The Glass Transition Temperature of Water: A Simulation Study

We report a computer simulation study of the glass transition for water. To mimic the difference between standard and hyperquenched glass, we generate glassy configurations with different cooling rates and calculate the $T$ dependence of the specific heat on heating. The absence of crystallization phenomena allows us, for properly annealed samples, to detect in the specific heat the simultaneous presence of a weak pre-peak (``shadow transition''), and an intense glass transition peak at higher temperature. We discuss the implications for the currently debated value of the glass transition temperature of water. We also compare our simulation results with the Tool-Narayanaswamy-Moynihan phenomenological model.Comment: submitted to Phys. Re

Solidity of Viscous Liquids

Recent NMR experiments on supercooled toluene and glycerol by Hinze and Bohmer show that small rotation angles dominate with only few large molecular rotations. These results are here interpreted by assuming that viscous liquids are solid-like on short length scales. A characteristic length, the "solidity length", separates solid-like behavior from liquid-like behavior.Comment: Plain RevTex file, no figure

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8[superscript +] T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4[superscript +] T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.Bill & Melinda Gates FoundationRagon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (AI091693)National Institutes of Health (U.S.) (AI095109)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32CA180586)Hertz Foundation (Graduate Fellowship)National Science Foundation (U.S.). Graduate Research Fellowshi

Metastable liquid-liquid phase transition in a single-component system with only one crystal phase and no density anomaly

We investigate the phase behavior of a single-component system in 3 dimensions with spherically-symmetric, pairwise-additive, soft-core interactions with an attractive well at a long distance, a repulsive soft-core shoulder at an intermediate distance, and a hard-core repulsion at a short distance, similar to potentials used to describe liquid systems such as colloids, protein solutions, or liquid metals. We showed [Nature {\bf 409}, 692 (2001)] that, even with no evidences of the density anomaly, the phase diagram has two first-order fluid-fluid phase transitions, one ending in a gas--low-density liquid (LDL) critical point, and the other in a gas--high-density liquid (HDL) critical point, with a LDL-HDL phase transition at low temperatures. Here we use integral equation calculations to explore the 3-parameter space of the soft-core potential and we perform molecular dynamics simulations in the interesting region of parameters. For the equilibrium phase diagram we analyze the structure of the crystal phase and find that, within the considered range of densities, the structure is independent of the density. Then, we analyze in detail the fluid metastable phases and, by explicit thermodynamic calculation in the supercooled phase, we show the absence of the density anomaly. We suggest that this absence is related to the presence of only one stable crystal structure.Comment: 15 pages, 21 figure

NQO2 is a reactive oxygen species generating off-target for acetaminophen

[Image: see text] The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity

Complex lithium ion dynamics in simulated LiPO3 glass studied by means of multi-time correlation functions

Molecular dynamics simulations are performed to study the lithium jumps in LiPO3 glass. In particular, we calculate higher-order correlation functions that probe the positions of single lithium ions at several times. Three-time correlation functions show that the non-exponential relaxation of the lithium ions results from both correlated back-and-forth jumps and the existence of dynamical heterogeneities, i.e., the presence of a broad distribution of jump rates. A quantitative analysis yields that the contribution of the dynamical heterogeneities to the non-exponential depopulation of the lithium sites increases upon cooling. Further, correlated back-and-forth jumps between neighboring sites are observed for the fast ions of the distribution, but not for the slow ions and, hence, the back-jump probability depends on the dynamical state. Four-time correlation functions indicate that an exchange between fast and slow ions takes place on the timescale of the jumps themselves, i.e., the dynamical heterogeneities are short-lived. Hence, sites featuring fast and slow lithium dynamics, respectively, are intimately mixed. In addition, a backward correlation beyond the first neighbor shell for highly mobile ions and the presence of long-range dynamical heterogeneities suggest that fast ion migration occurs along preferential pathways in the glassy matrix. In the melt, we find no evidence for correlated back-and-forth motions and dynamical heterogeneities on the length scale of the next-neighbor distance.Comment: 12 pages, 13 figure

Relaxation in the glass-former acetyl salicylic acid studied by deuteron magnetic resonance and dielectric spectroscopy

Supercooled liquid and glassy acetyl salicylic acid was studied using dielectric spectroscopy and deuteron relaxometry in a wide temperature range. The supercooled liquid is characterized by major deviations from thermally activated behavior. In the glass the secondary relaxation exhibits the typical features of a Johari-Goldstein process. Via measurements of spin-lattice relaxation times the selectively deuterated methyl group was used as a sensitive probe of its local environments. There is a large difference in the mean activation energy in the glass with respect to that in crystalline acetyl salicylic acid. This can be understood by taking into account the broad energy barrier distribution in the glass.Comment: 8 pages, 3 figures, Submitted to Phys. Rev.

Thermodynamic Behavior of a Model Covalent Material Described by the Environment-Dependent Interatomic Potential

Using molecular dynamics simulations we study the thermodynamic behavior of a single-component covalent material described by the recently proposed Environment-Dependent Interatomic Potential (EDIP). The parameterization of EDIP for silicon exhibits a range of unusual properties typically found in more complex materials, such as the existence of two structurally distinct disordered phases, a density decrease upon melting of the low-temperature amorphous phase, and negative thermal expansion coefficients for both the crystal (at high temperatures) and the amorphous phase (at all temperatures). Structural differences between the two disordered phases also lead to a first-order transition between them, which suggests the existence of a second critical point, as is believed to exist for amorphous forms of frozen water. For EDIP-Si, however, the unusual behavior is associated not only with the open nature of tetrahedral bonding but also with a competition between four-fold (covalent) and five-fold (metallic) coordination. The unusual behavior of the model and its unique ability to simulation the liquid/amorphous transition on molecular-dynamics time scales make it a suitable prototype for fundamental studies of anomalous thermodynamics in disordeered systems.Comment: 48 pages (double-spaced), 13 figure

The Economic Resource Receipt of New Mothers

U.S. federal policies do not provide a universal social safety net of economic support for women during pregnancy or the immediate postpartum period but assume that employment and/or marriage will protect families from poverty. Yet even mothers with considerable human and marital capital may experience disruptions in employment, earnings, and family socioeconomic status postbirth. We use the National Survey of Families and Households to examine the economic resources that mothers with children ages 2 and younger receive postbirth, including employment, spouses, extended family and social network support, and public assistance. Results show that many new mothers receive resources postbirth. Marriage or postbirth employment does not protect new mothers and their families from poverty, but education, race, and the receipt of economic supports from social networks do

Multiple unbiased approaches identify oxidosqualene cyclase as the molecular target of a promising anti-leishmanial

Phenotypic screening identified a benzothiophene compound with activity against Leishmania donovani, the causative agent of visceral leishmaniasis. Using multiple orthogonal approaches, oxidosqualene cyclase (OSC), a key enzyme of sterol biosynthesis, was identified as the target of this racemic compound and its enantiomers. Whole genome sequencing and screening of a genome-wide overexpression library confirmed that OSC gene amplification is associated with resistance to compound 1. Introduction of an ectopic copy of the OSC gene into wild-type cells reduced susceptibility to these compounds confirming the role of this enzyme in resistance. Biochemical analyses demonstrated the accumulation of the substrate of OSC and depletion of its product in compound (S)-1-treated-promastigotes and cell-free membrane preparations, respectively. Thermal proteome profiling confirmed that compound (S)-1 binds directly to OSC. Finally, modeling and docking studies identified key interactions between compound (S)-1 and the LdOSC active site. Strategies to improve the potency for this promising anti-leishmanial are proposed