Direct Measurement of the Nonlinear Refractive-index Coefficient Gamma at 355 Nm in Fused Silica and in BK-10 Glass

Optics Letters. Jan, 1984  |  Pubmed ID: 19718219

We have measured the nonlinear refractive-index coefficient gamma interferometrically at 355 nm in fused silica and in BK-10, a borosilicate crown glass. These measurements are the first reported direct ultraviolet measurements of the nonlinear index of refraction in any transparent glass. Our results are gamma = (2.5 +/- 1.2) x 10(-16) cm(2)/W and gamma = (1.7 +/- 0.8) x 10(-16) cm(2)/W, respectively, for fused silica and BK-10.

Selenium in Organic Synthesis

Science (New York, N.Y.). Jan, 1986  |  Pubmed ID: 17735010

The introduction, manipulation, and ultimate removal of selenium-containing functional groups allow a variety of synthetically useful processes to be accomplished in high overall yields under mild conditions. In particular, transformations such as allylic oxidations, nucleophile-induced cleavage reactions, regiospecific alkylations, and olefin cofunctionalizations can be readily achieved by taking advantage of selenium's unique properties.

Constraints on Anomalous Scattering of Neutrinos from Crystals

Physical Review Letters. Mar, 1987  |  Pubmed ID: 10034361

Generation of Squeezing in Two-photon Three-level Media

Optics Letters. Jun, 1988  |  Pubmed ID: 19745936

We present a fully quantum-mechanical theory of nondegenerate four-wave mixing processes in three-level cascades with a two-photon pump. The results are applied to the generation of squeezed states of light. We find almost perfect squeezing for some strong pump intensities and tunings within the Rabi sidebands. We find good broadband squeezing for low pump intensities and tunings outside a small region around central tuning. Both cases avoid regions of significant spontaneous emission.

Single-longitudinal-mode, Tunable, Pulsed Ti:sapphire Laser Oscillator

Optics Letters. Jan, 1989  |  Pubmed ID: 19749810

A 2.0-mJ/pulse, 2-nsec, single-longitudinal-mode Ti:sapphire laser oscillator has been demonstrated in a compact grazing-incidence cavity configuration similar to a Littman arrangement. The oscillator's output beam quality is TEM(00), making it attractive for doubling and mixing applications. With currently available optics the laser is tunable over greater than 2500 cm(-1) from 746 to 918 nm.

All-fiber Ring Soliton Laser Mode Locked with a Nonlinear Mirror

Optics Letters. Apr, 1991  |  Pubmed ID: 19773991

An amplifying nonlinear-optical fiber loop mirror is used as the gain element in an all-fiber ring laser. The resulting double-loop structure resembles a figure eight. The output of the amplifying nonlinear-optical fiber loop mirror is fed back to the input through an optical isolator to ensure unidirectional operation. The laser produces 2-ps transform-limited pulses. The pulse energy corresponds to that of the fundamental soliton in the fiber used.

Generation of Intense 10-ps, 193-nm Pulses Using Simple Distributed Feedback Dye Lasers and an ArF(*) Amplifier

Applied Optics. Nov, 1992  |  Pubmed ID: 20802565

A pair of holographic distributed feedback dye lasers is used to generate 10-ps pulses at two selected wavelengths that are mixed in a BBO crystal to produce a pulse ~ 10 ps in duration at 193 nm. This seed pulse is subsequently amplified in an ArF(*) excimer laser to an energy of 10-15 mJ with <40 microJ in amplified spontaneous emission. The pulses are nearly transform limited and diffraction limited.

Multiple Ionic Mechanisms Mediate Inhibition of Rat Motoneurones by Inhalation Anaesthetics

The Journal of Physiology. Nov, 1998  |  Pubmed ID: 9769427

1. We studied the effects of inhalation anaesthetics on the membrane properties of hypoglossal motoneurones in a neonatal rat brainstem slice preparation. 2. In current clamp, halothane caused a membrane hyperpolarization that was invariably associated with decreased input resistance; in voltage clamp, halothane induced an outward current and increased input conductance. Qualitatively similar results were obtained with isoflurane and sevoflurane. 3. The halothane current reversed near the predicted K+ equilibrium potential (EK) and was reduced in elevated extracellular K+ and in the presence of Ba2+ (2 mM). Moreover, the Ba2+-sensitive component of halothane current was linear and reversed near EK. The halothane current was not sensitive to glibenclamide or thyrotropin-releasing hormone (TRH). Therefore, the halothane current was mediated, in part, by activation of a Ba2+-sensitive K+ current distinct from the ATP- and neurotransmitter-sensitive K+ currents in hypoglossal motoneurones. 4. Halothane also inhibited Ih, a hyperpolarization-activated cationic current; this was primarily due to a decrease in the absolute amount of current, although halothane also caused a small, but statistically significant, shift in the voltage dependence of Ih activation. Extracellular Cs+ (3 mM) blocked Ih and a component of halothane-sensitive current with properties reminiscent of Ih. 5. A small component of halothane current, resistant to Ba2+ and Cs+, was observed in TTX-containing solutions at potentials depolarized to approximately -70 mV. Partial Na+ substitution by N-methyl-D-glucamine completely abolished this residual current, indicating that halothane also inhibited a TTX-resistant Na+ current active near rest potentials. 6. Thus, halothane activates a Ba2+-sensitive, relatively voltage-independent K+ current and inhibits both Ih and a TTX-insensitive persistent Na+ current in hypoglossal motoneurones. These effects of halothane decrease motoneuronal excitability and may contribute to the immobilization that accompanies inhalation anaesthesia.

Dual Methylation Pathways in Lignin Biosynthesis

The Plant Cell. Dec, 1998  |  Pubmed ID: 9836743

Caffeoyl-coenzyme A (CoA) O-methyltransferase (CCoAOMT) has been proposed to be involved in an alternative methylation pathway of lignin biosynthesis. However, no direct evidence has been available to confirm that CCoAOMT is essential for lignin biosynthesis. To understand further the methylation steps in lignin biosynthesis, we used an antisense approach to alter O-methyltransferase (OMT) gene expression and investigated the consequences of this alteration. We generated transgenic tobacco plants with a substantial reduction in CCoAOMT as well as plants with a simultaneous reduction in both CCoAOMT and caffeic acid O-methyltransferase (CAOMT). Lignin analysis showed that the reduction in CCoAOMT alone resulted in a dramatic decrease in lignin content. The reduction in CCoAOMT also led to a dramatic alteration in lignin composition. Both guaiacyl lignin and syringyl lignin were reduced in the transgenic plants. However, guaiacyl lignin was preferentially reduced, which resulted in an increase in the S/G (syringl/guaiacyl) ratio. We have also analyzed lignin content and composition in transgenic plants having a simultaneous reduction in both CCoAOMT and CAOMT. The reduction in both OMTs resulted in a further decrease in total lignin content. This is in sharp contrast to the effect that resulted from the reduction in CAOMT alone, which only decreased the syringl lignin unit without a reduction in overall lignin content. These results unequivocally demonstrate that methylation reactions in lignin biosynthesis are catalyzed by both CCoAOMT and CAOMT.

Books and Software: A Fitting Tribute to Cal Giddings

Analytical Chemistry. Sep, 1999  |  Pubmed ID: 21651086

A review of Advances in Chromatography, Vol. 38.

Calpain Activity in Bone Marrow Transplant-associated Thrombotic Thrombocytopenic Purpura

Bone Marrow Transplantation. Sep, 1999  |  Pubmed ID: 10490730

The pathophysiology of thrombotic thrombocytopenic purpura (TTP) is not well understood. Recent studies have described a platelet aggregating factor which has been characterized as a calcium-dependent cysteine protease (calpain) in patients with TTP. A type of TTP, sometimes called secondary TTP, has been associated with bone marrow transplantation (BMT). However, unlike primary adult TTP, BMT-TTP has important differences and often does not respond well to plasma exchange. We describe the measurement of calpain activity in a group of BMT patients (with and without the clinical syndrome of transplant-associated TTP). Calpain was measured using a functional assay (14C-serotonin platelet release with inhibition by the cysteine protease inhibitor, leupeptin) in the sera of patients following autologous (auto) or allogeneic (allo) BMT. We also independently diagnosed and graded the BMT-TTP on the day of blood sampling using a scale that related to the percentage schistocytes and lactic dehydrogenase level. Calpain activity was detected in 1/8 (13%) grade 0-1 (6 auto, 2 allo); 6/16 (38%) grade 2 (3 auto, 13 allo) 9/16 (56%) grade 3 (2 auto, 14 allo) and 8/8 (100%) grade 4 BMT-TTP. Pre-BMT samples were tested in 10 allo-BMT patients who had positive calpain results post-BMT. One patient gave positive results before the transplant. This patient developed grade 4 BMT-TTP (day 24 post-BMT) and died despite apheresis. Positive calpain results were highly associated with neurologic symptoms, P < 0.001. Nineteen of 24 (79%) patients with positive results had neurologic symptoms compared to three of 21 (14%) patients with negative results. In conclusion, calpain was detected in half of the BMT patients with mild to moderate BMT-TTP (grades 2-3) and was uniformly found in those with severe (grade 4) BMT-TTP. Typically the calpain activity develops as TTP complicates the transplant process. It is unknown whether calpain contributes to the pathogenesis of this disorder, or is a secondary event.

Bone Marrow Stromal Cells As a Vehicle for Gene Transfer

Gene Therapy. Sep, 1999  |  Pubmed ID: 10490771

Adoptive transfer of genetically modified somatic cells is playing an increasingly important role in the management of a wide spectrum of human diseases. Hematopoietic stem cells and lymphocytes have been used to transfer a variety of genes, however, they have limitations. In this study, the feasibility of retroviral gene transduction of bone marrow stromal cells, and the engraftment characteristics of these cells following infusion, was investigated in a murine transplantation model. Stromal cells derived from Balb/c mouse bone marrow were transduced with a replication-defective retrovirus containing the LacZ gene. Following three rounds of transduction, between 5 and 40% of the cells were positive for the LacZ gene. A total of 2 x 106 cells were infused into the same mouse strain. After the infusion, the LacZ gene was detected by PCR in the bone marrow, spleen, liver, kidney and lung; however, only the spleen and bone marrow samples were strongly positive. Quantitative PCR demonstrated that between 3 and 5% of spleen and bone marrow cells, and 1% of liver cells contained the LacZ gene at 3 weeks after infusion; <0.2% transduced cells were found in other organs. No difference was noted in engraftment between mice with or without irradiation before transplantation, suggesting that engraftment occurred without myeloablation. The infused transduced cells persisted for up to 24 weeks. Self-renewal of transplanted stromal cells was demonstrated in secondary transplant studies. Ease of culture and gene transduction and tissue specificity to hematopoietic organs (bone marrow, spleen, liver) is demonstrated, indicating that stromal cells may be an ideal vehicle for gene transfer.

Changes in Metabolism of TRH in Euthyroid Sick Syndrome

European Journal of Endocrinology / European Federation of Endocrine Societies. Oct, 1999  |  Pubmed ID: 10526245

The aim of this study was to examine the metabolism of a simple dose, intravenously administered TRH bolus of 200 microg, in patients with euthyroid sick syndrome (ESS).

The Use of Adjunctive GPIIb/IIIa Inhibitors in Patients with Unstable Angina/non-Q-wave MI Undergoing Percutaneous Coronary Intervention

International Journal of Cardiovascular Interventions. 1999  |  Pubmed ID: 12623570

Glycoprotein IIb/IIIa receptor inhibitors represent a relatively new therapeutic approach in the field of antiplatelet therapy. Following the development of abciximab a number of small molecule GPIIb/IIIa inhibitors have been introduced such as tirofiban and eptifibatide. In this fast-moving field the interventional cardiologist needs a framework to guide decision-making for the individual patient. This review covers the efficacy and safety data from the clinical trials of GPIIb/IIIa inhibitors in the context of patients undergoing percutaneous coronary intervention for unstable angina/non-Q-wave myocardial infarction. There is an increasing body of evidence to support the efficacy of GPIIb/IIIa inhibitors in reducing the risk of adverse ischemic events in high and low risk patients undergoing percutaneous coronary intervention. A number of unresolved efficacy and safety issues remain, including the duration of treatment before and after intervention; whether a reduction in the heparin dose would further decrease the risk of hemorrhage without affecting the periprocedural thrombotic rate in patients undergoing PTCA with adjunctive GPIIb/IIIa inhibitors; and the cost-effectiveness of this therapy. When a thorough analysis of cost-effectiveness has been made, it will be easier to advocate the widespread use of these agents in all patients undergoing coronary intervention.

Three-dimensional Contrast-enhanced MR Angiography with Real-time Fluoroscopic Triggering: Design Specifications and Technical Reliability in 330 Patient Studies

Radiology. May, 2000  |  Pubmed ID: 10796943

Technical reliability was determined for triggering three-dimensional (3D) contrast material-enhanced magnetic resonance (MR) angiography with MR fluoroscopy. Technical requirements for high reliability were also identified. Reliability was evaluated in 330 consecutive patient studies of the neck, thorax, abdomen, and pelvis. Contrast material arrival was detected fluoroscopically in 325 of the 330 studies (98.5%), and the 3D sequence was successfully triggered in 321 of 330 studies (97.3%). Fluoroscopic triggering of centrically encoded 3D MR angiographic acquisitions is a highly reliable means of obtaining 3D MR angiograms with high spatial resolution.

Monotherapy with Anti-CD40 Ligand Antibody (IDEC 131) for Non-human Primate Allograft Heart Transplantation

The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. Feb, 2001  |  Pubmed ID: 11250495

Prospective, Randomized, Multi-center Trial of Antibody Induction Therapy in Simultaneous Pancreas-kidney Transplantation

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Jul, 2003  |  Pubmed ID: 12814477

A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.

Analysis of Rat Testicular Protein Expression Following 91-day Exposure to JP-8 Jet Fuel Vapor

Proteomics. Jun, 2003  |  Pubmed ID: 12833526

We analyzed protein expression in preparations from whole testis in adult male Sprague-Dawley rats exposed for 6 h/d for 91 consecutive days to jet propulsion fuel-8 (JP-8) in the vapor phase (0, 250, 500, or 1000 mg/m(3) +/- 10%), simulating a range of possible human occupational exposures. Whole body inhalation exposures were carefully controlled to eliminate aerosol phase, and subjects were sacrificed within 48 h postexposure. Organ fractions were solubilized and separated via large-scale, high resolution two-dimensional electrophoresis, and gel patterns scanned, digitized and processed for statistical analysis. Seventy-six different testis proteins were significantly increased or decreased in abundance in vapor-exposed groups, compared to controls, and dose-response profiles were often nonlinear. A number of the proteins were identified by peptide mass fingerprinting and related to histopathological or physiological deficits shown in previously published studies to occur with repeated exposure to hydrocarbon fuels or solvents. These results demonstrate a significant effect of JP-8 exposure on protein expression, particularly in protein expression in the rodent testis, and suggest that a 91 d exposure to jet fuel vapor induces changes of equal or greater magnitude to those reported previously for shorter duration JP-8 aerosol exposures.

Neuronal Glucose Metabolism and Schizophrenia: Therapeutic Prospects?

Expert Review of Neurotherapeutics. Jan, 2003  |  Pubmed ID: 19810845

This review will focus on the treatment and prevention of schizophrenia in children and adolescents. Neurodevelopmental theories suggest that loss of gray matter and defective synaptic function are major etiological factors in this disease. The efficacy of current antipsychotic medications has been discussed, however, these drugs produce serious side effects and may adversely affect the developing brain. We propose a novel therapeutic approach, termed neuroenhancement, that aims to promote neuronal survival and optimize neuronal function through the use of drugs. The goal is to enhance glucose metabolism in the brain, which would support higher functional activity in neurons and provide neuroprotection. Future drug development for the treatment of childhood schizophrenia should focus more on optimization of neuronal function rather than tranquilization and symptomatic relief.

Provisional Diagnostic Criteria for Depression of Alzheimer's Disease: Description and Review

Expert Review of Neurotherapeutics. Jan, 2003  |  Pubmed ID: 19810852

This review centers on the development of diagnostic criteria for depression of Alzheimer's disease. It describes: risk-factors and neurobiological correlates, epidemiology, clinical characteristics and course, assessment, treatment, economics, a description of the criteria and future research directions. Overall, there is substantial evidence for depression of Alzheimer's disease. Further research is needed to better define core symptoms, clinical course and efficacy of treatments.

Oral Conditions and Quality of Life

The Journal of Ambulatory Care Management. Apr-Jun, 2006  |  Pubmed ID: 16552326

Oral conditions can have serious, disabling effects. The purposes of this study are 2-fold: first to estimate the prevalence and severity of self-reported oral problems in male veterans who use Department of Veterans Affairs (VA) outpatient medical (but not dental) care and, second, we examine to what extent the impact of oral conditions is associated with measures of general health and well-being. Male veteran users of outpatient VA medical care from the Veterans Health Study (N = 2425) were surveyed using questionnaires, which included sociodemographic information, the SF-36, the Geriatric Oral Health Assessment Index (GOHAI), and the Oral Health and Quality of Life (OHQOL) measure. Only 28% of these users of VA outpatient care rated their oral health as excellent or very good, 32% as good, and nearly 40% as fair or poor. Furthermore, only one half of respondents could always eat without discomfort, were pleased with the looks of their teeth, and had no worries about their teeth. Factor analysis of the SF-36, GOHAI, and OHQOL items confirmed that both the GOHAI and the OHQOL are separate and independent of the 8 scales of the SF-36. Regression analyses showed that the GOHAI but not the OHQOL is significantly associated with the mental and physical component summary scales of the SF-36 when both sociodemographics and disease burden are controlled for in the models. Oral problems, as measured by the GOHAI and the OHQOL, are significant burdens on the health and function of veterans who use VA outpatient care. Oral health, as measured by the GOHAI, contributes in an important way to the functional well-being of users of VA healthcare.

Applications of Methodologies of the Veterans Health Study in the VA Healthcare System: Conclusions and Summary

The Journal of Ambulatory Care Management. Apr-Jun, 2006  |  Pubmed ID: 16552327

The Veterans Health Study (VHS) had as its overarching goal the development, testing, and application of patient-centered assessments for monitoring patient outcomes in ambulatory care in large integrated care systems such as the Department of Veterans Affairs (VA). Unlike other previous studies, the VHS has capitalized on rich administrative databases restricted to the VA and linked to patient-centered outcomes. The VHS has developed a comprehensive set of general and disease-specific measures for use by systems of care for ambulatory patients. Chief among these assessments is the Veterans SF-36 Health Survey for measuring health-related quality of life in veteran ambulatory populations. The Veterans SF-36 Health Survey provides the cornerstone for this study and historically has been extensively disseminated and used in the VA with close to 2 million administrations nationally as part of its quality management system. National surveys administered by the VA since 1996 using the Veterans SF-36 Health Survey indicate important regional differences with implications for varying resource needs. Based upon the rich foundation provided by the VHS methodology, the VA has implemented some of these approaches as part of its quality monitoring system and can serve as a model for other large integrated systems of care.

Enhancement of Two-photon Absorption Cross-section in Macrocyclic Thiophenes with Cavities in the Nanometer Regime

The Journal of Physical Chemistry. B. Feb, 2007  |  Pubmed ID: 17266247

The linear and nonlinear optical properties of two thiophene-based cyclic molecules have been investigated. These molecules represent nanometer sized cavities which may be useful for novel photonic devices. By virtue of long-range interactions, these chromophores serve as novel architectures for enhanced two-photon absorption (TPA) properties. Measurements of the different size ring structures showed a 550% increase in the TPA cross-section for the larger macrocycle. Electronic structure calculations have suggested an increase in coupling of the excited states in these systems as the ring size is increased. Measurements of the ultrafast transient absorption and fluorescence were carried out with these systems in order to probe the interaction between the chromophores. The results of the transient decays as well as fluorescence anisotropy decay times gives stronger proof to the suggestion of delocalized states in the cyclic macrocycles. These results provide information regarding the optical properties of these novel systems useful for potential applications in photonics.

Cyanide Adducts with Human Plasma Proteins: Albumin As a Potential Exposure Surrogate

Chemical Research in Toxicology. Apr, 2007  |  Pubmed ID: 17373827

Cyanide (CN) is a ubiquitous environmental toxicant. The measurement of CN in whole blood is a common exposure assay, but values are error prone because of CN's rapid metabolism and clearance (t1/2 < 1 h) from this compartment. This study was undertaken to determine whether CN forms covalent adduct(s) with plasma proteins that could serve as stable biomarker(s) and potential surrogate(s) of exposure. When added to human blood, plasma, or serum, CN formed covalent adducts with immunoglobulin G (IgG) and serum albumin (HSA) in the plasma fraction. Covalent adducts were not detected in the cellular, primarily erythrocyte, fraction. With human, mouse, and rabbit IgGs, the reaction with CN occurred at intra- and/or interchain disulfide linkages in the heavy and light chains. Digestion of CN-treated HSA with trypsin or the endoproteinase Lys-C at basic pH produced tautomeric 2-iminothiazoline-4-carboxylyl/2-aminothiazolidine-4-carboxylyl (itcCys) N-terminal peptides exclusively, consistent with prior model peptide/protein studies showing that under basic conditions internal S-cyanylated-Cys residues cyclize with concomitant release of the upstream peptide. The most readily detectable reaction of CN with purified HSA was at Cys34, the only Cys of the 35 present not connected as internal cystines. Because CN does not react with free sulfhydryl groups, it is probable that S-cyanylation at Cys34 occurs at those residues that carry GSH, Cys, or other small molecules as mixed disulfides. Relatively less detectable, modified Cys residues were also identified at positions 53, 124, 392, 477, and 487. When 14CN was added to human serum or whole blood at concentrations spanning a putative nontoxic to lethal range, stable adduct formation with HSA occurred in a linear, concentration-dependent reaction that was complete within 2 h. These attributes of the reaction, coupled with a plasma compartment location, suggest that quantitation of CN bound to HSA would provide a much more reliable assessment of exposure than does measurement of CN in blood.

Mild and General Methods for the Palladium-catalyzed Cyanation of Aryl and Heteroaryl Chlorides

Organic Letters. Apr, 2007  |  Pubmed ID: 17385875

[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.

Neighboring Group Participation in the Additions of Iodonium and Bromonium Ions to N-alkoxycarbonyl-2-azabicyclo[2.2.n]alk-5-enes (n = 1,2)

The Journal of Organic Chemistry. Mar, 2008  |  Pubmed ID: 18290656

Additions of iodonium-X reagents to N-alkoxycarbonyl-2-azabicyclo[2.2.1]hept-5-enes and the homologous 2-azabicyclo[2.2.2]oct-5-enes have been found to mirror the outcomes of additions of bromonium-X reagents. Only rearranged products were observed for reactions of either of these halonium ion reagents with the azabicylo[2.2.1]hept-5-enes. For the azabicyclo[2.2.2]oct-5-enes, nitrogen participation in addition of IOH or BrOH was dependent on the N-alkoxycarbonyl group. With larger N-Boc, N-Cbz, or N-Troc protecting groups, unrearranged 5-anti-hydroxy-6-syn-I(or Br)-2-azabicyclo[2.2.2]octanes were formed by nucleophilic attack at C(5) on syn-halonium ions. The structure of N-methyl-8-anti-bromo-4-anti-hydroxy-2-azabicyclo[3.2.1]octane has been reassigned by X-ray analysis.

Selectfluor As a Nucleofuge in the Reactions of Azabicyclo[n.2.1]alkane Beta-halocarbamic Acid Esters (n = 2,3)

The Journal of Organic Chemistry. Mar, 2008  |  Pubmed ID: 18290657

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.

Microsecond Molecular Dynamics Simulation Shows Effect of Slow Loop Dynamics on Backbone Amide Order Parameters of Proteins

The Journal of Physical Chemistry. B. May, 2008  |  Pubmed ID: 18311962

A molecular-level understanding of the function of a protein requires knowledge of both its structural and dynamic properties. NMR spectroscopy allows the measurement of generalized order parameters that provide an atomistic description of picosecond and nanosecond fluctuations in protein structure. Molecular dynamics (MD) simulation provides a complementary approach to the study of protein dynamics on similar time scales. Comparisons between NMR spectroscopy and MD simulations can be used to interpret experimental results and to improve the quality of simulation-related force fields and integration methods. However, apparent systematic discrepancies between order parameters extracted from simulations and experiments are common, particularly for elements of noncanonical secondary structure. In this paper, results from a 1.2 micros explicit solvent MD simulation of the protein ubiquitin are compared with previously determined backbone order parameters derived from NMR relaxation experiments [Tjandra, N.; Feller, S. E.; Pastor, R. W.; Bax, A. J. Am. Chem. Soc. 1995, 117, 12562-12566]. The simulation reveals fluctuations in three loop regions that occur on time scales comparable to or longer than that of the overall rotational diffusion of ubiquitin and whose effects would not be apparent in experimentally derived order parameters. A coupled analysis of internal and overall motion yields simulated order parameters substantially closer to the experimentally determined values than is the case for a conventional analysis of internal motion alone. Improved agreement between simulation and experiment also is encouraging from the viewpoint of assessing the accuracy of long MD simulations.

Conformationally Constrained Farnesoid X Receptor (FXR) Agonists: Naphthoic Acid-based Analogs of GW 4064

Bioorganic & Medicinal Chemistry Letters. Aug, 2008  |  Pubmed ID: 18621523

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

Requirement for Nudel and Dynein for Assembly of the Lamin B Spindle Matrix

Nature Cell Biology. Mar, 2009  |  Pubmed ID: 19198602

The small guanosine triphosphatase Ran loaded with GTP (RanGTP) can stimulate assembly of the type V intermediate filament protein lamin B into a membranous lamin B spindle matrix, which is required for proper microtubule organization during spindle assembly. Microtubules in turn enhance assembly of the matrix. Here we report that the isolated matrix contains known spindle assembly factors such as dynein and Nudel. Using spindle assembly assays in Xenopus egg extracts, we show that Nudel regulates microtubule organization during spindle assembly independently of its function at kinetochores. Importantly, Nudel interacts directly with lamin B to facilitate the accumulation and assembly of lamin-B-containing matrix on microtubules in a dynein-dependent manner. Perturbing either Nudel or dynein inhibited the assembly of lamin B matrix. However, depleting lamin B still allowed the formation of matrices containing dynein and Nudel. Therefore, dynein and Nudel regulate assembly of the lamin B matrix. Interestingly, we found that whereas depleting lamin B resulted in disorganized spindle and spindle poles, disrupting the function of Nudel or dynein caused a complete lack of spindle pole focusing. We suggest that Nudel regulates microtubule organization in part by facilitating assembly of the lamin B spindle matrix in a dynein-dependent manner.

Self-assembly of Carbon Nanotubes into Two-dimensional Geometries Using DNA Origami Templates

Nature Nanotechnology. Jan, 2010  |  Pubmed ID: 19898497

A central challenge in nanotechnology is the parallel fabrication of complex geometries for nanodevices. Here we report a general method for arranging single-walled carbon nanotubes in two dimensions using DNA origami-a technique in which a long single strand of DNA is folded into a predetermined shape. We synthesize rectangular origami templates ( approximately 75 nm x 95 nm) that display two lines of single-stranded DNA 'hooks' in a cross pattern with approximately 6 nm resolution. The perpendicular lines of hooks serve as sequence-specific binding sites for two types of nanotubes, each functionalized non-covalently with a distinct DNA linker molecule. The hook-binding domain of each linker is protected to ensure efficient hybridization. When origami templates and DNA-functionalized nanotubes are mixed, strand displacement-mediated deprotection and binding aligns the nanotubes into cross-junctions. Of several cross-junctions synthesized by this method, one demonstrated stable field-effect transistor-like behaviour. In such organizations of electronic components, DNA origami serves as a programmable nanobreadboard; thus, DNA origami may allow the rapid prototyping of complex nanotube-based structures.

Modern Pathology Methods for Neural Investigations

Toxicologic Pathology. Jan, 2011  |  Pubmed ID: 21212254

This session at the 2010 joint symposium of the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP) explored modern neuropathology methods for assessing the neurotoxicologic potential of xenobiotics. Conventional techniques to optimally prepare and evaluate the central and peripheral neural tissues while minimizing artifact were reviewed, and optimal schemes were set forth for evaluation of the nervous system during both routine (i.e., general toxicity) studies and enhanced (i.e., specialized neurotoxicity) studies. Stereology was introduced as the most appropriate means of examining the possible impact of toxicants on neural cell numbers. A focused discussion on brain sampling took place among a panel of expert neuroscientists (anatomists and pathologists) and the audience regarding the proper balance between sufficient sampling and cost- and time-effectiveness of the analysis. No consensus was reached on section orientation (coronal sections of both sides vs. a parasagittal longitudinal section with several unilateral hemisections from the contralateral side), but most panelists favored sampling at least 8 sections (or approximately double to triple the current complement) in routine toxicity studies.

Breast and Lung Metastasis from Pancreatic Neuroendocrine Carcinoma

World Journal of Radiology. Jan, 2011  |  Pubmed ID: 21286493

Pancreatic neuroendocrine tumors (PNETs) are an uncommon malignancy, accounting for a small percentage of all pancreatic malignancies. Due to their insidious course, most PNETs present with metastatic disease. Although reports in the literature describe PNET metastasis to the liver, lung and brain, to date there are no reports of stage IV disease involving the breast. Moreover, the lack of consensus regarding classification and treatment of this entity leaves practitioners without standards of practice or a firm base from which to formulate prognosis. In this report, the case of a previously healthy 51-year-old woman with stage IV PNET is examined. After combined neoadjuvant therapy with 5-fluorouracil, carboplatin, etoposide and radiation, surgical resection revealed metastatic PNET to the breast and lung, with no microscopic evidence of residual disease within the pancreas. An extensive analysis of the presentation, diagnosis, imaging modalities, treatment options, and prognosis is included in the discussion. As demonstrated by our review, there is a need for further studies to delineate inconclusive evidence with respect to subtype classification, treatment and prognosis of PNETs.

Quantification of Protein Posttranslational Modifications Using Stable Isotope and Mass Spectrometry. II. Performance

Analytical Biochemistry. Feb, 2012  |  Pubmed ID: 22227056

In this report, we examine the performance of a mass spectrometry (MS)-based method for quantification of protein posttranslational modifications (PTMs) using stable isotope labeled internal standards. Uniform labeling of proteins and highly similar behavior of the labeled vs nonlabeled analyte pairs during chromatographic separation and electrospray ionization (ESI) provide the means to directly quantify a wide range of PTMs. In the companion report (Jiang et al., Anal. Biochem., 421 (2012) 506-516.), we provided principles and example applications of the method. Here we show satisfactory accuracy and precision for quantifying protein modifications by using the SILIS method when the analyses were performed on different types of mass spectrometers, such as ion-trap, time-of-flight (TOF), and quadrupole instruments. Additionally, the stable isotope labeled internal standard (SILIS) method demonstrated an extended linear range of quantification expressed in accurate quantification up to at least a 4 log concentration range on three different types of mass spectrometers. We also demonstrate that lengthy chromatographic separation is no longer required to obtain quality results, offering an opportunity to significantly shorten the method run time. The results indicate the potential of this methodology for rapid and large-scale assessment of multiple quality attributes of a therapeutic protein in a single analysis.

Development of an Instrument for a Primary Airway Provider's Performance With an ICU Multidisciplinary Team in Pediatric Respiratory Failure Using Simulation

Respiratory Care. Jan, 2012  |  Pubmed ID: 22273157

BACKGROUND: To develop a scoring system that can assess the multidisciplinary management of respiratory failure in pediatric ICU. Site: A single tertiary pediatric ICU. A simulation-based evaluation was conducted in patient care area auxiliary to ICU. SUBJECTS: Pediatric and emergency medicine residents, nurses, and respiratory therapists who work in pediatric ICU. INTERVENTIONS: A multidisciplinary focus group with experienced providers in pediatric ICU airway management and patient safety specialists was formed. A task-based scoring instrument was developed to evaluate a primary airway provider's performance through Healthcare Failure Mode and Effect Analysis. Reliability and validity of the instrument were evaluated using multidisciplinary simulation-based airway management training sessions. Each session was evaluated by three independent expert raters. A global assessment of the team performance and the previous experience in training were used to evaluate the validity of the instrument. RESULTS: Just-in-time Pediatric Airway Provider Performance: JIT-PAPPS version 3 with 34 taskbased items (14 technical, 20 behavioral) was developed. 85 teams led by resident airway provider were evaluated by three raters. Intraclass correlation coefficient for raters was 0.64. JIT-PAPPS score correlated well with the Global rating scale (r=0.71, p<0.0001). Mean total scores across the teams were positively associated with resident previous training participation (beta coefficient 7.1±0.9, p<0.001), suggesting good validity of the scale. CONCLUSIONS: A task-based scoring instrument for a primary airway provider's performance with multidisciplinary Pediatric ICU team on simulated pediatric respiratory failure was developed. Reliability and validity evaluation supports the developed scale.

Glycerol Accumulation in Edema Formation Following Diffuse Traumatic Brain Injury

Neurological Research. Mar, 2012  |  Pubmed ID: 22450152

Traumatic brain injury (TBI) induces brain edema via water and glycerol transport channels, called aquaporins (AQPs). The passage of glycerol across brain cellular compartments has been shown during edema. Using a modified impact/head acceleration rodent model of diffuse TBI, we assessed the role of hypoxia inducible factor (HIF)-1alpha in regulating AQP9 expression and glycerol accumulation during the edema formation. Adult (400?425 g) male Sprague-Dawley rats received a closed head injury with a weight drop (450 g, 2-m height) and were allowed to survive up to 48 hours. Some rat groups were administered 2-methoxyestradiol (2ME2, a HIF-1alpha inhibitor) 30 minutes after injury and were euthanized at 4 and 24 hours after injury. Brain edema was measured directly by water content, and glycerol concentration was determined by the Cayman Glycerol Assay. HIF-1alpha and AQP9 protein levels were assessed by Western immunoblotting. This study demonstrated a significant (P<0.05) increase in brain water content at 4?48 hours following impact. Cerebral glycerol was significantly (P<0.05) up-regulated at as early as 1 hour and remained at high levels for up to 48 hours. Similarly, significant (P<0.05) increases in HIF-1alpha and AQP9 protein levels were found at 1 hour and up to 48 hours after injury. Compared to untreated but injured rats, inhibition of HIF-1alpha by 2ME2 significantly (P<0.05) reduced the TBI-induced AQP9 up-regulation. This reduction was temporally associated with significant (P<0.05) decreases in both edema and glycerol accumulation. The data suggested an associated induction of HIF-1alpha, AQP9, and extracellular glycerol accumulation in edema formation following diffuse TBI. The implication of HIF-1alpha and AQP9 underlying TBI-induced edema formation offers possibilities for novel TBI therapies.