Structure and Reactivity Studies of Bis(pyridylimino)isoindolate Transition Metal Complexes.

In this dissertation, transition metal complexes supported by bpi-type (bpi = 1,3-bis(2’-pyridylimino)isoindolate) ligands were designed and synthesized to study their activity, selectivity, and stability in hydrogenation and dehydrogenation reactions and to determine the role of the bpi ligand in these transformations. A new family of ruthenium bpi complexes capable of catalyzing promoterless and chemoselective dehydrogenation of alcohols and amines with liberation of dihydrogen were developed. In particular, the bis(phosphine) ruthenium bMepi hydride (bMepi = 1,3-bis(6’-methyl-2’-pyridylimino)isoindolate) system mediates dehydrogenation of secondary alcohols to ketones, dehydrogenative coupling of primary alcohols to esters, and double dehydrogenation of primary amines to nitriles with high conversion efficiency. An unusual feature of this catalyst system is the high selectivity for secondary alcohol dehydrogenation in the presence of primary alcohols. By avoiding the use of hazardous reagents and harsh oxidants, these dehydrogenative transformations provide environmentally benign methodologies for fine and commodity chemical synthesis with high atom economy. Furthermore, to understand the relationship between catalyst structure and reactivity, the catalytic mechanism of acceptorless alcohol dehydrogenation was elucidated by a series of kinetic and isotopic labeling studies, isolation of intermediates, and evaluation of new ligand variants. The new chemical knowledge acquired in the mechanistic investigation was applied to conceptualize and develop three new projects: (1) iron bMepi systems that feature control over catalytic alkene hydroboration activity and regioselectivity by remote site modifications, (2) ruthenium bpi complexes capable of upgrading ethanol to 1-butanol with state-of-the-art activity (53% conversion and 265 turnovers per hour), and (3) a new series of multifunctional ruthenium complexes with appended Lewis acidic borane sites for studying how Lewis acidity influences the reactivity of the ruthenium hydride moiety and biases the system for stereoselective semi-hydrogenation of alkynes. Collectively, the studies presented in this dissertation demonstrate the new development of highly active and chemoselective catalysts capable of promoting challenging dehydrogenation reactions and showcase how precise structural, electronic, and cooperative interactions in the secondary coordination environment can be used to regulate metal-based catalysis.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120813/1/kueinin_1.pd

Contribution of active hair-bundle motility to nonlinear amplification in the mammalian cochlea

The cochlea’s high sensitivity stems from the active process of outer hair cells, which possess two force-generating mechanisms: active hair-bundle motility elicited by Ca(2+) influx and somatic motility mediated by the voltage-sensitive protein prestin. Although interference with prestin has demonstrated a role for somatic motility in the active process, it remains unclear whether hair-bundle motility contributes in vivo. We selectively perturbed the two mechanisms by infusing substances into the endolymph or perilymph of the chinchilla’s cochlea and then used scanning laser interferometry to measure vibrations of the basilar membrane. Blocking somatic motility, damaging the tip links of hair bundles, or depolarizing hair cells eliminated amplification. While reducing amplification to a lesser degree, pharmacological perturbation of active hair-bundle motility diminished or eliminated the nonlinear compression underlying the broad dynamic range associated with normal hearing. The results suggest that active hair-bundle motility plays a significant role in the amplification and compressive nonlinearity of the cochlea

Anti-oxidative, metal chelating and radical scavenging effects of protein hydrolysates from blue-spotted stingray

Purpose: To evaluate protein hydrolysates and membrane ultrafiltration fractions of blue-spotted stingray for metal chelating and radical scavenging activities, as well as protection against oxidative protein damage.Methods: Stingray protein isolates were hydrolysed with alcalase, papain and trypsin for 3 h. Alcalase hydrolysate was fractionated by membrane ultrafiltration to yield < 3, 3 - 10 and > 10 kDa fractions. Peptide contents, iron and copper chelating activity, 2, 2'-azino-bis(3- ethylbenzothiazoline-6-sulphonic acid) (ABTS) and hydroxyl radical scavenging activities, and protection against oxidative protein damage were evaluated.Results: Three-hour alcalase hydrolysate (3AH) had the highest peptide content and the lowest half maximal effective concentration (EC50) for ABTS radical scavenging (793.9 μg/mL), hydroxyl radical scavenging (6.93 mg/mL), iron chelating (116.4 μg/mL) and copper chelating  activity (2136.9 μg/mL) among the hydrolysates. Among the fractions of 3AH, < 3 kDa fraction had the best iron chelating activity, 3 - 10 kDa fraction exhibited the highest ABTS radical scavenging activity, while > 10 kDa fraction showed the best copper chelating activity. The < 3 kDa and 3 - 10 kDa fractions had similar levels of hydroxyl radical scavenging activity to reduced glutathione. The protective effects of 3AH and < 3 kDa fraction against oxidative protein damage were comparable to that of reduced glutathione.Conclusion: Alcalase is the best protease for producing hydrolysates with metal chelating and antioxidant activities from stingray proteins. Alcalase hydrolysate, specifically its < 3 kDa fraction, has potential for future applications in antioxidant therapy and health food formulation

In vivo assessment of brainstem depigmentation in Parkinson’s: potential as severity marker for multi-centre studies

Purpose: To investigate the pattern of neuromelanin signal intensity loss within the substantia nigra pars compacta (SNpc), locus coeruleus, and ventral tegmental area in Parkinson disease (PD); the specific aims were (a) to study regional magnetic resonance (MR) quantifiable depigmentation in association with PD severity and (b) to investigate whether imaging- and platform-dependent signal intensity variations can be normalized. Materials and Methods: This prospective case-control study was approved by the local ethics committee and the research department of Nottingham University Hospitals. Written informed consent was obtained from all participants before enrollment in the study. Sixty-nine participants (39 patients with PD and 30 control subjects) were investigated with neuromelanin-sensitive MR imaging by using two different 3-T platforms and three differing protocols. Neuromelanin-related volumes of the anterior and posterior SNpc, locus coeruleus, and ventral tegmental area were determined, and normalized neuromelanin volumes were assessed for protocol-dependent effects. Diagnostic test performance of normalized neuromelanin volume was investigated by using receiver operating characteristic analyses, and correlations with the Unified Parkinson’s Disease Rating Scale scores were tested. Results: Reduction of normalized neuromelanin volume in PD was most pronounced in the posterior SNpc (median, −83%; P < .001), followed by the anterior SNpc (−49%; P < .001) and the locus coeruleus (−37%; P < .05). Normalized neuromelanin volume loss of the posterior and whole SNpc allowed the best differentiation of patients with PD and control subjects (area under the receiver operating characteristic curve, 0.92 and 0.88, respectively). Normalized neuromelanin volume of the anterior, posterior, and whole SNpc correlated with Unified Parkinson’s Disease Rating Scale scores (r2 = 0.25, 0.22, and 0.28, respectively; all P < .05). Conclusion: PD-induced neuromelanin loss can be quantified across imaging protocols and platforms by using appropriate adjustment. Depigmentation in PD follows a distinct spatial pattern, affords high diagnostic accuracy, and is associated with disease severity

Effects of monthly feedback of VFA measured by dual BIA method in Japanese patients with obesity: a randomized controlled study

Objective: To investigate the effects of monthly feedback of changes in visceral fat area (VFA) as measured by dual bioelectrical impedance analysis method and the importance of VFA in individuals with obesity. Methods: Thirty‐eight Japanese patients with obesity underwent VFA measurements. The feedback group was given feedback on VFA measurements each month for 4 months. The control group underwent VFA measurements at the beginning and end of the study but was not informed of the results. All the study participants completed eating behaviour and weight efficacy lifestyle questionnaires. Results: Mean age was 53.9 (14.3) years; mean body mass index was 30.6 (4.3) kg m⁻². At the 4‐month follow‐up, there was no significant difference in VFA reduction between the control and feedback groups (−4.4% vs. −3.0%; 95% CI, −3.8 to 5.5). In post‐hoc analysis using the overall group irrespective of allocation, changes of eating style were significantly associated with a reduction in VFA at 4 months (p = 0.034). Conclusions: Monthly feedback on changes in VFA does not reduce VFA. More frequent feedback may be required. In post‐hoc analysis, changes of eating style were associated with a reduction in VFA

Effect of Coulomb interactions on the physical observables of graphene

We give an update of the situation concerning the effect of electron-electron interactions on the physics of a neutral graphene system at low energies. We revise old renormalization group results and the use of 1/N expansion to address questions of the possible opening of a low-energy gap, and the magnitude of the graphene fine structure constant. We emphasize the role of Fermi velocity as the only free parameter determining the transport and electronic properties of the graphene system and revise its renormalization by Coulomb interactions in the light of recent experimental evidence.Comment: Proceedings of the Nobel Symposium on graphene 2010, to appear as a special issue in Physica Script

Cohomology of bundles on homological Hopf manifold

We discuss the properties of complex manifolds having rational homology of $S^1 \times S^{2n-1}$ including those constructed by Hopf, Kodaira and Brieskorn-van de Ven. We extend certain previously known vanishing properties of cohomology of bundles on such manifolds.As an application we consider degeneration of Hodge-deRham spectral sequence in this non Kahler setting.Comment: To appear in Proceedings of 2007 conference on Several complex variables and Complex Geometry. Xiamen. Chin

Rational tuning of the reactivity of three-membered heterocycle ring-openings via SN2 reactions

The development of small molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the "electrophilic trap" that allows for a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. We here investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with an N- (aziridine), P- (phosphirane), O- (epoxide) and S-atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring-opening reaction of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C6H10Y with Y = NH, PH, O, S). It is revealed that the activation energy of the ring-opening reaction does not necessarily follow the trend that is expected from C-Y leaving-group bond strength, but steeply decreases from NH, to PH, to O, to S. We illustrate that the HOMONu-LUMOSubstrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.NWONWO-Rekentijd grant 17569 and 11116Bio-organic Synthesi

SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1

BACKGROUND We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown. METHODS A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer. RESULTS Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53. CONCLUSION Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity

Potential Impacts of Free Trade Areas and Common Currency on Sustainable Agricultural Export in Africa

Peer reviewedPublisher PD