Metadynamics molecular dynamics and isothermal Brownian-type molecular dynamics simulations for the chiral cluster Au18.

In an effort to gain insight into enantiomeric transitions, their transition mechanism, time span of transitions and distribution of time spans etc, we performed molecular dynamics (MD) simulations on chiral clusters Au10, Au15and Au18, and found that viable reaction coordinates can be deduced from simulation data for enlightening the enantiomeric dynamics for Au10and Au15, but not so for Au18. The failure in translating the Au18-L ⇌ Au18-R transitions by MD simulations has been chalked up to the thermal energykBTat 300 K being much lower than energy barriers separating the enantiomers of Au18. Two simulation strategies were taken to resolve this simulation impediment. The first one uses the well-tempered metadynamics MD (MMD) simulation, and the second one adeptly applies first a somewhat crude MMD simulation to locate a highly symmetrical isomer Au18Sand subsequently employed it as initial configuration in the MD simulation. In both strategies, we work in collective variable space of lower dimensionality. The well-tempered MMD simulation tactic was carried out aiming to offer a direct verification of Au18enantiomers, while the tactic to conduct MMD/MD simulations in two consecutive simulation steps was intended to provide an indirect evidence of the existence of enantiomers of Au18given that energy barriers separating them are much higher than ca.kBTat 300 K. This second tactic, in addition to confirming indirectly Au18-L and Au18-R starting from the symmetrical cluster Au18S, the simulation results shed light also on the mechanism akin to associative/nonassociative reaction transitions.

Idiopathic ileal volvulus with multiple concomitant infections in a starving man.

BACKGROUND: Small bowel volvulus is defined as the torsion of the small intestine, potentially leading to bowel obstruction, gangrene and perforation. It is a rare condition, especially in adults. CASE PRESENTATION: A 30-year-old man was retrieved from the jungle with severe weight loss and abdominal symptoms. He succumbed to death despite 22 days of intensive medical treatment. An autopsy revealed a ruptured gangrenous ileal volvulus with peritonitis and subdiaphragmatic abscess. Further laboratory analysis detected systemic Candida tropicalis and intestinal gramnegative bacterial sepsis, systemic Zika virus viremia, leptospirosis complicating rhabdomyolysis and disseminated intravascular coagulopathy, Type I Herpes Simplex virus infection of the tongue and upper gastrointestinal tract. The cause of death was the ruptured ileal volvulus, complicated with upper gastrointestinal bleeding due to Herpes simplex virus esophagitis in a malnourished patient with resolving leptospirosis and underlying Zika virus co-infection. CONCLUSION: Rare clinical scenarios of adult-onset intestinal volvulus with concomitant multiple infections precludes clinical diagnosis and early treatment, leading to devastating consequences of clinical outcome. The positive clinical and postmortem correlation is a good learning lesson in many disciplines of medicine and science.

Intraoperative frozen section sentinel lymph node assessment in breast cancer: A tertiary institution experience.

INTRODUCTION: Intraoperative frozen section lymph node assessment helps to predict axillary lymph node metastasis in breast cancer. However, the accuracy of this frozen section analysis may vary among institutions. This study describes our institution's experience in intraoperative analysis of sentinel lymph node and aims to determine the accuracy, sensitivity and specificity of our assessment. MATERIALS AND METHODS: We retrospectively analysed the histopathological material and data from 82 breast cancer patients diagnosed over a period of four years who underwent intraoperative frozen section evaluation of sentinel lymph nodes. RESULTS: Frozen section analysis detected metastasis in 13 out of 82 cases and definitive pathological examination on the paraffin section confirmed these positive findings. There was no false positive case (specificity of 100%). The true positive cases comprised seven macrometastases, five micrometastases and one isolated tumour cells. Sampling error was noted in two cases in which the malignant cells were only present in the deeper final paraffin sections (false negative rate of 13.3%). The test sensitivity was 86.7% and the accuracy rate was 97.5%. These findings are comparable to other published data. CONCLUSION: Intraoperative frozen section analysis is a safe and reliable method for assessment of sentinel lymph node. Knowledge on limitation of frozen section analysis with diligent evaluation of frozen section specimen will be beneficial in reducing interpretation error.

A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse.

Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics.

Nonlinear wave propagation in porous materials based on the Biot theory.

Nonlinearity must be considered with some porous granular media because of the large deformation under seismic waves. In this study, the propagation of nonlinear waves in porous media is studied based on the Biot theory and the governing equations are obtained by the Lagrangian formulation. Three new nonlinear parameters are introduced to consider the coupled nonlinearity between the solid and fluid components in porous media. It is shown that an additional nonlinear wave with a double frequency is generated by the coupling effect of linear fast and slow waves. When only a shear wave is applied at the source, no double-frequency nonlinear wave is predicted and three nonlinear longitudinal waves are generated. On the basis of the practical case studies, the effect of strong nonlinearity is computed under the influence of a one-dimensional single longitudinal wave source and a single shear wave source.

Identification of a novel HLA-B allele, HLA-B*40:238, in a Taiwanese individual.

The HLA-B*40:238 allele has one non-synonymous transversion from HLA-B*40:01:01 at nucleotide position 484.

Broadband signal response of thermo-acoustic devices and its applications.

Thermo-acoustic (TA) transducers are generation of sound speakers without any mechanical vibration system which exhibit an extremely wide frequency response range. In this paper, acoustic field responses to broadband input signals applied to both free-standing and nano-thinfilm-substrate thermo-acoustic devices are developed theoretically by using the Fourier transformation. A series of signals, including single-frequency signal, square root signal, periodic triangle wave signal, and periodic rectangular pulse signal, are applied to these TA devices in simulations and the acoustic pressure responses are investigated. The reproducibility of input signals is predicted. The single frequency results show good agreement with previously published experimental results. Alternative methods for reproducing the original signals with small distortion and low power consumption are introduced. The excellent performance of the TA devices on broadband signal responses will provide a design approach for sound parametric array and underwater communication equipment.

Use of density functional theory method to calculate structures of neutral carbon clusters Cn (3 ≤ n ≤ 24) and study their variability of structural forms.

In this work, we present modifications to the well-known basin hopping (BH) optimization algorithm [D. J. Wales and J. P. Doye, J. Phys. Chem. A 101, 5111 (1997)] by incorporating in it the unique and specific nature of interactions among valence electrons and ions in carbon atoms through calculating the cluster's total energy by the density functional tight-binding (DFTB) theory, using it to find the lowest energy structures of carbon clusters and, from these optimized atomic and electronic structures, studying their varied forms of topological transitions, which include a linear chain, a monocyclic to a polycyclic ring, and a fullerene/cage-like geometry. In this modified BH (MBH) algorithm, we define a spatial volume within which the cluster's lowest energy structure is to be searched, and introduce in addition a cut-and-splice genetic operator to increase the searching performance of the energy minimum than the original BH technique. The present MBH/DFTB algorithm is, therefore, characteristically distinguishable from the original BH technique commonly applied to nonmetallic and metallic clusters, technically more thorough and natural in describing the intricate couplings between valence electrons and ions in a carbon cluster, and thus theoretically sound in putting these two charged components on an equal footing. The proposed modified minimization algorithm should be more appropriate, accurate, and precise in the description of a carbon cluster. We evaluate the present algorithm, its energy-minimum searching in particular, by its optimization robustness. Specifically, we first check the MBH/DFTB technique for two representative carbon clusters of larger size, i.e., C60 and C72 against the popular cut-and-splice approach [D. M. Deaven and K. M. Ho, Phys. Rev. Lett. 75, 288 (1995)] that normally is combined with the genetic algorithm method for finding the cluster's energy minimum, before employing it to investigate carbon clusters in the size range C3-C24 studying their topological transitions. An effort was also made to compare our MBH/DFTB and its re-optimized results carried out by full density functional theory (DFT) calculations with some early DFT-based studies.

Effect of changes to the school food environment on eating behaviours and/or body weight in children: a systematic review.

Previous school obesity-prevention reviews have included multi-component interventions. Here, we aimed to review the evidence for the effect of isolated food environment interventions on both eating behaviours (including food purchasing) and/or body weight. Five electronic databases were searched (last updated 30 November 2013). Of the 1,002 unique papers identified, 55 reported on school food environment changes, based on a review of titles and abstracts. Thirty-seven further papers were excluded, for not meeting the inclusion criteria. The final selection consisted of 18 papers (14 United States, 4 United Kingdom). Two studies had a body mass index (BMI) outcome, 14 assessed purchasing or eating behaviours and two studies assessed both weight and behaviour. Seventeen of 18 papers reported a positive outcome on either BMI (or change in BMI) or the healthfulness of food sold or consumed. Two studies were rated as strong quality and 11 as weak. Only three studies included a control group. A school environment supportive of healthy eating is essential to combat heavy marketing of unhealthy food. Modification of the school food environment (including high-level policy changes at state or national level) can have a positive impact on eating behaviours. A need exists, however, for further high-quality studies.

Precursory signatures of protein folding/unfolding: from time series correlation analysis to atomistic mechanisms.

Folded conformations of proteins in thermodynamically stable states have long lifetimes. Before it folds into a stable conformation, or after unfolding from a stable conformation, the protein will generally stray from one random conformation to another leading thus to rapid fluctuations. Brief structural changes therefore occur before folding and unfolding events. These short-lived movements are easily overlooked in studies of folding/unfolding for they represent momentary excursions of the protein to explore conformations in the neighborhood of the stable conformation. The present study looks for precursory signatures of protein folding/unfolding within these rapid fluctuations through a combination of three techniques: (1) ultrafast shape recognition, (2) time series segmentation, and (3) time series correlation analysis. The first procedure measures the differences between statistical distance distributions of atoms in different conformations by calculating shape similarity indices from molecular dynamics simulation trajectories. The second procedure is used to discover the times at which the protein makes transitions from one conformation to another. Finally, we employ the third technique to exploit spatial fingerprints of the stable conformations; this procedure is to map out the sequences of changes preceding the actual folding and unfolding events, since strongly correlated atoms in different conformations are different due to bond and steric constraints. The aforementioned high-frequency fluctuations are therefore characterized by distinct correlational and structural changes that are associated with rate-limiting precursors that translate into brief segments. Guided by these technical procedures, we choose a model system, a fragment of the protein transthyretin, for identifying in this system not only the precursory signatures of transitions associated with α helix and ß hairpin, but also the important role played by weaker correlations in such protein folding dynamics.

Peptide dynamics by molecular dynamics simulation and diffusion theory method with improved basis sets.

Improved basis sets for the study of polymer dynamics by means of the diffusion theory, and tests on a melt of cis-1,4-polyisoprene decamers, and a toluene solution of a 71-mer syndiotactic trans-1,2-polypentadiene were presented recently [R. Gaspari and A. Rapallo, J. Chem. Phys. 128, 244109 (2008)]. The proposed hybrid basis approach (HBA) combined two techniques, the long time sorting procedure and the maximum correlation approximation. The HBA takes advantage of the strength of these two techniques, and its basis sets proved to be very effective and computationally convenient in describing both local and global dynamics in cases of flexible synthetic polymers where the repeating unit is a unique type of monomer. The question then arises if the same efficacy continues when the HBA is applied to polymers of different monomers, variable local stiffness along the chain and with longer persistence length, which have different local and global dynamical properties against the above-mentioned systems. Important examples of this kind of molecular chains are the proteins, so that a fragment of the protein transthyretin is chosen as the system of the present study. This peptide corresponds to a sequence that is structured in ß-sheets of the protein and is located on the surface of the channel with thyroxin. The protein transthyretin forms amyloid fibrils in vivo, whereas the peptide fragment has been shown [C. P. Jaroniec, C. E. MacPhee, N. S. Astrof, C. M. Dobson, and R. G. Griffin, Proc. Natl. Acad. Sci. U.S.A. 99, 16748 (2002)] to form amyloid fibrils in vitro in extended ß-sheet conformations. For these reasons the latter is given considerable attention in the literature and studied also as an isolated fragment in water solution where both experimental and theoretical efforts have indicated the propensity of the system to form ß turns or α helices, but is otherwise predominantly unstructured. Differing from previous computational studies that employed implicit solvent, we performed in this work the classical molecular dynamics simulation on a realistic model solution with the peptide embedded in an explicit water environment, and calculated its dynamic properties both as an outcome of the simulations, and by the diffusion theory in reduced statistical-mechanical approach within HBA on the premise that the mode-coupling approach to the diffusion theory can give both the long-range and local dynamics starting from equilibrium averages which were obtained from detailed atomistic simulations.

IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections.

IgG is the predominant immunoglobulin in cervicovaginal mucus (CVM), yet how immunoglobulin G (IgG) in mucus can protect against infections is not fully understood. IgG diffuses rapidly through cervical mucus, slowed only slightly by transient adhesive interactions with mucins. We hypothesize that this almost unhindered diffusion allows IgG to accumulate rapidly on pathogen surfaces, and the resulting IgG array forms multiple weak adhesive crosslinks to mucus gel that effectively trap (immobilize) pathogens, preventing them from initiating infections. Here, we report that herpes simplex virus serotype 1 (HSV-1) readily penetrated fresh, pH-neutralized ex vivo samples of CVM with low or no detectable levels of anti-HSV-1 IgG but was trapped in samples with even modest levels of anti-HSV-1 IgG. In samples with little or no endogenous anti-HSV-1 IgG, addition of exogenous anti-HSV-1 IgG, affinity-purified from intravenous immunoglobulin, trapped virions at concentrations below those needed for neutralization and with similar potency as endogenous IgG. Deglycosylating purified anti-HSV-1 IgG, or removing its Fc component, markedly reduced trapping potency. Finally, a non-neutralizing IgG against HSV-gG significantly protected mice against vaginal infection, and removing vaginal mucus by gentle lavage abolished protection. These observations suggest that IgG-Fc has a glycan-dependent "muco-trapping" effector function that may provide exceptionally potent protection at mucosal surfaces.

Epitaxial growth of graphene on 6H-silicon carbide substrate by simulated annealing method.

We grew graphene epitaxially on 6H-SiC(0001) substrate by the simulated annealing method. The mechanisms that govern the growth process were investigated by testing two empirical potentials, namely, the widely used Tersoff potential [J. Tersoff, Phys. Rev. B 39, 5566 (1989)] and its more refined version published years later by Erhart and Albe [Phys. Rev. B 71, 035211 (2005)]. Upon contrasting the results obtained by these two potentials, we found that the potential proposed by Erhart and Albe is generally more physical and realistic, since the annealing temperature at which the graphene structure just coming into view at approximately 1200 K is unambiguously predicted and close to the experimentally observed pit formation at 1298 K within which the graphene nucleates. We evaluated the reasonableness of our layers of graphene by calculating carbon-carbon (i) average bond-length, (ii) binding energy, and (iii) pair correlation function. Also, we compared with related experiments the various distance of separation parameters between the overlaid layers of graphene and substrate surface.

Characterization of the novel HLA-DPA1*02:02:04 allele.

HLA-DPA1*02:02:04 is identical to DPA1*02:02:03 except for a synonymous change at nucleotide position 138 (C to G) in exon 2.

Identification of a novel HLA-B allele, B*07:162, in a Taiwanese individual.

The new allele, HLA-B*07:162, is identical to HLA-B*07:12 in exon 2 but has a non-synonymous substitution at position 419 (A to C) in exon 3.

Pinned modes in lossy lattices with local gain and nonlinearity.

We introduce a discrete linear lossy system with an embedded "hot spot" (HS), i.e., a site carrying linear gain and complex cubic nonlinearity. The system can be used to model an array of optical or plasmonic waveguides, where selective excitation of particular cores is possible. Localized modes pinned to the HS are constructed in an implicit analytical form, and their stability is investigated numerically. Stability regions for the modes are obtained in the parameter space of the linear gain and cubic gain or loss. An essential result is that the interaction of the unsaturated cubic gain and self-defocusing nonlinearity can produce stable modes, although they may be destabilized by finite-amplitude perturbations. On the other hand, the interplay of the cubic loss and self-defocusing gives rise to a bistability.

Melting behavior of Ag14 cluster: an order parameter by instantaneous normal modes.

This paper studies the melting behavior of Ag(14) cluster employing the instantaneous normal mode (INM) analysis that was previously developed for bimetallic cluster Ag(17)Cu(2). The isothermal Brownian-type molecular dynamics simulation is used to generate atom configurations of Ag(14) at different temperatures up to 1500 K. At each temperature, these atomic configurations are then analyzed by the INM technique. To delve into the melting behavior of Ag(14) cluster which differs from Ag(17)Cu(2) by the occurrence of an anomalous prepeak in the specific heat curve in addition to the typical principal peak, we appeal to examining the order parameter τ(T) defined in the context of the INM method. Two general approaches are proposed to calculate τ(T). In one, τ(T) is defined in terms of the INM vibrational density of states; in another, τ(T) is defined considering the cluster as a rigid body with its rotational motions described by three orthogonal eigenvectors. Our results for Ag(14) by these two methods indicate the mutual agreement of τ(T) calculated and also the consistent interpretation of the melting behavior with the specific heat data. The order parameter τ(T) provides in addition an insightful interpretation between the melting of clusters and the concept of broken symmetry which has been found successful in studies of the melting transition of bulk systems.

Comparative study of cluster Ag17Cu2 by instantaneous normal mode analysis and by isothermal Brownian-type molecular dynamics simulation.

We perform isothermal Brownian-type molecular dynamics simulations to obtain the velocity autocorrelation function and its time Fourier-transformed power spectral density for the metallic cluster Ag(17)Cu(2). The temperature dependences of these dynamical quantities from T = 0 to 1500 K were examined and across this temperature range the cluster melting temperature T(m), which we define to be the principal maximum position of the specific heat is determined. The instantaneous normal mode analysis is then used to dissect the cluster dynamics by calculating the vibrational instantaneous normal mode density of states and hence its frequency integrated value I(j) which is an ensemble average of all vibrational projection operators for the jth atom in the cluster. In addition to comparing the results with simulation data, we look more closely at the entities I(j) of all atoms using the point group symmetry and diagnose their temperature variations. We find that I(j) exhibit features that may be used to deduce T(m), which turns out to agree very well with those inferred from the power spectral density and specific heat.

Caspase-3-mediated degradation of condensin Cap-H regulates mitotic cell death.

Mitotic death is a major form of cell death in cancer cells that have been treated with chemotherapeutic drugs. However, the mechanisms underlying this form of cell death is poorly understood. Here, we report that the loss of chromosome integrity is an important determinant of mitotic death. During prolonged mitotic arrest, caspase-3 is activated and it cleaves Cap-H, a subunit of condensin I. The depletion of Cap-H results in the loss of condensin I complex at the chromosomes, thus affecting the integrity of the chromosomes. Consequently, DNA fragmentation by caspase-activated DNase is facilitated, thus driving the cell towards mitotic death. By expressing a caspase-resistant form of Cap-H, mitotic death is abrogated and the cells are able to reenter interphase after a long mitotic delay. Taken together, we provide new insights into the molecular events that occur during mitotic death.

Identification of the novel allele HLA-B*13:01:03 by sequence-based typing method in a Taiwanese individual.

A new human leukocyte antigen (HLA)-B allele, B*13:01:03 (B*130103), has been found in a Taiwanese individual. It differs from B*13:01:01 (B*130101) by a synonymous substitution at codon 113 (CAT->CAC).