Water hexamer: Self-consistent phonons versus reversible scaling versus replica exchange molecular dynamics

Classical free energies for the cage and prism isomers of water hexamer computed by the self- consistent phonons (SCP) method and reversible scaling (RS) method are presented for several flexible water potentials. Both methods have been augmented with a rotational correction for improved accuracy when working with clusters. Comparison of the SCP results with the RS results suggests a fairly broad temperature range over which the SCP approximation can be expected to give accurate results for systems of water clusters, and complements a previously reported assessment of SCP. Discrepancies between the SCP and RS results presented here, and recently published replica exchange molecular dynamics (REMD) results bring into question the convergence of the REMD and accompanying replica exchange path integral molecular dynamics results. In addition to the ever-present specter of unconverged results, several possible sources for the discrepancy are explored based on inherent characteristics of the methods used.Comment: Submitted to Journal Chemical Physic

Anomalous quantum and isotope effects in water clusters: Physical phenomenon, model artifact, or bad approximation?

Free energy differences $\Delta F:=F-F_{\text{prism}}$ are computed for several isomers of water hexamer relative to the "prism" isomer using the self-consistent phonons method. %$\Delta F:=F-F({prism})$ We consider the isotope effect defined by the quantity $\delta F_{D_2O}:=\Delta F_{\rm D_2O}-\Delta F_{\rm H_2O}$, and the quantum effect, $\delta F_{\hbar=0}:=\Delta F_{\hbar=0}-\Delta F_{\rm H_2O}$, and evaluate them using different flexible water models. While both $\delta F_{D_2O}$ and $\delta F_{\hbar=0}$ are found to be rather small for all of the potentials, they are especially small for two of the empirical models, q-TIP4P/F and TTM3-F, compared to q-SPC/Fw and the two {\it abinitio}-based models, WHBB and HBB2-pol. This qualitative difference in the properties of different water models cannot be explained by one being "more accurate" than the other. We speculate as to whether the observed anomalies are caused by the special properties of water systems, or are an artifact of either the potential energy surface form/parametrization or the numerical approximation used.Comment: Submitted to Journal of Chemical Physic

Assessing the Performance of the Diffusion Monte Carlo Method as Applied to the Water Monomer, Dimer, and Hexamer

The Diffusion Monte Carlo (DMC) method is applied to the water monomer, dimer, and hexamer, using q-TIP4P/F, one of the most simple, empirical water models with flexible monomers. The bias in the time step ($\Delta\tau$) and population size ($N_w$) is investigated. For the binding energies, the bias in $\Delta\tau$ cancels nearly completely, while a noticeable bias in $N_w$ still remains. However, for the isotope shift, (e.g, in the dimer binding energies between (H$_2$O)$_2$ and (D$_2$O)$_2$) the systematic errors in $N_w$ do cancel. Consequently, very accurate results for the latter (within $\sim 0.01$ kcal/mol) are obtained with relatively moderate numerical effort ($N_w\sim 10^3$). For the water hexamer and its (D$_2$O)$_6$ isotopomer the DMC results as a function of $N_w$ are examined for the cage and prism isomers. For a given isomer, the issue of the walker population leaking out of the corresponding basin of attraction is addressed by using appropriate geometric constraints. The population size bias for the hexamer is more severe, and in order to maintain accuracy similar to that of the dimer, the population size $N_w$ must be increased by about two orders of magnitude. Fortunately, when the energy difference between cage and prism is taken, the biases cancel, thereby reducing the systematic errors to within $\sim 0.01$ kcal/mol when using a population of $N_w=4.8\times 10^5$ walkers. Consequently, a very accurate result for the isotope shift is also obtained. Notably, both the quantum and the isotope effects for the prism-cage energy difference are small.Comment: 11 pages, 5 figures, 36 references. Submitted to the Journal of Physical Chemistr

Small size boundary effects on two-pion interferometry

The Bose-Einstein correlations of two identically charged pions are derived when these particles, the most abundantly produced in relativistic heavy ion collisions, are confined in finite volumes. Boundary effects on single pion spectrum are also studied. Numerical results emphasize that conventional formulation usually adopted to describe two-pion interferometry should not be used when the source size is small, since this is the most sensitive case to boundary effects. Specific examples are considered for better illustration.Comment: more discussion on Figure4 and diffuse boundar

Multiregional origins of the domesticated tetraploid wheats

We used genotyping-by-sequencing (GBS) to investigate the evolutionary history of domesticated tetraploid wheats. With a panel of 189 wild and domesticated wheats, we identified 1,172,469 single nucleotide polymorphisms (SNPs) with a read depth ≥3. Principal component analyses (PCAs) separated the Triticum turgidum and Triticum timopheevii accessions, as well as wild T. turgidum from the domesticated emmers and the naked wheats, showing that SNP typing by GBS is capable of providing robust information on the genetic relationships between wheat species and subspecies. The PCAs and a neighbour-joining analysis suggested that domesticated tetraploid wheats have closest affinity with wild emmers from the northern Fertile Crescent, consistent with the results of previous genetic studies on the origins of domesticated wheat. However, a more detailed examination of admixture and allele sharing between domesticates and different wild populations, along with genome-wide association studies (GWAS), showed that the domesticated tetraploid wheats have also received a substantial genetic input from wild emmers from the southern Levant. Taking account of archaeological evidence that tetraploid wheats were first cultivated in the southern Levant, we suggest that a pre-domesticated crop spread from this region to southeast Turkey and became mixed with a wild emmer population from the northern Fertile Crescent. Fixation of the domestication traits in this mixed population would account for the allele sharing and GWAS results that we report. We also propose that feralization of the component of the pre-domesticated population that did not acquire domestication traits has resulted in the modern wild population from southeast Turkey displaying features of both the domesticates and wild emmer from the southern Levant, and hence appearing to be the sole progenitor of domesticated tetraploids when the phylogenetic relationships are studied by methods that assume a treelike pattern of evolution.This work was supported by: TAB, 339941, European Research Council; TAB, NE/M010805/1, Natural Environment Research Councilinfo:eu-repo/semantics/publishedVersio

Adapting to survive: how Candida spp. respond to environmental physiological constraints

Candida species are important human pathogens and have emerged as a leading cause of nosocomial fungal infections. In order to survive and proliferate within the human host, these species have to adapt to the different niches and assimilate the available nutrients. For instance, during infection, they can encounter glucose-poor microenvironments and some studies have suggested that the ability to use non-fermentable carbon sources affects the virulence of these pathogens. Our studies have demonstrated that the presence of alternative carbon sources such as lactate and acetate influence Candida biofilm formation, antifungal drug resistance and immune recognition. Additionally, there is evidence that carboxylate transporters have a role on these processes. An overview of the most significant results will be presented.Our data support the view that the different carbon sources present in the host niches affect directly the physiology of Candida cells, with implications on how these pathogens respond to antifungal treatment

P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Evaluate the potential role of p38 inhibitors for the treatment of osteoarthritis using an animal model of joint degeneration (iodoacetate-induced arthritis) and a pain model (Hargraeves assay).</p> <p>Methods</p> <p>P38 kinase activity was evaluated in a kinase assay by measuring the amount of phosphorylated substrate ATF2 using a phosphoATF2 (Thr⁷¹) specific primary antibody and an alkaline phosphate coupled secondary antibody and measuring the OD at 405 nm. TNFα and IL-1β secretion from LPS stimulated THP-1 monocytic cells and human peripheral blood mononuclear cells were measured by ELISA. Rats treated with vehicle or p38 inhibitor were injected intra-articularly in one knee with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The effect of p38 inhibitors on hyperalgesia was evaluated in rats given an intraplantar injection of carrageenan and 4 h later the paw withdrawal time to a radiant heat source was measured.</p> <p>Results</p> <p>SB-203580 and VX-745 are both potent inhibitors of p38 with IC₅₀s of 136 ± 64 nM and 35 ± 14 nM (mean ± S.D.), respectively. Similarly, SB-203580 and VX-745 potently inhibited TNF release from LPS stimulated human THP-1 cells with IC₅₀s of 72 ± 15 nM; and 29 ± 14 nM (mean ± S.D.) respectively. TNF release from LPS stimulated human peripheral blood mononuclear cells was inhibited with IC₅₀s 16 ± 6 nM and 14 ± 8 nM, (mean ± S.D.) for SB-203580 and VX-745 and IL-1 was inhibited with IC₅₀s of 20 ± 8 nM and 15 ± 4 nM (mean ± S.D.), respectively. SB-203580 and VX-745 administered orally at a dose of 50 mg/kg resulted in the significant (p < 0.05) inhibition of joint degeneration in the rat iodoacetate model of 45% and 31%, respectively. SB-203580 demonstrated a dose related inhibition of joint degeneration of 30, 25, 12 and 8% at 50, 25, 10 and 5 mg/kg p.o. b.i.d. in the rat iodoacetate model. Similarly, both p38 inhibitors significantly (p < 0.05) attenuated the pain response (paw withdrawal time) in the Hargraeves hyperalgesia assay when administered orally at 30, 10 and 3 mg/kg.</p> <p>Conclusion</p> <p>SB203580 and VX-745 demonstrated attenuation of both cartilage degeneration and pain in animal models and suggest that p38 inhibitors may be a useful approach for the treatment of osteoarthritis.</p