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  • 1
    Language: English
    In: Medical hypotheses, November 2017, Vol.109, pp.114-118
    Description: Meningitis is an infectious disease commonly arising from a bacterial etiology. The rapid progression of morbidity and mortality due to bacterial meningitis requires critical and imminent time-dependent clinical intervention. Although it is unambiguously clear that bacteria must infiltrate the cerebrospinal fluid, the sequence of events in the pathogenesis of bacterial meningitis has not been fully elucidated. Most reviews of the pathogenesis of bacterial meningitis do not specify the anatomical location of bacteria following BBB traversal. We propose an additional hypothesis focusing on the Virchow-Robin space (VRS). The VRS consists of a small, but identifiable perivascular space formed by a sheath of cells derived from the pia mater. The VRS has been described as an immunological space and possibly having a role in several neuropathological diseases. Solute exchange between cerebrospinal fluid and extracellular fluid occurs at the VRS, with subsequent drainage into the subarachnoid space. Because the VRS is continuous with the subpial space, a more direct route to the meninges is facilitated. The involvement of the VRS may have profound implications on the pathogenesis and therapeutic strategies: (1) nasopharyngeal colonization; (2) penetration into the blood stream after crossing the mucosal and epithelial membranes; (3) proliferation in the bloodstream; (4) extravasations through the endothelium of the post-capillary venules to the perivascular VRS; (5) migration from VRS to subpial space; (6) traversal through pia mater, entering the CSF in the subarachnoid space; (7) invasion of the meninges. The implication of the VRS in the pathogenesis of bacterial meningitis would be twofold. First, the VRS could provide an additional route of entry of bacteria into the brain. Second, the VRS could provide an area for bacterial proliferation, and thereby serve as a bacterial reservoir in relatively close proximity to the meninges. The clinical consequences of this hypothesis are: 1) clinical interpretation of laboratory findings, and 2) effective antibiotic delivery into the VRS. If the role of the VRS is established as part of bacterial meningitis pathogenesis, antibiotic pharmacokinetics and pharmacodynamics in the VRS need to be determined. This may result in developing novel antibiotic delivery and clinical strategies to improve morbidity and mortality.
    Keywords: Brain -- Physiopathology ; Meningitis, Bacterial -- Physiopathology ; Pia Mater -- Physiopathology ; Subarachnoid Space -- Physiopathology
    ISSN: 03069877
    E-ISSN: 1532-2777
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  • 2
    Language: English
    In: Biochemistry, 16 October 2012, Vol.51(41), pp.8278-92
    Description: Lipopolysaccharide α-1,4-galactosyltransferase C (LgtC) from Neisseria meningitidis is responsible for a key step in lipooligosaccharide biosynthesis involving the transfer of α-galactose from the sugar donor UDP-galactose to a terminal acceptor lactose. Crystal structures of the complexes of LgtC with Mn(2+) and the sugar donor analogue UDP-2-deoxy-2-fluorogalactose in the absence and presence of the sugar acceptor analogue 4'-deoxylactose provided key insights into the galactosyl-transfer mechanism. Combined with kinetic analyses, the enzymatic mechanism of LgtC appears to involve a "front-side attack" S(N)i-like mechanism with a short-lived oxocarbenium-phosphate ion pair intermediate. As a prerequisite for investigating the required roles of structural dynamics in this catalytic mechanism by nuclear magnetic resonance techniques, the transverse relaxation-optimized amide (15)N heteronuclear single-quantum correlation and methyl (13)C heteronuclear multiple-quantum correlation spectra of LgtC in its apo, substrate analogue, and product complexes were partially assigned. This was accomplished using a suite of complementary spectroscopic approaches, combined with selective isotopic labeling and mutagenesis of all the isoleucine residues in the protein. Only ~70% of the amide signals could be detected, whereas more than the expected number of methyl signals were observed, indicating that LgtC adopts multiple interconverting conformational states. Chemical shift perturbation mapping provided insights into substrate and product binding, including the demonstration that the sugar donor analogue (UDP-2FGal) associates with LgtC only in the presence of a metal ion (Mg(2+)). These spectral assignments provide the foundation for detailed studies of the conformational dynamics of LgtC.
    Keywords: Bacterial Proteins -- Chemistry ; Glycosyltransferases -- Chemistry ; Neisseria Meningitidis -- Enzymology
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 3
    Language: English
    In: Biochemistry, 15 January 2013, Vol.52(2), pp.320-32
    Description: Neisseria meningitidis α-1,4-galactosyltransferase C (LgtC) is responsible for the transfer of α-galactose from donor UDP-galactose to the lipooligosaccharide terminal acceptor lactose. Crystal structures of its substrate analogue complexes have provided key insights into the galactosyl transfer mechanism, including a hypothesized need for active site mobility. Accordingly, we have used nuclear magnetic resonance spectroscopy to probe the structural dynamics of LgtC in its apo form and with bound substrate analogues. More than the expected number of signals were observed in the methyl-TROSY spectra of apo LgtC, indicating that the protein adopts multiple conformational states. Magnetization transfer experiments showed that the predominant states, termed "a" and "b", are in equilibrium on a time scale of seconds. Their relative populations change with temperature and mutations, and only the "b" state is competent for substrate binding. For both states, relaxation dispersion studies also revealed substantial millisecond time scale motions of isoleucine side chains within and distal to the active site. Although altered, these motions were still detected in LgtC with a noncovalently bound donor analogue. A mutant, LgtC-Q189E, which forms an unexpected glycosyl-enzyme intermediate via a residue (Asp190) distal from its active site, was also investigated. Apo LgtC-Q189E did not show any enhanced motions that might account for the dramatic structural change required for the galactosylation of Asp190, yet formation of a trapped glycosyl-enzyme intermediate substantially reduced its millisecond time scale conformational mobility. Although further studies are required to link the detected motions of LgtC with its enzymatic mechanism, this work clearly demonstrates the complex structural dynamics of a model glycosyltransferase.
    Keywords: Galactosyltransferases -- Chemistry ; Neisseria Meningitidis -- Enzymology
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 4
    In: Circulation, 2018, Vol.138(Suppl_1 Suppl 1), pp.A16217-A16217
    Description: Introduction: Bicuspid aortic valve (BAV) associated aortopathy portends an increased risk of ascending aortic aneurysm formation and dissection/rupture. We previously showed increased oxidative stress-induced cell death for aortic smooth muscle cells (SMCs) isolated from BAV patients when compared to SMCs isolated from patients with the morphologically normal tricuspid aortic valve (TAV). Furthermore, there is evidence of increased activity of calpain, a calcium dependent protease that can regulate oxidative stress in vasculature, in BAV aortic tissue.Hypothesis: We hypothesize that oxidative stress-induced cell death in BAV-associated aortopathy is mediated by calpain-induced caspase-3.Methods: Calpain and caspase-3 activity were quantified in serum-deprived primary human SMC populations isolated from BAV (n=9) and TAV (n=12) aortic specimens treated with 1mM of tert-butyl hydroperoxide (tBHP) for 3 hours. We measured tBHP-induced cell death in the presence and absence of the calpain inhibitor calpeptin (30μM) in BAV (n=9) and TAV (n=8) using a MTS-based assay.Results: tBHP-induced calpain activity was higher for BAV SMCs when compared with TAV SMCs (65 ± 16.9% vs. 45.9 ± 5.9%, p=0.02). tBHP-induced caspase 3 activity was higher for BAV SMCs compared with TAV SMCs (222 ± 69% vs. 140 ± 8%, p〈0.01, respectively). Calpain inhibition alleviated tBHP-induced cell death in TAV SMCs (66.4 ± 6.7% vs. 93.2 ± 9.3%, p=0.05), and did not affect BAV SMCs (53.6 ± 6.8% vs. 66.3 ± 5.9%, p=0.34).Conclusions: These data highlights the clear differences in cellular biology between TAV and BAV SMCs. It demonstrates that the increased vulnerability of BAV SMCs to oxidative stress compared to TAV SMCs may be due to caspase-3, which has been previously shown to be induced by calpain. Despite increased induction of calpain by tBHP in BAV SMCs, calpain inhibition did not affect oxidative stress induced cell death for BAV SMCs as it did for TAV SMCs. Therefore, calpain is unlikely to be an important effector in BAV SMCs as it is for TAV SMCs in regulating oxidative stress-induced cellular death.
    ISSN: 0009-7322
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  • 5
    Language: English
    In: Annals of Medicine and Surgery, January 2016, Vol.5, pp.S97-S97
    Keywords: Medicine
    ISSN: 2049-0801
    E-ISSN: 2049-0801
    Source: ScienceDirect Journals (Elsevier)
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  • 6
    Language: English
    In: The Journal of biological chemistry, 18 March 2016, Vol.291(12), pp.6396-411
    Description: Retrotransposons are eukaryotic mobile genetic elements that transpose by reverse transcription of an RNA intermediate and are derived from retroviruses. The Ty1 retrotransposon of Saccharomyces cerevisiae belongs to the Ty1/Copia superfamily, which is present in every eukaryotic genome. Insertion of Ty1 elements into the S. cerevisiae genome, which occurs upstream of genes transcribed by RNA Pol III, requires the Ty1 element-encoded integrase (IN) protein. Here, we report that Ty1-IN interacts in vivo and in vitro with RNA Pol III-specific subunits to mediate insertion of Ty1 elements upstream of Pol III-transcribed genes. Purification of Ty1-IN from yeast cells followed by mass spectrometry (MS) analysis identified an enrichment of peptides corresponding to the Rpc82/34/31 and Rpc53/37 Pol III-specific subcomplexes. GFP-Trap purification of multiple GFP-tagged RNA Pol III subunits from yeast extracts revealed that the majority of Pol III subunits co-purify with Ty1-IN but not two other complexes required for Pol III transcription, transcription initiation factors (TF) IIIB and IIIC. In vitro binding studies with bacterially purified RNA Pol III proteins demonstrate that Rpc31, Rpc34, and Rpc53 interact directly with Ty1-IN. Deletion of the N-terminal 280 amino acids of Rpc53 abrogates insertion of Ty1 elements upstream of the hot spot SUF16 tRNA locus and abolishes the interaction of Ty1-IN with Rpc37. The Rpc53/37 complex therefore has an important role in targeting Ty1-IN to insert Ty1 elements upstream of Pol III-transcribed genes.
    Keywords: RNA Polymerase III ; Saccharomyces Cerevisiae ; Ty1 Element ; Integrase ; Retrotransposon ; Retrovirus ; Trna Gene ; Transposable Element (Te) ; Retroelements ; Integrases -- Physiology ; RNA Polymerase III -- Metabolism ; Saccharomyces Cerevisiae -- Genetics
    E-ISSN: 1083-351X
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  • 7
    Language: English
    In: Chest, October 2018, Vol.154(4), pp.41A-41A
    Keywords: Medicine
    ISSN: 0012-3692
    E-ISSN: 1931-3543
    Source: ScienceDirect Journals (Elsevier)
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  • 8
    Language: English
    In: Chest, October 2018, Vol.154(4), pp.482A-483A
    Keywords: Medicine
    ISSN: 0012-3692
    E-ISSN: 1931-3543
    Source: ScienceDirect Journals (Elsevier)
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  • 9
    Language: English
    In: Applied Mathematics & Optimization, 2015, Vol.71(3), pp.533-569
    Description: We study how continuous time Bertrand and Cournot competitions, in which firms producing similar goods compete with one another by setting prices or quantities respectively, can be analyzed as continuum dynamic mean field games. Interactions are of mean field type in the sense that the demand faced by a producer is affected by the others through their average price or quantity. Motivated by energy or consumer goods markets, we consider the setting of a dynamic game with uncertain market demand, and under the constraint of finite supplies (or exhaustible resources). The continuum game is characterized by a coupled system of partial differential equations: a backward Hamilton–Jacobi–Bellman partial differential equation (PDE) for the value function, and a forward Kolmogorov PDE for the density of players. Asymptotic approximation enables us to deduce certain qualitative features of the game in the limit of small competition. The equilibrium of the game is further studied using numerical solutions, which become very tractable by considering the tail distribution function instead of the density itself. This also allows us to consider Dirac delta distributions to use the continuum game to mimic finite $$N$$ N -player nonzero-sum differential games, the advantage being having to deal with two coupled PDEs instead of $$N$$ N . We find that, in accordance with the two-player game, a large degree of competitive interaction causes firms to slow down production. The continuum system can therefore be used qualitative as an approximation to even small player dynamic games.
    Keywords: Mathematics ; Calculus of Variations and Optimal Control; Optimization ; Systems Theory, Control ; Theoretical, Mathematical and Computational Physics ; Mathematical Methods in Physics ; Numerical and Computational Physics ; Engineering ; Mathematics;
    ISSN: 0095-4616
    E-ISSN: 1432-0606
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  • 10
    In: American Journal of Health-System Pharmacy, 2014, Vol.71(19), pp.1662-1667
    Description: PURPOSE: Significant improvements in order-to-administration times for critical first doses of i.v. antibiotic therapy through the use of automated dispensing cabinets (ADCs) are reported. METHODS: In a retrospective pre–post analysis conducted at a large academic medical center, pharmacy and medical records were reviewed to evaluate average times to administration of first doses of i.v. piperacillin–tazobactam therapy during designated periods before and after the addition of selected i.v. antibiotics to ADCs on patient care units. Inpatients who received a specified i.v. piperacillin–tazobactam formulation were included in the analysis. The primary endpoint was the total time from prescribing to administration; the impact of ADC use on other time intervals (e.g., from scanning of orders to administration, from pharmacist verification and release of orders to administration) was also evaluated. RESULTS: A total of 121 subjects were included in the preimplementation (n = 65) and postimplementation (n = 56) samples. There was a significant 1.7-hour reduction in the mean ± S.D. order-to-administration time (from 4.5 ± 4.1 to 2.9 ± 2.5 hours, p = 0.009) for piperacillin–tazobactam first doses with the use of ADCs. Subgroup analyses showed significant reductions in the mean ± S.D. scan-to-administration time (from 3.3 ± 3.4 to 1.7 ± 1.5 hours, p = 0.001) and release-to-administration time (from 2.4 ± 2.4 to 1.4 ± 1.5 hours, p = 0.034). CONCLUSION: The addition of a piperacillin–tazobactam product and other commonly used i.v. antibiotics to ADCs was associated with a significantly reduced order-to-administration time for piperacillin–tazobactam first doses. This change was accounted for by a significant reduction in the time between order entry and drug administration.
    Keywords: Antibiotics -- Usage ; Antibiotics -- Analysis ; Antibiotics -- Technology Application ; Pharmacy -- Usage ; Pharmacy -- Analysis ; Pharmacy -- Technology Application ; Pharmacists -- Analysis ; Pharmacists -- Technology Application ; Medical Schools -- Analysis ; Medical Schools -- Technology Application ; Drugstores -- Usage ; Drugstores -- Analysis ; Drugstores -- Technology Application ; Hospital Patients -- Analysis ; Hospital Patients -- Technology Application;
    ISSN: 1079-2082
    E-ISSN: 15352900
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