Transport properties of dense fluid argon

We calculate using molecular dynamics simulations the transport properties of realistically modeled fluid argon at pressures up to $\simeq 50GPa$ and temperatures up to $3000K$. In this context we provide a critique of some newer theoretical predictions for the diffusion coefficients of liquids and a discussion of the Enskog theory relevance under two different adaptations: modified Enskog theory (MET) and effective diameter Enskog theory. We also analyze a number of experimental data for the thermal conductivity of monoatomic and small diatomic dense fluids.Comment: 8 pages, 6 figure

Titration of syntaxin1 in Mammalian synapses reveals multiple roles in vesicle docking, priming, and release probability.

Synaptic vesicles undergo sequential steps in preparation for neurotransmitter release. Individual SNARE proteins and the SNARE complex itself have been implicated in these processes. However, discrete effects of SNARE proteins on synaptic function have been difficult to assess using complete loss-of-function approaches. We therefore used a genetic titration technique in cultured mouse hippocampal neurons to evaluate the contribution of the neuronal SNARE protein Syntaxin1 (Stx1) in vesicle docking, priming, and release probability. We generated graded reductions of total Stx1 levels by combining two approaches, namely, endogenous hypomorphic expression of the isoform Stx1B and RNAi-mediated knockdown. Proximity of synaptic vesicles to the active zone was not strongly affected. However, overall release efficiency of affected neurons was severely impaired, as demonstrated by a smaller readily releasable pool size, slower refilling rate of primed vesicles, and lower release probability. Interestingly, dose-response fitting of Stx1 levels against readily releasable pool size and vesicular release probability showed similar Kd (dissociation constant) values at 18% and 19% of wild-type Stx1, with cooperativity estimates of 3.4 and 2.5, respectively. This strongly suggests that priming and vesicle fusion share the same molecular stoichiometry, and are governed by highly related mechanisms

CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism

In this study, we investigated the role of CD38 in a pristane-induced murine model of lupus. CD38-deficient (Cd38-/-) but not ART2-deficient (Art2-/-) mice developed less severe lupus compared to wild type (WT) mice, and their protective phenotype consisted of (i) decreased IFN-I-stimulated gene expression, (ii) decreased numbers of peritoneal CCR2hiLy6Chi inflammatory monocytes, TNF-α-producing Ly6G+ neutrophils and Ly6Clo monocytes/macrophages, (iii) decreased production of anti-single-stranded DNA and anti-nRNP autoantibodies, and (iv) ameliorated glomerulonephritis. Cd38-/- pristane-elicited peritoneal exudate cells had defective CCL2 and TNF-α secretion following TLR7 stimulation. However, Tnf-α and Cxcl12 gene expression in Cd38-/- bone marrow (BM) cells was intact, suggesting a CD38-independent TLR7/TNF-α/CXCL12 axis in the BM. Chemotactic responses of Cd38-/- Ly6Chi monocytes and Ly6G+ neutrophils were not impaired. However, Cd38-/- Ly6Chi monocytes and Ly6Clo monocytes/macrophages had defective apoptosis-mediated cell death. Importantly, mice lacking the cation channel TRPM2 (Trpm2-/-) exhibited very similar protection, with decreased numbers of PECs, and apoptotic Ly6Chi monocytes and Ly6Clo monocytes/macrophages compared to WT mice. These findings reveal a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via an apoptosis-driven mechanism. Furthermore, given the implications of CD38 in the activation of TRPM2, our data suggest that CD38 modulation of pristane-induced apoptosis is TRPM2-dependent.We would like to thank Dr. Yasuo Mori for providing the Tr pm 2−/− mice, Clara Sánchez for animal husbandry at the IPBLN-CSIC Animal Facility, and Thomas S. Simpler and Uma Mudunuru for animal husbandry at the University of Alabama at Birmingham (UAB). We would also like to thank Laura Montosa from the Centro de Instrumentación Cientifica (CIC) at the Universidad de Granada (UGR) for technical support with microscopy, as well as Mohamed Tassi and Ana Santos at CIC, UGR, and Sandra García-Jiménez, Victoria Romero-del-Amo, Gemma Palencia-López, and Samuel Ruiz-Santiago at Campus Formación Granada for tissue preparations, H&E staining, and other staining procedures. Work performed in the Sancho lab was supported in part by the European Commission in collaboration with the following Funding Agencies: (i) Junta de Andalucía (J.A.), Consejería Innovación Ciencia y Empresa y Consejería Educación y Ciencia, Project: PC08-CTS-04046 to J.S. and M.Z., and (ii) Ministerio de Economía y Competitividad (MINECO), Projects: SAF-2011-27261 to J.S. and M.Z. and SAF2014-55088-R to R.M. Work performed in the Lund lab was supported by funds provided by UAB.S

Simultaneous free-volume modeling of the self-diffusion coefficient and dynamic viscosity at high pressure

International audienceA free-volume model of the dynamic viscosity and the self-diffusion coefficients was discussed. The temperature-pressure variations of the dynamic viscosity and the self-diffusion coefficients of small molecules were predicted. The compounds, carbon tetrachloride, cyclohexane, benzene, chlorotrifluoromethane, tetramethylsilane and methylcyclohexane were used for the investigation. The relation between microstructure, free volume and different complex thermophysical properties were emphasized by the model

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed

Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1–2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks

The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses

<div><p>Alveolar macrophages orchestrate pulmonary innate immunity and are essential for early immune surveillance and clearance of microorganisms in the airways. Inflammatory signaling must be sufficiently robust to promote host defense but limited enough to prevent excessive tissue injury. Macrophages in the lungs utilize multiple transcriptional and post-transcriptional mechanisms of inflammatory gene expression to delicately balance the elaboration of immune mediators. RNA terminal uridyltransferases (TUTs), including the closely homologous family members Zcchc6 (TUT7) and Zcchc11 (TUT4), have been implicated in the post-transcriptional regulation of inflammation from studies conducted <i>in vitro</i>. <i>In vivo</i>, we observed that Zcchc6 is expressed in mouse and human primary macrophages. Zcchc6-deficient mice are viable and born in Mendelian ratios and do not exhibit an observable spontaneous phenotype under basal conditions. Following an intratracheal challenge with <i>S</i>. <i>pneumoniae</i>, Zcchc6 deficiency led to a modest but significant increase in the expression of select cytokines including IL-6, CXCL1, and CXCL5. These findings were recapitulated <i>in vitro</i> whereby Zcchc6-deficient macrophages exhibited similar increases in cytokine expression due to bacterial stimulation. Although loss of Zcchc6 also led to increased neutrophil emigration to the airways during pneumonia, these responses were not sufficient to impact host defense against infection.</p></div