Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

AbstractDespite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs

Family of Hermitian Low-Momentum Nucleon Interactions with Phase Shift Equivalence

Using a Schmidt orthogonalization transformation, a family of Hermitian low-momentum NN interactions is derived from the non-Hermitian Lee-Suzuki (LS) low-momentum NN interaction. As special cases, our transformation reproduces the Hermitian interactions for Okubo and Andreozzi. Aside from their common preservation of the deuteron binding energy, these Hermitian interactions are shown to be phase shift equivalent, all preserving the empirical phase shifts up to decimation scale Lambda. Employing a solvable matrix model, the Hermitian interactions given by different orthogonalization transformations are studied; the interactions can be very different from each other particularly when there is a strong intruder state influence. However, because the parent LS low-momentum NN interaction is only slightly non-Hermitian, the Hermitian low-momentum nucleon interactions given by our transformations, including the Okubo and Andreozzi ones, are all rather similar to each other. Shell model matrix elements given by the LS and several Hermitian low-momentum interactions are compared.Comment: 10 pages, 7 figure

Health-related quality of life in patients with pulmonary arterial hypertension

BACKGROUND: Improved outcomes with expanding treatment options for patients with pulmonary arterial hypertension present the opportunity to consider additional end-points in approaching therapy, including factors that influence health-related quality of life. However, comparatively little is known about health-related quality of life and its determinants in patients with pulmonary arterial hypertension. METHODS: Health-related quality of life was evaluated in a cross sectional study of 155 outpatients with pulmonary arterial hypertension using generic and respiratory-disease specific measurement tools. Most patients had either World Health Organization functional Class II or III symptoms. Demographic, hemodynamic and treatment variables were assessed for association with health-related quality of life scores. RESULTS: Patients with pulmonary arterial hypertension suffered severe impairments in both physical and emotional domains of health-related quality of life. Patients with idiopathic ("primary") pulmonary arterial hypertension had the best, and those with systemic sclerosis the worst health-related quality of life. Greater six-minute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. Hemodynamic measurements, however, did not correlate with health-related quality of life scores. No differences in health-related quality of life were found between patients who were being treated with calcium channel antagonists, bosentan or continuously infused epoprostenol at the time of quality of life assessment. CONCLUSION: Health-related quality of life is severely impaired in patients with pulmonary arterial hypertension and is associated with measures of functional status. Specific associations with impaired health-related quality of life suggest potential areas for targeted intervention

Evidence for He I 10830 \AA~ absorption during the transit of a warm Neptune around the M-dwarf GJ 3470 with the Habitable-zone Planet Finder

Understanding the dynamics and kinematics of out-flowing atmospheres of hot and warm exoplanets is crucial to understanding the origins and evolutionary history of the exoplanets near the evaporation desert. Recently, ground based measurements of the meta-stable Helium atom's resonant absorption at 10830 \AA~has become a powerful probe of the base environment which is driving the outflow of exoplanet atmospheres. We report evidence for the He I 10830 \AA~in absorption (equivalent width $\sim$ $0.012 \pm 0.002$ \AA) in the exosphere of a warm Neptune orbiting the M-dwarf GJ 3470, during three transits using the Habitable Zone Planet Finder (HPF) near infrared spectrograph. This marks the first reported evidence for He I 10830 \AA\, atmospheric absorption for a planet orbiting an M-dwarf. Our detected absorption is broad and its blueshifted wing extends to -36 km/sec, the largest reported in the literature to date. We modelled the state of Helium atoms in the exosphere of GJ3470b based on assumptions on the UV and X-ray flux of GJ 3470, and found our measurement of flux-weighted column density of meta-stable state Helium $(N_{He^2_3S} = 2.4 \times 10^{10} \mathrm{cm^{-2}})$, derived from our transit observations, to be consistent with model, within its uncertainties. The methodology developed here will be useful to study and constrain the atmospheric outflow models of other exoplanets like GJ 3470b which are near the edge of the evaporation desert.Comment: Accepted in Ap

Climate vulnerability assessment for Pacific salmon and steelhead in the California Current Large Marine Ecosystem.

Major ecological realignments are already occurring in response to climate change. To be successful, conservation strategies now need to account for geographical patterns in traits sensitive to climate change, as well as climate threats to species-level diversity. As part of an effort to provide such information, we conducted a climate vulnerability assessment that included all anadromous Pacific salmon and steelhead (Oncorhynchus spp.) population units listed under the U.S. Endangered Species Act. Using an expert-based scoring system, we ranked 20 attributes for the 28 listed units and 5 additional units. Attributes captured biological sensitivity, or the strength of linkages between each listing unit and the present climate; climate exposure, or the magnitude of projected change in local environmental conditions; and adaptive capacity, or the ability to modify phenotypes to cope with new climatic conditions. Each listing unit was then assigned one of four vulnerability categories. Units ranked most vulnerable overall were Chinook (O. tshawytscha) in the California Central Valley, coho (O. kisutch) in California and southern Oregon, sockeye (O. nerka) in the Snake River Basin, and spring-run Chinook in the interior Columbia and Willamette River Basins. We identified units with similar vulnerability profiles using a hierarchical cluster analysis. Life history characteristics, especially freshwater and estuary residence times, interplayed with gradations in exposure from south to north and from coastal to interior regions to generate landscape-level patterns within each species. Nearly all listing units faced high exposures to projected increases in stream temperature, sea surface temperature, and ocean acidification, but other aspects of exposure peaked in particular regions. Anthropogenic factors, especially migration barriers, habitat degradation, and hatchery influence, have reduced the adaptive capacity of most steelhead and salmon populations. Enhancing adaptive capacity is essential to mitigate for the increasing threat of climate change. Collectively, these results provide a framework to support recovery planning that considers climate impacts on the majority of West Coast anadromous salmonids

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

Properties and Evolution of the Redback Millisecond Pulsar Binary PSR J2129-0429

PSR J2129−0429 is a "redback" eclipsing millisecond pulsar binary with an unusually long 15.2 hr orbit. It was discovered by the Green Bank Telescope in a targeted search of unidentified Fermi gamma-ray sources. The pulsar companion is optically bright (mean m_R = 16.6 mag), allowing us to construct the longest baseline photometric data set available for such a system. We present 10 years of archival and new photometry of the companion from the Lincoln Near-Earth Asteroid Research Survey, the Catalina Real-time Transient Survey, the Palomar Transient Factory, the Palomar 60 inch, and the Las Cumbres Observatory Global Telescope. Radial velocity spectroscopy using the Double-Beam Spectrograph on the Palomar 200 inch indicates that the pulsar is massive: 1.74 ± 0.18 M_☉. The G-type pulsar companion has mass 0.44 ± 0.04 M_☉, one of the heaviest known redback companions. It is currently 95 ± 1% Roche-lobe filling and only mildly irradiated by the pulsar. We identify a clear 13.1 mmag yr^(−1) secular decline in the mean magnitude of the companion as well as smaller-scale variations in the optical light curve shape. This behavior may indicate that the companion is cooling. Binary evolution calculations indicate that PSR J2129−0429 has an orbital period almost exactly at the bifurcation period between systems that converge into tighter orbits as black widows and redbacks and those that diverge into wider pulsar–white dwarf binaries. Its eventual fate may depend on whether it undergoes future episodes of mass transfer and increased irradiation

The Set2/Rpd3S Pathway Suppresses Cryptic Transcription without Regard to Gene Length or Transcription Frequency

In cells lacking the histone methyltransferase Set2, initiation of RNA polymerase II transcription occurs inappropriately within the protein-coding regions of genes, rather than being restricted to the proximal promoter. It was previously reported that this “cryptic” transcription occurs preferentially in long genes, and in genes that are infrequently transcribed. Here, we mapped the transcripts produced in an S. cerevisiae strain lacking Set2, and applied rigorous statistical methods to identify sites of cryptic transcription at high resolution. We find that suppression of cryptic transcription occurs independent of gene length or transcriptional frequency. Our conclusions differ with those reported previously because we obtained a higher-resolution dataset, we accounted for the fact that gene length and transcriptional frequency are not independent variables, and we accounted for several ascertainment biases that make cryptic transcription easier to detect in long, infrequently transcribed genes. These new results and conclusions have implications for many commonly used genomic analysis approaches, and for the evolution of high-fidelity RNA polymerase II transcriptional initiation in eukaryotes

Evidence for He I 10830 Å Absorption during the Transit of a Warm Neptune around the M-dwarf GJ 3470 with the Habitable-zone Planet Finder

Understanding the dynamics and kinematics of outflowing atmospheres of hot and warm exoplanets is crucial to understanding the origins and evolutionary history of the exoplanets near the evaporation desert. Recently, ground-based measurements of the meta-stable helium atom's resonant absorption at 10830 Å has become a powerful probe of the base environment which is driving the outflow of exoplanet atmospheres. We report evidence for the He I 10830 Å in absorption (equivalent width ~0.012 ± 0.002 Å) in the exosphere of a warm Neptune orbiting the M-dwarf GJ 3470, during three transits using the Habitable Zone Planet Finder near-infrared spectrograph. This marks the first reported evidence for He I 10830 Å atmospheric absorption for a planet orbiting an M-dwarf. Our detected absorption is broad and its blueshifted wing extends to −36 km s⁻¹, the largest reported in the literature to date. We modeled the state of helium atoms in the exosphere of GJ3470b based on assumptions on the UV and X-ray flux of GJ 3470, and found our measurement of flux-weighted column density of meta-stable state helium (N_(He2/3S) = 2.4×10¹⁰cm⁻²), derived from our transit observations, to be consistent with the model, within its uncertainties. The methodology developed here will be useful to study and constrain the atmospheric outflow models of other exoplanets like GJ 3470b, which are near the edge of the evaporation desert