109 research outputs found
Local structures of polar wurtzites Zn_{1-x}Mg_{x}O studied by Raman and {67}Zn/{25}Mg NMR spectroscopies and by total neutron scattering
Local compositions and structures of Zn_{1-x}Mg_{x}O alloys have been
investigated by Raman and solid-state {67}Zn/{25}Mg nuclear magnetic resonance
(NMR) spectroscopies, and by neutron pair-distribution-function (PDF) analyses.
The E2(low) and E2(high) Raman modes of Zn_{1-x}Mg_{x}O display Gaussian- and
Lorentzian-type profiles, respectively. At higher Mg substitutions, both modes
become broader, while their peak positions shift in opposite directions. The
evolution of Raman spectra from Zn_{1-x}Mg_{x}O solid solutions are discussed
in terms of lattice deformation associated with the distinct coordination
preferences of Zn and Mg. Solid-state magic-angle-spinning (MAS) NMR studies
suggest that the local electronic environments of {67}Zn in ZnO are only weakly
modified by the 15% substitution of Mg for Zn. {25}Mg MAS spectra of
Zn_{0.85}Mg_{0.15}O show an unusual upfield shift, demonstrating the prominent
shielding ability of Zn in the nearby oxidic coordination sphere. Neutron PDF
analyses of Zn_{0.875}Mg_{0.125}O using a 2x2x1 supercell corresponding to
Zn_{7}MgO_{8} suggest that the mean local geometry of MgO_{4} fragments concurs
with previous density functional theory (DFT)-based structural relaxations of
hexagonal wurtzite MgO. MgO_{4} tetrahedra are markedly compressed along their
c-axes and are smaller in volume than ZnO_{4} units by ~6%. Mg atoms in
Zn_{1-x}Mg_{x}O have a shorter bond to the -axial oxygen atom than to the
three lateral oxygen atoms, which is distinct from the coordination of Zn. The
precise structure, both local and average, of Zn_{0.875}Mg_{0.125}O obtained
from time-of-flight total neutron scattering supports the view that
Mg-substitution in ZnO results in increased total spontaneous polarization.Comment: 12 pages, 14 figures, 2 table
The Effect of Alternative Graphical Displays Used to Present the Benefits of Antibiotics for Sore Throat on Decisions about Whether to Seek Treatment: A Randomized Trial
In a randomized trial, Cheryl Carling and colleagues evaluate how people respond to different statistical presentations regarding the consequences of taking antibiotic treatment for sore throat
A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice
Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation
Transgenic Rat Model of Neurodegeneration Caused by Mutation in the TDP Gene
TDP-43 proteinopathies have been observed in a wide range of neurodegenerative diseases. Mutations in the gene encoding TDP-43 (i.e., TDP) have been identified in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobe degeneration associated with motor neuron disease. To study the consequences of TDP mutation in an intact system, we created transgenic rats expressing normal human TDP or a mutant form of human TDP with a M337V substitution. Overexpression of mutant, but not normal, TDP caused widespread neurodegeneration that predominantly affected the motor system. TDP mutation reproduced ALS phenotypes in transgenic rats, as seen by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. This robust rat model also recapitulated features of TDP-43 proteinopathies including the formation of TDP-43 inclusions, cytoplasmic localization of phosphorylated TDP-43, and fragmentation of TDP-43 protein. TDP transgenic rats will be useful for deciphering the mechanisms underlying TDP-43–related neurodegenerative diseases
Rate Effects on Timing, Key Velocity, and Finger Kinematics in Piano Performance
We examined the effect of rate on finger kinematics in goal-directed actions of pianists. In addition, we evaluated whether movement kinematics can be treated as an indicator of personal identity. Pianists' finger movements were recorded with a motion capture system while they performed melodies from memory at different rates. Pianists' peak finger heights above the keys preceding keystrokes increased as tempo increased, and were attained about one tone before keypress. These rate effects were not simply due to a strategy to increase key velocity (associated with tone intensity) of the corresponding keystroke. Greater finger heights may compensate via greater tactile feedback for a speed-accuracy tradeoff that underlies the tendency toward larger temporal variability at faster tempi. This would allow pianists to maintain high temporal accuracy when playing at fast rates. In addition, finger velocity and accelerations as pianists' fingers approached keys were sufficiently unique to allow pianists' identification with a neural-network classifier. Classification success was higher in pianists with more extensive musical training. Pianists' movement “signatures” may reflect unique goal-directed movement kinematic patterns, leading to individualistic sound
Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis
BACKGROUND: Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; Low-Tidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians. OBJECTIVES: We selected these five trials and asked: Question 1--What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2--What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR >15%; >20%; >25%)? METHODS: Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence). MAIN FINDINGS: Answer 1--The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2--If we aim for a RRR>15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62-65% for the Low-Tidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR >20% or >25%, all probabilities of benefits become lower independent of the degree of skepticism. CONCLUSIONS: Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
Two-pore domain potassium channels enable action potential generation in the absence of voltage-gated potassium channels
Frailty modelling for survival data from multi-centre clinical trials
Despite the use of standardized protocols in, multi-centre, randomized clinical trials, outcome may vary between centres. Such heterogeneity may alter the interpretation and reporting of the treatment effect. Below, we propose a general frailty modelling approach for investigating, inter alia, putative treatment-by-centre interactions in time-to-event data in multi-centre clinical trials. A correlated random effects model is used to model the baseline risk and the treatment effect across centres. It may be based on shared, individual or correlated random effects. For inference we develop the hierarchical-likelihood (or h-likelihood) approach which facilitates computation of prediction intervals for the random effects with proper precision. We illustrate our methods using disease-free time-to-event data on bladder cancer patients participating in an European Organization for Research and Treatment of Cancer trial, and a simulation study. We also demonstrate model selection using h-likelihood criteria
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