Stoichiometry control of magnetron sputtered Bi2_2Sr2_2Ca1−x_{1-x}Yx_xCu2_2Oy_y (0≤\lex≤\le0.5) thin film, composition spread libraries: Substrate bias and gas density factors

A magnetron sputtering method for the production of thin-film libraries with a spatially varying composition, x, in Bi2Sr2Ca1-xYxCu2Oy (0<=x<=0.5) has been developed. Two targets with a composition of Bi2Sr2YCu2O_{8.5 + \delta} and Bi_2Sr_2CaCu_2O_{8 + \delta} are co-sputtered with appropriate masks. The target masks produce a linear variation in opposite, but co-linear radial direction, and the rotation speed of the substrate table is sufficient to intimately mix the atoms. EDS/WDS composition studies of the films show a depletion of Sr and Bi that is due to oxygen anion resputtering. The depletion is most pronounced at the centre of the film (i.e. on-axis with the target) and falls off symmetrically to either side of the 75 mm substrate. At either edge of the film the stoichiometry matches the desired ratios. Using a 12 mTorr process gas of argon and oxygen in a 2:1 ratio, the strontium depletion is corrected. The bismuth depletion is eliminated by employing a rotating carbon brush apparatus which supplies a -20 V DC bias to the sample substrate. The negative substrate bias has been used successfully with an increased chamber pressure to eliminate the resputtering effect across the film. The result is a thin film composition spread library with the desired stoichiometry.Comment: 16 pages, 12 figures, 4 tables, submitted to Physica C - Superconductivity (April 15, 2005), elsart.st

Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites

Comparison of IPX066 with carbidopa–levodopa plus entacapone in advanced PD patients

AbstractBackgroundIPX066, an investigational extended-release carbidopa–levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E).MethodsAt baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily “off” time during waking hours (from patient diaries).ResultsOf 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent “off” time (24.0% vs. 32.5%; p < 0.0001), lower “off” time (3.8 vs. 5.2 h/day; p < 0.0001), and higher “on” time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E.ConclusionsIn advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated

Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase–ceramide pathway

Amyloid-β peptide (Aβ) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Aβ induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Aβ-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Aβ and ceramide induced OLG death. In addition, Aβ activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Aβ cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death. Furthermore, nSMase inhibition by 3-O-methyl-sphingomyelin or by gene knockdown using antisense oligonucleotides attenuated Aβ-induced OLG death. Glutathione (GSH) precursors inhibited Aβ activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Aβ-induced death. These results suggest that Aβ induces OLG death by activating the nSMase–ceramide cascade via an oxidative mechanism

Accessing the entire overdoped regime in pristine YBa2Cu3O6 + x by application of pressure

We uncover the previously inaccessible overdoped regime to attain the complete superconducting dome in a pristine high temperature cuprate superconductor, by applying pressures up to 280 kbar to single crystals near stoichiometric YBa[subscript 2]Cu[subscript3]O[subscript 7]. The obtained superconducting phase boundary as a function of hole doping closely follows the form of the superconducting dome in La[subscript 2−x]Sr[subscript x]CuO[subscript 4]. Measurements are now enabled to trace the evolution of various entangled phases and the Fermi surface from the underdoped to overdoped regime in a single high purity cuprate superconducting family of materials.Royal Society (Great Britain)Winton Programme for the Physics of SustainabilityCambridge-MIT InstituteSeventh Framework Programme (European Commission) (Grants FP/2007-2013, ERC 337425 and EPSRC EP/M000524/1

Atrial fibrillation and outcomes in heart failure with preserved versus reduced left ventricular ejection fraction

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) are 2 of the most common cardiovascular conditions nationally and AF frequently complicates HF. We examined how AF has impacts on adverse outcomes in HF-PEF versus HF-REF within a large, contemporary cohort. METHODS AND RESULTS: We identified all adults diagnosed with HF-PEF or HF-REF based on hospital discharge and ambulatory visit diagnoses and relevant imaging results for 2005-2008 from 4 health plans in the Cardiovascular Research Network. Data on demographic features, diagnoses, procedures, outpatient pharmacy use, and laboratory results were ascertained from health plan databases. Hospitalizations for HF, stroke, and any reason were identified from hospital discharge and billing claims databases. Deaths were ascertained from health plan and state death files. Among 23 644 patients with HF, 11 429 (48.3%) had documented AF (9081 preexisting, 2348 incident). Compared with patients who did not have AF, patients with AF had higher adjusted rates of ischemic stroke (hazard ratio [HR] 2.47 for incident AF; HR 1.57 for preexisting AF), hospitalization for HF (HR 2.00 for incident AF; HR 1.22 for preexisting AF), all-cause hospitalization (HR 1.45 for incident AF; HR 1.15 for preexisting AF), and death (incident AF HR 1.67; preexisting AF HR 1.13). The associations of AF with these outcomes were similar for HF-PEF and HF-REF, with the exception of ischemic stroke. CONCLUSIONS: AF is a potent risk factor for adverse outcomes in patients with HF-PEF or HF-REF. Effective interventions are needed to improve the prognosis of these high-risk patients