Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix.

The refinement of biomolecular crystallographic models relies on geometric restraints to help to address the paucity of experimental data typical in these experiments. Limitations in these restraints can degrade the quality of the resulting atomic models. Here, an integration of the full all-atom Amber molecular-dynamics force field into Phenix crystallographic refinement is presented, which enables more complete modeling of biomolecular chemistry. The advantages of the force field include a carefully derived set of torsion-angle potentials, an extensive and flexible set of atom types, Lennard-Jones treatment of nonbonded interactions and a full treatment of crystalline electrostatics. The new combined method was tested against conventional geometry restraints for over 22 000 protein structures. Structures refined with the new method show substantially improved model quality. On average, Ramachandran and rotamer scores are somewhat better, clashscores and MolProbity scores are significantly improved, and the modeling of electrostatics leads to structures that exhibit more, and more correct, hydrogen bonds than those refined using traditional geometry restraints. In general it is found that model improvements are greatest at lower resolutions, prompting plans to add the Amber target function to real-space refinement for use in electron cryo-microscopy. This work opens the door to the future development of more advanced applications such as Amber-based ensemble refinement, quantum-mechanical representation of active sites and improved geometric restraints for simulated annealing

Algebraic Aspects of Abelian Sandpile Models

The abelian sandpile models feature a finite abelian group G generated by the operators corresponding to particle addition at various sites. We study the canonical decomposition of G as a product of cyclic groups G = Z_{d_1} X Z_{d_2} X Z_{d_3}...X Z_{d_g}, where g is the least number of generators of G, and d_i is a multiple of d_{i+1}. The structure of G is determined in terms of toppling matrix. We construct scalar functions, linear in height variables of the pile, that are invariant toppling at any site. These invariants provide convenient coordinates to label the recurrent configurations of the sandpile. For an L X L square lattice, we show that g = L. In this case, we observe that the system has nontrivial symmetries coming from the action of the cyclotomic Galois group of the (2L+2)th roots of unity which operates on the set of eigenvalues of the toppling matrix. These eigenvalues are algebraic integers, whose product is the order |G|. With the help of this Galois group, we obtain an explicit factorizaration of |G|. We also use it to define other simpler, though under-complete, sets of toppling invariants.Comment: 39 pages, TIFR/TH/94-3

Domain wall QCD with physical quark masses

We present results for several light hadronic quantities ($f_\pi$, $f_K$, $B_K$, $m_{ud}$, $m_s$, $t_0^{1/2}$, $w_0$) obtained from simulations of 2+1 flavor domain wall lattice QCD with large physical volumes and nearly-physical pion masses at two lattice spacings. We perform a short, O(3)%, extrapolation in pion mass to the physical values by combining our new data in a simultaneous chiral/continuum `global fit' with a number of other ensembles with heavier pion masses. We use the physical values of $m_\pi$, $m_K$ and $m_\Omega$ to determine the two quark masses and the scale - all other quantities are outputs from our simulations. We obtain results with sub-percent statistical errors and negligible chiral and finite-volume systematics for these light hadronic quantities, including: $f_\pi$ = 130.2(9) MeV; $f_K$ = 155.5(8) MeV; the average up/down quark mass and strange quark mass in the $\bar {\rm MS}$ scheme at 3 GeV, 2.997(49) and 81.64(1.17) MeV respectively; and the neutral kaon mixing parameter, $B_K$, in the RGI scheme, 0.750(15) and the $\bar{\rm MS}$ scheme at 3 GeV, 0.530(11).Comment: 131 pages, 30 figures. Updated to match published versio

Periodic One-Dimensional Hopping Model with one Mobile Directional Impurity

Analytic solution is given in the steady state limit for the system of Master equations describing a random walk on one-dimensional periodic lattices with arbitrary hopping rates containing one mobile, directional impurity (defect bond). Due to the defect, translational invariance is broken, even if all other rates are identical. The structure of Master equations lead naturally to the introduction of a new entity, associated with the walker-impurity pair which we call the quasi-walker. The velocities and diffusion constants for both the random walker and impurity are given, being simply related to that of the quasi-particle through physically meaningful equations. Applications in driven diffusive systems are shown, and connections with the Duke-Rubinstein reptation models for gel electrophoresis are discussed.Comment: 31 LaTex pages, 5 Postscript figures included, to appear in Journal of Statistical Physic

Motion of a driven tracer particle in a one-dimensional symmetric lattice gas

We study the dynamics of a tracer particle subject to a constant driving force $E$ in a one-dimensional lattice gas of hard-core particles whose transition rates are symmetric. We show that the mean displacement of the driven tracer grows in time, $t$, as $\sqrt{\alpha t}$, rather than the linear time dependence found for driven diffusion in the bath of non-interacting (ghost) particles. The prefactor $\alpha$ is determined implicitly, as the solution of a transcendental equation, for an arbitrary magnitude of the driving force and an arbitrary concentration of the lattice gas particles. In limiting cases the prefactor is obtained explicitly. Analytical predictions are seen to be in a good agreement with the results of numerical simulations.Comment: 21 pages, LaTeX, 4 Postscript fugures, to be published in Phys. Rev. E, (01Sep, 1996

Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats

Peer reviewedPublisher PD

A case study in identifying acceptable bitrates for human face recognition tasks

Face recognition from images or video footage requires a certain level of recorded image quality. This paper derives acceptable bitrates (relating to levels of compression and consequently quality) of footage with human faces, using an industry implementation of the standard H.264/MPEG-4 AVC and the Closed-Circuit Television (CCTV) recording systems on London buses. The London buses application is utilized as a case study for setting up a methodology and implementing suitable data analysis for face recognition from recorded footage, which has been degraded by compression. The majority of CCTV recorders on buses use a proprietary format based on the H.264/MPEG-4 AVC video coding standard, exploiting both spatial and temporal redundancy. Low bitrates are favored in the CCTV industry for saving storage and transmission bandwidth, but they compromise the image usefulness of the recorded imagery. In this context, usefulness is determined by the presence of enough facial information remaining in the compressed image to allow a specialist to recognize a person. The investigation includes four steps: (1) Development of a video dataset representative of typical CCTV bus scenarios. (2) Selection and grouping of video scenes based on local (facial) and global (entire scene) content properties. (3) Psychophysical investigations to identify the key scenes, which are most affected by compression, using an industry implementation of H.264/MPEG-4 AVC. (4) Testing of CCTV recording systems on buses with the key scenes and further psychophysical investigations. The results showed a dependency upon scene content properties. Very dark scenes and scenes with high levels of spatial–temporal busyness were the most challenging to compress, requiring higher bitrates to maintain useful information

Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats

Background Ischemic stroke is the major cause of long-term severe disability and death in aged population. Cell death in the infarcted region of the brain induces immune reaction leading to further progression of tissue damage. Immunomodulatory function of mesenchymal stem cells (MSCs) has been shown in multiple preclinical studies; however, it has not been successfully translated to a routine clinical practice due to logistical, economical, regulatory, and intellectual property obstacles. It has been recently demonstrated that therapeutic effect of intravenously administered MSCs can be recapitulated by extracellular vesicles (EVs) derived from them. However, in contrast to MSCs, EVs were not capable to decrease stroke-induced neuroinflammation. Therefore, the aim of the study was to investigate if intra-arterial delivery of MSC-derived EVs will have stronger impact on focal brain injury-induced neuroinflammation, which mimics ischemic stroke, and how it compares to MSCs. Methods The studies were performed in adult male Wistar rats with focal brain injury induced by injection of 1 mu l of 50 nmol ouabain into the right hemisphere. Two days after brain insult, 5 x 10(5) human bone marrow MSCs (hBM-MSCs) labeled with Molday ION or 1.3 x 10(9) EVs stained with PKH26 were intra-arterially injected into the right hemisphere under real-time MRI guidance. At days 1, 3, and 7 post-transplantation, the rats were decapitated, the brains were removed, and the presence of donor cells or EVs was analyzed. The cellular immune response in host brain was evaluated immunohistochemically, and humoral factors were measured by multiplex immunoassay. Results hBM-MSCs and EVs transplanted intra-arterially were observed in the rat ipsilateral hemisphere, near the ischemic region. Immunohistochemical analysis of brain tissue showed that injection of hBM-MSCs or EVs leads to the decrease of cell activation by ischemic injury, i.e., astrocytes, microglia, and infiltrating leucocytes, including T cytotoxic cells. Furthermore, we observed significant decrease of pro-inflammatory cytokines and chemokines after hBM-MSC or EV infusion comparing with non-treated rats with focal brain injury. Conclusions Intra-arterially injected EVs attenuated neuroinflammation evoked by focal brain injury, which mimics ischemic stroke, and this effect was comparable to intra-arterial hBM-MSC transplantation. Thus, intra-arterial injection of EVs might be an attractive therapeutic approach, which obviates MSC-related obstacles

Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophage