72 research outputs found
Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents
Background Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. Methods A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. Results The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which selexipag may be considered as a treatment option. Conclusions The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH
Subcellular localization of Mitf in monocytic cells
Microphthalmia-associated transcription factor (Mitf) is a transcription factor that plays an important role in regulating the development of several cell lineages. The subcellular localization of Mitf is dynamic and is associated with its transcription activity. In this study, we examined factors that affect its subcellular localization in cells derived from the monocytic lineage since Mitf is present abundantly in these cells. We identified a domain encoded by Mitf exon 1B1b to be important for Mitf to commute between the cytoplasm and the nucleus. Deletion of this domain disrupts the shuttling of Mitf to the cytoplasm and results in its retention in the nucleus. M-CSF and RANKL both induce nuclear translocation of Mitf. We showed that Mitf nuclear transport is greatly influenced by ratio of M-CSF/Mitf protein expression. In addition, cell attachment to a solid surface also is needed for the nuclear transport of Mitf
JADES NIRSpec Spectroscopy of GN-z11: Lyman- emission and possible enhanced nitrogen abundance in a luminous galaxy
We present JADES JWST/NIRSpec spectroscopy of GN-z11, the most luminous
candidate Lyman break galaxy in the GOODS-North field with
. We derive a redshift of (lower than previous
determinations) based on multiple emission lines in our low and medium
resolution spectra over m. We significantly detect the continuum
and measure a blue rest-UV spectral slope of . Remarkably, we see
spatially-extended Lyman- in emission (despite the highly-neutral IGM
expected at this early epoch), offset 555 km/s redward of the systemic
redshift. From our measurements of collisionally-excited lines of both low- and
high-ionization (including [O II] , [Ne III] and C
III] ) we infer a high ionization parameter (). We
detect the rarely-seen N IV] and N III] lines in
both our low and medium resolution spectra, with other high ionization lines
seen in low resolution spectrum such as He II (blended with O III]) and C IV
(with a possible P-Cygni profile). Based on the observed rest-UV line ratios,
we cannot conclusively rule out photoionization from AGN. The high C III]/He II
ratios, however, suggest a likely star-formation explanation. If the observed
emission lines are powered by star formation, then the strong N III]
observed may imply an unusually high abundance. Balmer
emission lines (H, H) are also detected, and if powered by star
formation rather than an AGN we infer a star formation rate of (depending on the IMF) and low dust attenuation. Our
NIRSpec spectroscopy confirms that GN-z11 is a remarkable galaxy with extreme
properties seen 430 Myr after the Big Bang.Comment: Submitted to Astronomy & Astrophysics, 14 pages, 9 figure
JWST reveals a possible galaxy merger in triply-lensed MACS0647JD
MACS0647JD is a triply-lensed galaxy originally discovered with
the Hubble Space Telescope. Here we report new JWST imaging, which clearly
resolves MACS0647JD as having two components that are either merging
galaxies or stellar complexes within a single galaxy. Both are very small, with
stellar masses and radii . The brighter
larger component "A" is intrinsically very blue (), likely due
to very recent star formation and no dust, and is spatially extended with an
effective radius . The smaller component "B" appears redder
(), likely because it is older () with mild dust
extinction (), and a smaller radius . We
identify galaxies with similar colors in a high-redshift simulation, finding
their star formation histories to be out of phase. With an estimated stellar
mass ratio of roughly 2:1 and physical projected separation ,
we may be witnessing a galaxy merger 400 million years after the Big Bang. We
also identify a candidate companion galaxy C away, likely
destined to merge with galaxies A and B. The combined light from galaxies A+B
is magnified by factors of 8, 5, and 2 in three lensed images JD1, 2, and
3 with F356W fluxes , , (AB mag 25.1, 25.6, 26.6).
MACS0647JD is significantly brighter than other galaxies recently discovered
at similar redshifts with JWST. Without magnification, it would have AB mag
27.3 (). With a high confidence level, we obtain a photometric
redshift of based on photometry measured in 6 NIRCam filters
spanning , out to rest-frame. JWST NIRSpec
observations planned for January 2023 will deliver a spectroscopic redshift and
a more detailed study of the physical properties of MACS0647JD.Comment: 27 pages, 14 figures, submitted to Natur
Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study
Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality
Robust estimation of bacterial cell count from optical density
Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data
Exposure to Microbial Metabolite Butyrate Prolongs the Survival Time and Changes the Growth Pattern of Human Papillomavirus 16 E6/E7-Immortalized Keratinocytes in Vivo.
Human papillomavirus (HPV) is a ubiquitous human pathogen that can be cleared by host immunity. Nonetheless, a small percentage of the patients develop persistent infection with oncogenic HPV, which poses an increased risk of developing HPV-associated malignancy. Although cell-mediated immunity is a known systemic factor, local factors that influence persistent HPV infection have not been fully investigated. HPV-related head/neck cancers have a strong site preference for the oropharynx, suggesting the existence of unique local factors that promote HPV-induced oncogenesis. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Because butyrate is a potent epigenetic modulator, it could be an environmental factor influencing the development of HPV-positive oropharyngeal malignancy. In this study, we showed that butyrate treatment changed the property of HPV16 E6/E7-immortalized keratinocytes. In vitro, the treatment increased the cells' migration ability, slowed the growth, and increased the genotoxic resistance. When implanted in the syngeneic mice, the treated keratinocytes survived longer and exhibited a different growth pattern. The survival advantage obtained after butyrate exposure may increase the susceptibility of HPV-infected oropharyngeal keratinocytes to further malignant transformation. These results suggest that fermentation products of tonsillar bacteria may play an important role in the long-term persistence of high-risk HPV infection, which is a critical risk factor for developing HPV-positive oropharyngeal malignancy
- …