Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there ...is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and Δ
H
f
for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in Δ
H
f
decreased by about 10 %; for organic solids, the AUE in Δ
H
f
dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol
-1
in PM6 and 10.8 kcal/mol
-1
in PM7 to 3.8 kcal/mol
-1
. The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved.
Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, ...we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk of late-onset disorders.
Contrary to the long-held view that most humans harbour only identical mitochondrial genomes, deep resequencing has uncovered unanticipated extreme genetic variation within mitochondrial DNA (mtDNA). ...Most, if not all, humans contain multiple mtDNA genotypes (heteroplasmy); specific patterns of variants accumulate in different tissues, including cancers, over time; and some variants are preferentially passed down or suppressed in the maternal germ line. These findings cast light on the origin and spread of mtDNA mutations at multiple scales, from the organelle to the human population, and challenge the conventional view that high percentages of a mutation are required before a new variant has functional consequences.
Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter ...optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol(-1). For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol(-1). The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6-31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6-31G*: 7.4, and AM1: 10.0 kcal mol(-1). Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries.
AGE/RAGE signaling has been a well-studied cascade in many different disease states, particularly diabetes. Due to the complex nature of the receptor and multiple intersecting pathways, the AGE/RAGE ...signaling mechanism is still not well understood. The purpose of this review is to highlight key areas of AGE/RAGE mediated vascular calcification as a complication of diabetes. AGE/RAGE signaling heavily influences both cellular and systemic responses to increase bone matrix proteins through PKC, p38 MAPK, fetuin-A, TGF-β, NFκB, and ERK1/2 signaling pathways in both hyperglycemic and calcification conditions. AGE/RAGE signaling has been shown to increase oxidative stress to promote diabetes-mediated vascular calcification through activation of Nox-1 and decreased expression of SOD-1. AGE/RAGE signaling in diabetes-mediated vascular calcification was also attributed to increased oxidative stress resulting in the phenotypic switch of VSMCs to osteoblast-like cells in AGEs-induced calcification. Researchers found that pharmacological agents and certain antioxidants decreased the level of calcium deposition in AGEs-induced diabetes-mediated vascular calcification. By understanding the role the AGE/RAGE signaling cascade plays diabetes-mediated vascular calcification will allow for pharmacological intervention to decrease the severity of this diabetic complication.
In the open access book Higher Flight, pre-eminent scholar and activist James B. Stewart offers a much-needed critical assessment of the current state of Black/Africana studies in order to chart a ...path forward. In three equally groundbreaking sections, Stewart clarifies and refines the distinctive approaches that currently define the field; shows how creative production in particular can serve as a unique means of cultural analysis and political mobilization; and suggests how to restore the balance between intellectual inquiry and direct action in order to improve the actual lived experiences of people of African descent. Each section incorporates various forms of expression, including Stewart’s essays, speeches, and poems, and the book as a whole covers a vast range of figures, issues, and phenomena, from W.E.B, Du Bois to James Baldwin, from conscious hip-hop to the Black Lives Matter movement, from Hurricane Katrina to Covid-19, and very much in between. Written with an accessible authoritativeness few Black/Africana scholar-activists can match, Stewart offers a must-read not only for researchers, but also for graduate students and advanced undergraduate students interested in Black/Africana studies, diaspora studies, ethnic studies, Black womanist/feminist studies, and American studies, as well as in African American history, culture, politics, economics, literature, and philosophy. The ebook editions of this book are available open access under a CC BY-NC-ND 4.0 licence on bloomsburycollections.com. Open access was funded by the Bloomsbury Open Collections Library Collective.
Underexpanded jet releases from circular nozzles have been studied extensively both experimentally and numerically. However, jet releases from rectangular openings have received much less attention ...and information on their dispersion behaviour is not as widely available. In this paper, Computational Fluid Dynamics (CFD) is used to assess the suitability of using a pseudo-source approach to model jet releases from rectangular openings. A comparative study is performed to evaluate the effect of nozzle shape on jet structure and dispersion characteristics for underexpanded hydrogen jet releases. Jet releases issuing from a circular nozzle and rectangular nozzles with aspect ratios ranging from two to eight are modelled, including resolution of the near-field behaviour. The experimental work of Ruggles and Ekoto (2012, 2014) is used as a basis for validating the modelling approach used and an additional case study, in which jets with a stagnation-to-ambient pressure ratio of 300:1 are modelled, is also performed. The CFD results show that for the 10:1 pressure ratio release the hazard volume and hazard distance remain largely unaffected by nozzle shape. For the higher pressure release, the hazard volume is larger for the rectangular nozzle releases than the equivalent release through a circular orifice, though the distance to lower flammability limit is comparable across the range of nozzle shapes considered. For both of the release pressures simulated the CFD results illustrate that a pseudo-source approach produces conservative results for all nozzle shapes considered. This finding has useful practical implications for consequence analysis in industrial applications, such as the assessment of leaks from flanges and connections in pipework.
In recent years, chemical imaging was prognosticated to become one of the key analytical applications for laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). However, moderate ...spatial resolution and the associated measurement time required for a larger sampling area, have restricted this versatile, high sensitivity technique from being routinely used in two-dimensional chemical imaging. This work describes the development and investigation of a low dispersion sample chamber (tube cell), which allows improvement of the imaging capabilities by reduction of the single LA shot duration to 30 ms (full width at 1% maximum). The new tube cell is based on a constant laminar flow and a well-controlled delivery of the laser-ablated aerosol into the transport system, leading to minimized tailing of the aerosol washout and helping to separate the signals even at repetition rates as high as 20–30 Hz. To demonstrate the improved imaging capabilities, microstructured metallic thin film patterns were analyzed at a spatial resolution of a few micrometers. The LA-ICP-MS results obtained were comparable to Synchrotron-based micro-X-ray fluorescence (SR-microXRF). The suitability of the newly designed cell for multielement acquisitions was demonstrated using a simultaneous ICP-Mattauch–Herzog-MS. Finally, the novel laser ablation cell was applied to image the distribution of a metal-tagged biomarker in a thin section of breast cancer tissue. This application demonstrates that the technique is able to produce subcellular (∼1 μm) spatial resolution, which is crucial for morphological assessment in cancer diagnostics.
The applicability of the newly developed PM6 method for modeling proteins is investigated. In order to allow the geometries of such large systems to be optimized rapidly, three modifications were ...made to the conventional semiempirical procedure: the matrix algebra method for solving the self-consistent field (SCF) equations was replaced with a localized molecular orbital method (MOZYME), Baker’s Eigenfollowing technique for geometry optimization was replaced with the L-BFGS function minimizer, and some of the integrals used in the NDDO set of approximations were replaced with point-charge and polarization functions. The resulting method was used in the unconstrained geometry optimization of 45 proteins ranging in size from a simple nonapeptide of 244 atoms to an importin consisting of 14,566 atoms. For most systems, PM6 gave structures in good agreement with the reported X-ray structures. Some derived properties, such as pKa and bulk elastic modulus, were also calculated. The applicability of PM6 to model transition states was investigated by simulating a hypothetical reaction step in the chymotrypsin-catalyzed hydrolysis of a peptide bond. A proposed technique for generating accurate protein geometries, starting with X-ray structures, was examined.
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