Polar intermetallic crystals and quasicrystals

Two main questions guide these investigations of polar intermetallic compounds: (1) Where are the atoms, based on observed electron densities via diffraction? and (2) What gives rise to the observed structures, based on chemical bonding and electronic structure theory? At nearly equal Au: Al molar ratios, NaZn13-derivatives of Sr/Ca(AuxAl1–x)12–13 show a progression from cubic to tetragonal, to orthorhombic, and then monoclinic symmetry with subtle decreasing Au concentrations, results which reveal preferential ordering of Au and Al to maximize the number of Au–Al (or Al-rich) shortest distances. In the Au-rich region of the Ca–Au–Al system, the 1/0 crystalline approximant (CA) CaAu3+xAl1–x and icosahedral quasicrystal (i-QC) CaAu4.5–xAl1.5+x were discovered, and the i-QC is shown to irreversibly transform into the 2/1 CA Ca13Au56.79(6)Al21.20 via in-situ, high-energy, variable-temperature powder X-ray diffraction (XRD). The QC was characterized from high-energy single-crystal XRD to have icosahedral symmetry, ܲ݉3ത5ത, and a quasilattice (aQC = 5.383(4) Å) in close agreement to those calculated from the 1/0 and 2/1 CAs (aQC-Calc.1/0 = 5.336(2)–5.354(2) Å; aQC-Calc.2/1 = 5.364(6) Å). Following the polar intermetallic depiction from the calculated electronic structures, the 1/0 and 2/1 CA crystal structures show formally electronegative Au+Al sharing polyhedra and electropositive Ca in the voids or in intervening shells so that overall, the 2/1 CA can be described as interpenetrating and edge-sharing icosahedra. The origin of hexagonal ScAuAl, in which the unit cell is distorted due to long-short alternating Au–Au chains, is rationalized from a Peierls-type distortion of its calculated electronic structures. Chemical pressure effects and valence electron count variations were examined in the series CaAuAl–ScAuAl–TiAuAl. In general, the calculated electronic structures of all these (Sr/Ca/Sc)–Au–Al crystalline compounds reveal significant Sr/Ca/Sc– (Au+Al) polar-covalent interactions that contribute to structural cohesion and preferential ordering to maximize the number of Au–Al shortest distances

Development of a robotic system for automatic organic chemistry synthesis

Automated chemical synthesis carries great promises of safety, efficiency and reproducibility for both research and industry laboratories. Current approaches are based on specifically-designed automation systems, which present two major drawbacks: (i) existing apparatus must be modified to be integrated into the automation systems; (ii) such systems are not flexible and would require substantial re-design to handle new reactions or procedures. In this paper, we propose a system based on a robot arm which, by mimicking the motions of human chemists, is able to perform complex chemical reactions without any modifications to the existing setup used by humans. The system is capable of precise liquid handling, mixing, filtering, and is flexible: new skills and procedures could be added with minimum effort. We show that the robot is able to perform a Michael reaction, reaching a yield of 34%, which is comparable to that obtained by a junior chemist (undergraduate student in Chemistry)

Propranolol treatment of infantile hemangioma endothelial cells: A molecular analysis

Infantile hemangiomas (IHs) are non-malignant, largely cutaneous vascular tumors affecting approximately 5–10% of children to varying degrees. During the first year of life, these tumors are strongly proliferative, reaching an average size ranging from 2 to 20 cm. These lesions subsequently stabilize, undergo a spontaneous slow involution and are fully regressed by 5 to 10 years of age. Systemic treatment of infants with the non-selective β-adrenergic receptor blocker, propranolol, has demonstrated remarkable efficacy in reducing the size and appearance of IHs. However, the mechanism by which this occurs is largely unknown. In this study, we sought to understand the molecular mechanisms underlying the effectiveness of β blocker treatment in IHs. Our data reveal that propranolol treatment of IH endothelial cells, as well as a panel of normal primary endothelial cells, blocks endothelial cell proliferation, migration, and formation of the actin cytoskeleton coincident with alterations in vascular endothelial growth factor receptor-2 (VEGFR-2), p38 and cofilin signaling. Moreover, propranolol induces major alterations in the protein levels of key cyclins and cyclin-dependent kinase inhibitors, and modulates global gene expression patterns with a particular affect on genes involved in lipid/sterol metabolism, cell cycle regulation, angiogenesis and ubiquitination. Interestingly, the effects of propranolol were endothelial cell-type independent, affecting the properties of IH endothelial cells at similar levels to that observed in neonatal dermal microvascular and coronary artery endothelial cells. This data suggests that while propranolol markedly inhibits hemangioma and normal endothelial cell function, its lack of endothelial cell specificity hints that the efficacy of this drug in the treatment of IHs may be more complex than simply blockage of endothelial function as previously believed

The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila

Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim) and Period (Per) are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load) or tolerance (endurance of the pathogenic effects of infection). Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim-independent; moreover, infection-induced AMP gene expression is not circadian-regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis) can have significant effects on long-term survival of infection

DNA polymerase switching: effects on spontaneous mutagenesis in Escherichia coli

Escherichia coli possesses five known DNA polymerases (pols). Pol III holoenzyme is the cell's main replicase, while pol I is responsible for the maturation of Okazaki fragments and filling gaps generated during nucleotide excision repair. Pols II, IV and V are significantly upregulated as part of the cell's global SOS response to DNA damage and under these conditions, may alter the fidelity of DNA replication by potentially interfering with the ability of pols I and III to complete their cellular functions. To test this hypothesis, we determined the spectrum of rpoB mutations arising in an isogenic set of mutL strains differentially expressing the chromosomally encoded pols. Interestingly, mutagenic hot spots in rpoB were identified that are susceptible to the actions of pols I–V. For example, in a recA730 lexA(Def) mutL background most transversions were dependent upon pols IV and V. In contrast, transitions were largely dependent upon pol I and to a lesser extent, pol III. Furthermore, the extent of pol I-dependent mutagenesis at one particular site was modulated by pols II and IV. Our observations suggest that there is considerable interplay among all five E. coli polymerases that either reduces or enhances the mutagenic load on the E. coli chromosome

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants