75 research outputs found
Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia
Specific mutations in the human gene encoding the Wiskott-Aldrich syndrome protein (WASp) that compromise normal auto-inhibition of WASp result in unregulated activation of the actin-related protein 2/3 complex and increased actin polymerizing activity. These activating mutations are associated with an X-linked form of neutropenia with an intrinsic failure of myelopoiesis and an increase in the incidence of cytogenetic abnormalities. To study the underlying mechanisms, active mutant WASpI294T was expressed by gene transfer. This caused enhanced and delocalized actin polymerization throughout the cell, decreased proliferation, and increased apoptosis. Cells became binucleated, suggesting a failure of cytokinesis, and micronuclei were formed, indicative of genomic instability. Live cell imaging demonstrated a delay in mitosis from prometaphase to anaphase and confirmed that multinucleation was a result of aborted cytokinesis. During mitosis, filamentous actin was abnormally localized around the spindle and chromosomes throughout their alignment and separation, and it accumulated within the cleavage furrow around the spindle midzone. These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization
Cosmological parameters from SDSS and WMAP
We measure cosmological parameters using the three-dimensional power spectrum
P(k) from over 200,000 galaxies in the Sloan Digital Sky Survey (SDSS) in
combination with WMAP and other data. Our results are consistent with a
``vanilla'' flat adiabatic Lambda-CDM model without tilt (n=1), running tilt,
tensor modes or massive neutrinos. Adding SDSS information more than halves the
WMAP-only error bars on some parameters, tightening 1 sigma constraints on the
Hubble parameter from h~0.74+0.18-0.07 to h~0.70+0.04-0.03, on the matter
density from Omega_m~0.25+/-0.10 to Omega_m~0.30+/-0.04 (1 sigma) and on
neutrino masses from <11 eV to <0.6 eV (95%). SDSS helps even more when
dropping prior assumptions about curvature, neutrinos, tensor modes and the
equation of state. Our results are in substantial agreement with the joint
analysis of WMAP and the 2dF Galaxy Redshift Survey, which is an impressive
consistency check with independent redshift survey data and analysis
techniques. In this paper, we place particular emphasis on clarifying the
physical origin of the constraints, i.e., what we do and do not know when using
different data sets and prior assumptions. For instance, dropping the
assumption that space is perfectly flat, the WMAP-only constraint on the
measured age of the Universe tightens from t0~16.3+2.3-1.8 Gyr to
t0~14.1+1.0-0.9 Gyr by adding SDSS and SN Ia data. Including tensors, running
tilt, neutrino mass and equation of state in the list of free parameters, many
constraints are still quite weak, but future cosmological measurements from
SDSS and other sources should allow these to be substantially tightened.Comment: Minor revisions to match accepted PRD version. SDSS data and ppt
figures available at http://www.hep.upenn.edu/~max/sdsspars.htm
Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis
BACKGROUND:
Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS.
METHODS:
Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months).
RESULTS:
Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery.
CONCLUSION:
This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc
Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study
Aims: To investigate if recent technical and procedural developments in percutaneous coronary intervention (PCI) significantly influence outcomes in appropriately selected patients with three-vessel (3VD) coronary artery disease. Methods and results: The SYNTAX II study is a multicenter, all-comers, open-label, single arm study that investigated the impact of a contemporary PCI strategy on clinical outcomes in patients with 3VD in 22 centres from four European countries. The SYNTAX-II strategy includes: heart team decision-making utilizing the SYNTAX Score II (a clinical tool combining anatomical and clinical factors), coronary physiology guided revascularisation, implantation of thin strut bio-resorbable-polymer drug-eluting stents, intravascular ultrasound (IVUS) guided stent implantation, contemporary chronic total occlusion revascularisation techniques and guideline-directed medical therapy. The rate of major adverse cardiac and cerebrovascular events (MACCE [composite of all-cause death, cerebrovascular event, any myocardial infarction and any revascularisation]) at one year was compared to a predefined PCI cohort from the original SYNTAX-I trial selected on the basis of equipoise 4-year mortality between CABG and PCI. As an exploratory endpoint, comparisons were made with the historical CABG cohort of the original SYNTAX-I trial. Overall 708 patients were screened and discussed within the heart team; 454 patients were deemed appropriate to undergo PCI. At one year, the SYNTAX-II strategy was superior to the equipoise-derived SYNTAX-I PCI cohort (MACCE SYNTAX-II 10.6% vs. SYNTAX-I 17.4%; HR 0.58, 95% CI 0.39-0.85, P= 0.006). This difference was driven by a significant reduction in the incidence of MI (HR 0.27, 95% CI 0.11-0.70, P= 0.007) and revascularisation (HR 0.57, 95% CI 0.37-0.9, P = 0.015). Rates of all-cause death (HR 0.69, 95% CI 0.27-1.73, P = 0.43) and stroke (HR 0.69, 95% CI 0.10-4.89, P = 0.71) were similar. The rate of definite stent thrombosis was significantly lower in SYNTAX-II (HR 0.26, 95% CI 0.07-0.97, P = 0.045). Conclusion: At one year, clinical outcomes with the SYNTAX-II strategy were associated with improved clinical results compared to the PCI performed in comparable patients from the original SYNTAX-I trial. Longer term follow-up is awaited and a randomized clinical trial with contemporary CABG is warranted
Parameterizing Functions of Soil-Water Soluble Reactive Phosphorus Flux for an Ecohydrological Model of Formerly Drained Riparian Wetlands in the Lake Champlain Basin
Elevated phosphorus (P) concentrations in numerous freshwater lakes in North America are leading to a higher frequency of potentially harmful cyanobacteria blooms. Lake Champlain is an example and in 2016 the U.S. EPA passed a stringent P total maximum daily load limit for the Vermont tributaries to the lake. Wetland restoration may help reduce P loading by increasing water and sediment retention and over 4000 potential wetland restoration sites have been identified in Vermont. Most candidate sites overlay historically drained agricultural fields with potentially high existing amounts of legacy soil P. The fate and transport of this legacy soil P will be affected by hydrologic modifications. We are developing a wetland biogeochemical process model to be used in conjunction with hydraulic models (e.g., HEC-RAS) to estimate the effect of restoration activity on floodplain P balance. This poster focuses on the development of functions that relate soil properties of Vermont wetlands to P sorption dynamics and soluble reactive P (SRP) diffusion rates across the soil-water interface. As expected, results from spring flood monitoring and lab simulated floods indicate that soil-to-water SRP flux is greater under lower floodwater oxygen conditions and negatively correlated with time since farming. Future research will whether simple soil tests (e.g., water extractable P) and/or widely collected state soil test data (e.g., Modified Morgan extractable P, Al, Fe used in the Northeast) could be used to estimate flux parameters in process models that simulate the effects of wetland restoration on P dynamics
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The Breathing Plasmasphere: Erosion and Refilling
Global observations of He+ ions from the Imager for Magnetopause-to-Aurora Global Exploration mission Extreme Ultraviolet Imager are used to examine the dynamics of plasmasphere content using integrated mass through times of erosion and refilling for (Formula presented.). Perhaps the most basic and important attributes of the plasmasphere are its mass and spatial distribution. However, our understanding is often constrained by the method of measurement. Storm-time loss of plasmasphere content is a kind of exhalation where plasma is lost. Refilling or inhalation into the body of the plasmasphere occurs during the following calm. Using a follow-the-mass approach, storm-time plasmasphere loss for (Formula presented.) is found to range from 32% to 62% during three events. Plasma lost inside the average eroded plasmapause boundary ranges from 22% to 42% and outside from 35% to 72%. Following the start of refilling, the innermost L-shells show the lowest observed refilling rates. Mass refilling rates at higher L-shells rise to a maximum observed ∼6 Mt/day near L = 4.5 that is less at higher L-shells (Mt/d = 1,000 kg/day). More variability and higher refilling rates are found during lower solar activity. The mass content of the plasmasphere between L = 1.5 and 3.0 was also followed for 54 days when it exhibited eight “breathes.” Using this analogy, only the first inhale/exhale is “deep.” The remaining carry forward the consequences of past and continued activity that prevents full recovery. There appears to be a month-long declining trend in the mass of the inner plasmasphere during the last two thirds of this time. © 2021. American Geophysical Union. All Rights Reserved. This article has been contributed to by US Government employees and their work is in the public domain in the USA.Public domain articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Evaluating trade-offs of a large, infrequent sediment diversion for restoration of a forested wetland in the Mississippi delta
© 2018 Elsevier Ltd Flood control levees cut off the supply of sediment to Mississippi delta coastal wetlands, and contribute to putting much of the delta on a trajectory for continued submergence in the 21st century. River sediment diversions have been proposed as a method to provide a sustainable supply of sediment to the delta, but the frequency and magnitude of these diversions needs further assessment. Previous studies suggested operating river sediment diversions based on the size and frequency of natural crevasse events, which were large (\u3e5000 m3/s) and infrequent (active \u3c once a year) in the last naturally active delta. This study builds on these previous works by quantitatively assessing tradeoffs for a large, infrequent diversion into the forested wetlands of the Maurepas swamp. Land building was estimated for several diversion sizes and years inactive using a delta progradation model. A benefit-cost analysis (BCA) combined model land building results with an ecosystem service valuation and estimated costs. Results demonstrated that land building is proportional to diversion size and inversely proportional to years inactive. Because benefits were assumed to scale linearly with land gain, and costs increase with diversion size, there are disadvantages to operating large diversions less often, compared to smaller diversions more often for the immediate project area. Literature suggests that infrequent operation would provide additional gains (through increased benefits and reduced ecosystem service costs) to the broader Lake Maurepas-Pontchartrain-Borgne ecosystem. Future research should incorporate these additional effects into this type of BCA, to see if this changes the outcome for large, infrequent diversions
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