Dominant gain-of-function mutations in Hsp104p reveal crucial roles for the middle region

Heat-shock protein 104 (Hsp104p) is a protein-remodeling factor that promotes survival after extreme stress by disassembling aggregated proteins and can either promote or prevent the propagation of prions (protein-based genetic elements). Hsp104p can be greatly overexpressed without slowing growth, suggesting tight control of its powerful protein-remodeling activities. We isolated point mutations in Hsp104p that interfere with this control and block cell growth. Each mutant contained alterations in the middle region (MR). Each of the three MR point mutations analyzed in detail had distinct phenotypes. In combination with nucleotide binding site mutations, Hsp104p(T499I) altered bud morphology and caused septin mislocalization, colocalizing with the misplaced septins. Point mutations in the septin Cdc12p suppressed this phenotype, suggesting that it is due to direct Hsp104p–septin interactions. Hsp104p(A503V) did not perturb morphology but stopped cell growth. Remarkably, when expressed transiently, the mutant protein promoted survival after extreme stress as effectively as did wild-type Hsp104p. Hsp104p(A509D) had no deleterious effects on growth or morphology but had a greatly reduced ability to promote thermotolerance. That mutations in an 11-amino acid stretch of the MR have such profound and diverse effects suggests the MR plays a central role in regulating Hsp104p function

Accuracy of computerized tomography in determining hepatic tumor size in patients receiving liver transplantation or resection

Computerized tomography (CT) of liver is used in oncologic practice for staging tumors, evaluating response to treatment, and screening patients for hepatic resection. Because of the impact of CT liver scan on major treatment decisions, it is important to assess its accuracy. Patients undergoing liver transplantation or resection provide a unique opportunity to test the accuracy of hepatic-imaging techniques by comparison of finding of preoperative CT scan with those at gross pathologic examination of resected specimens. Forty-one patients who had partial hepatic resection (34 patients) or liver transplantation (eight patients) for malignant (30 patients) or benign (11 patients) tumors were evaluable. Eight (47%) of 17 patients with primary malignant liver tumors, four (31%) of 13 patients with metastatic liver tumors, and two (20%) of 10 patients with benign liver tumors had tumor nodules in resected specimens that were not apparent on preoperative CT studies. These nodules varied in size from 0.1 to 1.6 cm. While 11 of 14 of these nodules were 1.0 cm. These results suggest that conventional CT alone may be insufficient to accurately determine the presence or absence of liver metastases, extent of liver involvement, or response of hepatic metastases to treatment

The Turbulent Warm Ionized Medium: Emission Measure Distribution and MHD Simulations

We present an analysis of the distribution of H-alpha emission measures for the warm ionized medium (WIM) of the Galaxy using data from the Wisconsin H-Alpha Mapper (WHAM) Northern Sky Survey. Our sample is restricted to Galactic latitudes |b| > 10. We removed sightlines intersecting nineteen high-latititude classical H II regions, leaving only sightlines that sample the diffuse WIM. The distribution of EM sin |b| for the full sample is poorly characterized by a single normal distribution, but is extraordinarily well fit by a lognormal distribution, with = 0.146 +/- 0.001 and standard deviation 0.190 +/- 0.001. drops from 0.260 +/- 0.002 at Galactic latitude 10<|b|<30 to 0.038 +/- 0.002 at Galactic latitude 60<|b|<90. The distribution may widen slightly at low Galactic latitude. We compare the observed EM distribution function to the predictions of three-dimensional magnetohydrodynamic simulations of isothermal turbulence within a non-stratified interstellar medium. We find that the distribution of EM sin |b| is well described by models of mildy supersonic turbulence with a sonic Mach number of ~1.4-2.4. The distribution is weakly sensitive to the magnetic field strength. The model also successfully predicts the distribution of dispersion measures of pulsars and H-alpha line profiles. In the best fitting model, the turbulent WIM occupies a vertical path length of 400-500 pc within the 1.0-1.8 kpc scale height of the layer. The WIM gas has a lognormal distribution of densities with a most probable electron density n_{pk} = 0.03 cm^{-3}. We also discuss the implications of these results for interpreting the filling factor, the power requirement, and the magnetic field of the WIM.Comment: 16 pages, 13 figures, ApJ in press. Replacement reflects version accepted for publicatio

Frequency of and Prognostic Significance of Atrial Fibrillation in Patients Undergoing Transcatheter Aortic Valve Implantation

The prognostic implications of preexisting atrial fibrillation (AF) and new-onset AF (NOAF) in transcatheter aortic valve implantation (TAVI) remain uncertain. This study assesses the epidemiology of AF in patients treated with TAVI and evaluates their outcomes according to the presence of preexisting AF or NOAF. A retrospective analysis of 708 patients undergoing TAVI from 2 heart hospitals was performed. Patients were divided into 3 study groups: sinus rhythm (n = 423), preexisting AF (n = 219), and NOAF (n = 66). Primary outcomes of interest were all-cause death and stroke both at 30-day and at 1-year follow-up. Preexisting AF was present in 30.9% of our study population, whereas NOAF was observed in 9.3% of patients after TAVI. AF and NOAF patients showed a higher rate of 1-year all-cause mortality compared with patients in sinus rhythm (14.6% vs 6.5% for preexisting AF and 16.3% vs 6.5% for NOAF, p = 0.007). No differences in 30-day mortality were observed between groups. In patients with AF (either preexisting and new-onset), those discharged with single antiplatelet therapy displayed higher mortality rates at 1 year (42.9% vs 11.7%, p = 0.006). Preexisting AF remained an independent predictor of mortality at 1-year follow-up (hazard ratio [HR] 2.34, 95% CI 1.22 to 4.48, p = 0.010). Independent predictors of NOAF were transapical and transaortic approach as well as balloon postdilatation (HR 3.48, 95% CI 1.66 to 7.29, p = 0.001; HR 5.08, 95% CI 2.08 to 12.39, p <0.001; HR 2.76, 95% CI 1.25 to 6.08, p = 0.012, respectively). In conclusion, preexisting AF is common in patients undergoing TAVI and is associated with a twofold increased risk of 1-year mortality. This negative effect is most pronounced in patients discharged with single antiplatelet therapy compared with other antithrombotic regimens

Extra-planar gas in the spiral galaxy NGC 4559

We present 21-cm line observations of the spiral galaxy NGC 4559, made with the Westerbork Synthesis Radio Telescope. We have used them to study the HI distribution and kinematics, the relative amount and distribution of luminous and dark matter in this galaxy and, in particular, the presence of extra-planar gas. Our data do reveal the presence of such a component, in the form of a thick disk, with a mass of 5.9 x 10^8 Mo (one tenth of the total HI mass) and a mean rotation velocity 25-50 km/s lower than that of the thin disk. The extra-planar gas may be the result of galactic fountains but accretion from the IGM cannot be ruled out. With this study we confirm that lagging, thick HI layers are likely to be common in spiral galaxies.Comment: 17 pages, 10 figures. Accepted for publication in A&

A Phase 2 study of cisplatin analog CI-973 in the treatment of patients with refractory, advanced ovarian cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71591/1/j.1525-1438.1996.06040257.x.pd

Effect of a Voltage Probe on the Phase-Coherent Conductance of a Ballistic Chaotic Cavity

The effect of an invasive voltage probe on the phase-coherent conduction through a ballistic chaotic cavity is investigated by random-matrix theory. The entire distribution P(G) of the conductance G is computed for the case that the cavity is coupled to source and drain by two point contacts with a quantized conductance of 2 e^2/h, both in the presence (beta = 1) and absence (beta = 2) of time-reversal symmetry. The loss of phase-coherence induced by the voltage probe causes a crossover from P(G) ~ G^(-1 + beta/2) to a Gaussian centered at G = e^2/h with a beta-dependent width. ***Submitted to Physical Review B.***Comment: 9 pages, REVTeX-3.0, 4 postscript figures appended as self-extracting archive, INLO-PUB-941020

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis

OBJECTIVES Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc. METHODS We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied. RESULTS From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors. CONCLUSIONS Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care

The energy source of the filaments around the giant galaxy NGC1275

The brightest galaxy in the nearby Perseus cluster, NGC1275, is surrounded by a network of filaments. These were first observed through their Halpha emission but are now known to have a large molecular component with a total mass approaching 10^11Msun of gas. The filaments are embedded in hot intracluster gas and stretch over 80 kpc. They have an unusual low excitation spectrum which is well modelled by collisional heating and ionization by secondary electrons. Here we note that the surface radiative flux from the outer filaments is close to the energy flux impacting on them from particles in the hot gas. We propose that the secondary electrons within the cold filaments, which excite the observed submillimetre through UV emission, are due to the hot surrounding gas efficiently penetrating the cold gas through reconnection diffusion. Some of the soft X-ray emission seen from the filaments is then due to charge exchange, although this is insufficient to account for all the observed X-ray flux. The filaments are complex with multiphase gas. Interpenetration of hot and cold gas leads to the filaments growing in mass, at a rate of up to 100Msunpyr. The lack of soft X-ray cooling emission in cool core clusters is then due to the non-radiative cooling of hot gas on mixing with cold gas around and within the central galaxy.Comment: 7 pages, 4 figures, MNRAS in pres