Engaging Commercial Specialists Early to Avoid/Mitigate Disputes

This presentation discusses how the early engagement of commercial specialists can help avoid/mitigate disputes. Avoiding/mitigating disputes requires clear communication supported by clear documentation, both of which depend upon a proper understanding of the commercial issues at play. Through active and early engagement of commercial specialists, you can ensure the right resources are available at the right time to avoid/mitigate disputes. Learn what commercial specialists to involve, when to involve them, and the value they bring

Apparatus for real-time acoustic imaging of Rayleigh-Benard convection

We have designed and built an apparatus for real-time acoustic imaging of convective flow patterns in optically opaque fluids. This apparatus takes advantage of recent advances in two-dimensional ultrasound transducer array technology; it employs a modified version of a commercially available ultrasound camera, similar to those employed in non-destructive testing of solids. Images of convection patterns are generated by observing the lateral variation of the temperature dependent speed of sound via refraction of acoustic plane waves passing vertically through the fluid layer. The apparatus has been validated by observing convection rolls in both silicone oil and ferrofluid.Comment: 20 pages, 11 figures, submitted to the Review of Scientific Instrument

Enhancing the activity of oxygen-evolution and chlorine-evolution electrocatalysts by atomic layer deposition of TiO₂

We report that TiO₂ coatings formed via atomic layer deposition (ALD) may tune the activity of IrO₂, RuO₂, and FTO for the oxygen-evolution and chlorine-evolution reactions (OER and CER). Electrocatalysts exposed to ∼3–30 ALD cycles of TiO₂ exhibited overpotentials at 10 mA cm⁻² of geometric current density that were several hundred millivolts lower than uncoated catalysts, with correspondingly higher specific activities. For example, the deposition of TiO₂ onto IrO₂ yielded a 9-fold increase in the OER-specific activity in 1.0 M H₂SO₄ (0.1 to 0.9 mA cm_(ECSA)⁻² at 350 mV overpotential). The oxidation state of titanium and the potential of zero charge were also a function of the number of ALD cycles, indicating a correlation between oxidation state, potential of zero charge, and activity of the tuned electrocatalysts

Enhancing the activity of oxygen-evolution and chlorine-evolution electrocatalysts by atomic layer deposition of TiO₂

We report that TiO₂ coatings formed via atomic layer deposition (ALD) may tune the activity of IrO₂, RuO₂, and FTO for the oxygen-evolution and chlorine-evolution reactions (OER and CER). Electrocatalysts exposed to ∼3–30 ALD cycles of TiO₂ exhibited overpotentials at 10 mA cm⁻² of geometric current density that were several hundred millivolts lower than uncoated catalysts, with correspondingly higher specific activities. For example, the deposition of TiO₂ onto IrO₂ yielded a 9-fold increase in the OER-specific activity in 1.0 M H₂SO₄ (0.1 to 0.9 mA cm_(ECSA)⁻² at 350 mV overpotential). The oxidation state of titanium and the potential of zero charge were also a function of the number of ALD cycles, indicating a correlation between oxidation state, potential of zero charge, and activity of the tuned electrocatalysts

Murine Leukemia Virus Spreading in Mice Impaired in the Biogenesis of Secretory Lysosomes and Ca2+-Regulated Exocytosis

Retroviruses have been observed to bud intracellularly into multivesicular bodies (MVB), in addition to the plasma membrane. Release from MVB is thought to occur by Ca(2+)-regulated fusion with the plasma membrane.To address the role of the MVB pathway in replication of the murine leukemia virus (MLV) we took advantage of mouse models for the Hermansky-Pudlak syndrome (HPS) and Griscelli syndrome. In humans, these disorders are characterized by hypopigmentation and immunological alterations that are caused by defects in the biogenesis and trafficking of MVBs and other lysosome related organelles. Neonatal mice for these disease models lacking functional AP-3, Rab27A and BLOC factors were infected with Moloney MLV and the spread of virus into bone marrow, spleen and thymus was monitored. We found a moderate reduction in MLV infection levels in most mutant mice, which differed by less than two-fold compared to wild-type mice. In vitro, MLV release form bone-marrow derived macrophages was slightly enhanced. Finally, we found no evidence for a Ca(2+)-regulated release pathway in vitro. Furthermore, MLV replication was only moderately affected in mice lacking Synaptotagmin VII, a Ca(2+)-sensor regulating lysosome fusion with the plasma membrane.Given that MLV spreading in mice depends on multiple rounds of replication even moderate reduction of virus release at the cellular level would accumulate and lead to a significant effect over time. Thus our in vivo and in vitro data collectively argue against an essential role for a MVB- and secretory lysosome-mediated pathway in the egress of MLV

Copper Selenophosphate, Cu₃PSe₄, Nanoparticle Synthesis: Octadecane Is the Key to a Simplified, Atom-Economical Reaction

Nanoparticle syntheses are designed to produce the desired product in high yield but traditionally neglect atom-economy. Here we report that the simple, but significant, change of the solvent from 1-octadecene (1-ODE) to the operationally inert octadecane (ODA) permits an atom-economical synthesis of copper selenophosphate (Cu3PSe4) nanoparticles. This change eliminates the competing selenium (Se) delivery pathways from our first report that required an excess of Se. Instead Se0powder is dispersed in ODA, which promotes a formal eight-electron transfer between Cu3–xP and Se0. Powder X-ray diffraction and transmission electron microscopy confirm the purity of the Cu3PSe4, while 1H and 13C NMR indicate the absence of oxidized ODA or Se species. We utilize the direct pathway to gain insights into stoichiometry and ligand identity using thermogravimetric analysis and X-ray photoelectron spectroscopy. Given the prevalence of 1-ODE in nanoparticle synthesis, this approach could be applied to other chalcogenide reaction pathways to improve stoichiometry and atom-economy

LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs.

The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described

LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs.

The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described

LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates.

Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood-brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure-activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site