, and 57 of 151 (37.7%) with ranibizumab had improvement of DR severity (adjusted difference: 11.7%; 95% CI, 2.9% to 20.6%; P = .004 for aflibercept vs bevacizumab; 8.9%; 95% CI, 1.7% to 16.1%; P = .01 for ranibizumab vs bevacizumab; and 2.9%; 95% CI, -5.7% to 11.4%; P = .51 for aflibercept vs ranibizumab). At 2 years, 33 eyes (24.8%) in the aflibercept group, 25 eyes (22.1%) in the bevacizumab group, and 40 eyes (31.0%) in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab (adjusted difference: 50.4%; 95% CI, 26.8% to 74.0%; P < .001 for aflibercept vs bevacizumab; 20.4%; 95% CI, -3.1% to 44.0%; P = .09 for ranibizumab vs bevacizumab; and 30.0%; 95% CI, 4.4% to 55.6%; P = .02 for aflibercept vs ranibizumab). These rates and treatment group differences appeared to be maintained at 2 years. Despite the reduced numbers of injections in the second year, 66 (59.5%) of NPDR and 28 (70.0%) of PDR eyes that manifested improvement at 1 year maintained improvement at 2 years. Two-year cumulative rates for retinopathy worsening ranged from 7.1% to 10.2% and 17.2% to 26.4% among anti-VEGF groups for NPDR and PDR eyes, respectively. No statistically significant treatment differences were noted.
At 1 and 2 years, eyes with NPDR receiving anti-VEGF treatment for DME may experience improvement in DR severity. Less improvement was demonstrated with bevacizumab at 1 year than with aflibercept or ranibizumab. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with PDR at baseline. All 3 anti-VEGF treatments were associated with low rates of DR worsening. These data provide additional outcomes that might be considered when choosing an anti-VEGF agent to treat DME.
Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well ...as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.
T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8
T cell ...differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8
T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8
T cells demonstrate superior pathogen control. Genome-wide methylation analysis identified a number of differentially methylated regions in TET2-deficient versus wild-type CD8
T cells. These differentially methylated regions did not occur at the loci of differentially expressed memory markers; rather, several hypermethylated regions were identified in known transcriptional regulators of CD8
T cell memory fate. Together, these data demonstrate that TET2 is an important regulator of CD8
T cell fate decisions.
The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium ...aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.
We present the discovery and validation of two TESS exoplanets orbiting nearby M dwarfs: TOI-2084 b, and TOI-4184b. We characterized the host stars by combining spectra from
Shane
/Kast and
Magellan
.../FIRE, spectral energy distribution analysis, and stellar evolutionary models. In addition, we used Gemini-South/Zorro & -North/Alopeke high-resolution imaging, archival science images, and statistical validation packages to support the planetary interpretation. We performed a global analysis of multi-colour photometric data from TESS and ground-based facilities in order to derive the stellar and planetary physical parameters for each system. We find that TOI-2084 band TOI-4184 bare sub-Neptune-sized planets with radii of
R
p
= 2.47 ± 0.13
R
⊕
and
R
p
= 2.43 ± 0.21
R
⊕
, respectively. TOI-2084 b completes an orbit around its host star every 6.08 days, has an equilibrium temperature of
T
eq
= 527 ± 8 K and an irradiation of
S
p
= 12.8 ± 0.8
S
⊕
. Its host star is a dwarf of spectral M2.0 ± 0.5 at a distance of 114 pc with an effective temperature of
T
eff
= 3550 ± 50 K, and has a wide, co-moving M8 companion at a projected separation of 1400 au. TOI-4184 b orbits around an M5.0 ± 0.5 type dwarf star (
K
mag
= 11.87) each 4.9 days, and has an equilibrium temperature of
T
eq
= 412 ± 8 K and an irradiation of
S
p
= 4.8 ± 0.4
S
⊕
. TOI-4184 is a metal poor star (Fe/H = −0.27 ± 0.09 dex) at a distance of 69 pc with an effective temperature of
T
eff
= 3225 ± 75 K. Both planets are located at the edge of the sub-Jovian desert in the radius-period plane. The combination of the small size and the large infrared brightness of their host stars make these new planets promising targets for future atmospheric exploration with JWST.
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