Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson's disease.

BACKGROUND: Classical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes. METHODS: 5851 patients with Parkinson's disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were resampled at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms. RESULTS: 5851 patients with Parkinson's disease (mean (SD) age, 61.02 (12.61) years; 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 5%-6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of -0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives. CONCLUSIONS: Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.

Carbocation Stability in H-ZSM5 at High Temperature.

Zeolites are common catalysts for multiple industrial applications, including alcohol dehydration to produce olefins, and given their commercial importance, reaction mechanisms in zeolites have long been proposed and studied. Some proposed reaction mechanisms for alcohol dehydration exhibit noncyclic carbocation intermediates or transition states that resemble carbocations, and several previous studies suggest that the tert-butyl cation is the only noncyclic cation more stable than the corresponding chemisorbed species with the hydrocarbon bound to the framework oxygen (i.e., an alkoxide). To determine if carbocations can exist at high temperatures in zeolites, where these catalysts are finding new applications for biomass vapor-phase upgrading (∼500 °C), the stability of carbocations and the corresponding alkoxides were calculated with two ONIOM embedding methods (M06-2X/6-311G(d,p):M06-2X/3-21G) and (PBE-D3/6-311G(d,p):PBE-D3/3-21G) and plane-wave density functional theory (DFT) using the PBE functional corrected with entropic and Tkatchenko-Scheffler van der Waals corrections. The embedding methods tested are unreliable at finding minima for primary carbocations, and only secondary or higher carbocations can be described with embedding methods consistent with the periodic DFT results. The relative energy between the carbocations and alkoxides differs significantly between the embedding and the periodic DFT methods. The difference is between ∼0.23 and 14.30 kcal/mol depending on the molecule, the model, and the functional chosen for the embedding method. At high temperatures, the pw-DFT calculations predict that the allyl, isopropyl, and sec-butyl cations exhibit negligible populations while acetyl and tert-butyl cations exhibit significant populations (>10%). Moreover, the periodic DFT results indicate that mechanisms including secondary and tertiary carbocations intermediates or carbocations stabilized by adjacent oxygen or double bonds are possible at high temperatures relevant to some industrial uses of zeolite catalysts, although as the minority species in most cases.

Hydrodeoxygenation by deuterium gas--a powerful way to provide insight into the reaction mechanisms.

This study demonstrates the use of isotopic labelling and NMR to study the HDO process. As far as we know, this is the first reported effort to trace the incorporation of hydrogen in the HDO process of lignin pyrolysis oil thereby providing key fundamental insight into its reaction mechanism.

Quaternary amine-induced peptide degradation via cyclization.

In this study, we investigated intramolecular cyclizations in peptides containing quaternary amines. Two types of cyclization reactions are studied: (a) those involving a trimethylammonium butyric acid (TMAB) charge tag and (b) those involving trimethylated lysine. Both types of reactions result in the release of trimethylamine via an S(N)2 mechanism involving a lone pair of electrons on the oxygen or nitrogen. In the case of the TMAB charge tag cyclization, the oxygen attack mechanism leading to a five-membered ring is the preferred pathway. In the trimethylated lysine cyclizations, the preferred pathway involves the nitrogen nucleophile resulting in the formation of a six-membered ring. The similarities and differences between the two reactions are analyzed.

Subnanometer cobalt oxide clusters as selective low temperature oxidative dehydrogenation catalysts.

The discovery of more efficient, economical, and selective catalysts for oxidative dehydrogenation is of immense economic importance. However, the temperatures required for this reaction are typically high, often exceeding 400 °C. Herein, we report the discovery of subnanometer sized cobalt oxide clusters for oxidative dehydrogenation of cyclohexane that are active at lower temperatures than reported catalysts, while they can also eliminate the combustion channel. These results found for the two cluster sizes suggest other subnanometer size (CoO)x clusters will also be active at low temperatures. The high activity of the cobalt clusters can be understood on the basis of density functional studies that reveal highly active under-coordinated cobalt atoms in the clusters and show that the oxidized nature of the clusters substantially decreases the binding energy of the cyclohexene species which desorb from the cluster at low temperature.

Size-dependent subnanometer Pd cluster (Pd4, Pd6, and Pd17) water oxidation electrocatalysis.

Water oxidation is a key catalytic step for electrical fuel generation. Recently, significant progress has been made in synthesizing electrocatalytic materials with reduced overpotentials and increased turnover rates, both key parameters enabling commercial use in electrolysis or solar to fuels applications. The complexity of both the catalytic materials and the water oxidation reaction makes understanding the catalytic site critical to improving the process. Here we study water oxidation in alkaline conditions using size-selected clusters of Pd to probe the relationship between cluster size and the water oxidation reaction. We find that Pd4 shows no reaction, while Pd6 and Pd17 deposited clusters are among the most active (in terms of turnover rate per Pd atom) catalysts known. Theoretical calculations suggest that this striking difference may be a demonstration that bridging Pd-Pd sites (which are only present in three-dimensional clusters) are active for the oxygen evolution reaction in Pd6O6. The ability to experimentally synthesize size-specific clusters allows direct comparison to this theory. The support electrode for these investigations is ultrananocrystalline diamond (UNCD). This material is thin enough to be electrically conducting and is chemically/electrochemically very stable. Even under the harsh experimental conditions (basic, high potential) typically employed for water oxidation catalysts, UNCD demonstrates a very wide potential electrochemical working window and shows only minor evidence of reaction. The system (soft-landed Pd4, Pd6, or Pd17 clusters on a UNCD Si-coated electrode) shows stable electrochemical potentials over several cycles, and synchrotron studies of the electrodes show no evidence for evolution or dissolution of either the electrode material or the clusters.

Magnetism in lithium-oxygen discharge product.

Nonaqueous lithium-oxygen batteries have a much superior theoretical gravimetric energy density compared to conventional lithium-ion batteries, and thus could render long-range electric vehicles a reality. A molecular-level understanding of the reversible formation of lithium peroxide in these batteries, the properties of major/minor discharge products, and the stability of the nonaqueous electrolytes is required to achieve successful lithium-oxygen batteries. We demonstrate that the major discharge product formed in the lithium-oxygen cell, lithium peroxide, exhibits a magnetic moment. These results are based on dc-magnetization measurements and a lithium-oxygen cell containing an ether-based electrolyte. The results are unexpected because bulk lithium peroxide has a significant band gap. Density functional calculations predict that superoxide-type surface oxygen groups with unpaired electrons exist on stoichiometric lithium peroxide crystalline surfaces and on nanoparticle surfaces; these computational results are consistent with the magnetic measurement of the discharged lithium peroxide product as well as EPR measurements on commercial lithium peroxide. The presence of superoxide-type surface oxygen groups with spin can play a role in the reversible formation and decomposition of lithium peroxide as well as the reversible formation and decomposition of electrolyte molecules.

Collective vibrations in cluster models for semiconductor surfaces: vibrational spectra of acetylenyl and methylacetylenyl functionalized Si(111).

The geometries and harmonic vibrational frequencies of the acetylenyl and methylacetylenyl functionalized Si(111) surfaces are investigated using quantum chemical calculations. The vibrational spectra are computed using a previously introduced method whereby the collective vibrational modes that correspond to the vibrations of the infinite periodic system are derived from modest sized cluster models. Our predictions should be useful for the interpretation of the experimental spectra when they become available. The symmetry elements of the methylacetylenyl Si(111) surface that are derived from the space group of the optimized structure and a vibrational mode resulting from photon-adsorbate coupling are explored.

The emergence of collective vibrations in cluster models: quantum chemical study of the methyl-terminated Si(111) surface.

In this paper we present structures and harmonic vibrational frequencies for the methylated silicon (111) surface from quantum chemical calculations using both cluster models and periodic boundary conditions. The results from both calculations are in very good agreement with experimentally determined frequencies. We demonstrate that relatively small cluster models already show the emergence of collective vibrational modes and provide a general method for the assignment of vibrational frequencies for extended surfaces from cluster models. Finally, we discuss a vibrational mode that results from the coupling between near-surface phonons and the silicon-carbon bending modes.

An unusual case of abdominal pain in a female child.

Non-traumatic abdominal pain is a common presenting complaint in emergency department (ED) patients, quoted in some contemporary literature as being the third most frequent reason for ED visits. We present the ED and hospital course of an unusual case of an 11 year old female with right lower quadrant abdominal pain. The admission assessment of this patient was "possible appendicitis versus gastroenteritis"; however, laparatomy revealed a right adnexal torsion. The need for emergency medicine physicians to always include gynecologic and other less common causes in the differential diagnosis and workup of abdominal pain in children is emphasized.