24 results on '"Weiss DR"'
Search Results
2. CHASING INFERTILITY – THE CHAT BOT-WAY TO INCREASE FERTILITY AWARENESS
- Author
-
Helene Schenk, Nina Reinschissler, Gregor Weiss Dr, and Michael Schenk Dr
- Subjects
Infertility ,Reproductive Medicine ,Fertility awareness ,medicine ,Obstetrics and Gynecology ,medicine.disease ,Psychology ,Demography - Published
- 2021
- Full Text
- View/download PDF
3. Isolation and characterization of a phospholipase A2 from an inflammatory exudate
- Author
-
R Franson, Dr, R Dobrow, Dr, J Weiss, Dr, P Elsbach, Dr, and W B Weglicki, Dr
- Subjects
phospholipid ,Ca2+ dependence ,positional specificity ,molecular size ,cationic protein ,polymorphonuclear leukocyte ,Biochemistry ,QD415-436 - Abstract
Sterile peritoneal exudates produced in rabbits injected with 1% glycogen contain a phospholipase A activity in a cell-free supernatant fraction that hydrolyzed a synthetic phospholipid (1,2-diacyl-sn-glycero-3-phospho-ethanolamine) and phospholipids of autoclaved Escherichia coli. This phospholipase activity (phosphatidylacylhydrolase EC 3.1.1.4) exhibited an apparent bimodal pH optimum (pH 6.0 and pH 7.5) and was Ca2+-dependent; Mg2+ and monovalent cations (Na+ and K+) did not substitute for Ca2+ in the reaction; EDTA was a potent inhibitor. The phospholipase hydrolyzed 1-[1-14C]palmitoyl-2-acyl-sn-glycero-3-phosphoethanolamine to form only radio-active lysophosphatidylethanolamine as the product, indicating that the enzyme had phospholipase A2 specificity. The phospholipase A2 was purified 302-fold by two successive chromatographic steps on carboxymethyl Sephadex. Gel filtration (Sephadex G75) of the purified enzyme resulted in a single peak of biological activity with a molecular weight of approximately 14,800. The same estimate of molecular weight was obtained by SDS–polyacrylamide gel electrophoresis, which yielded a single band. Polyacrylamide gel electrophoresis of this fraction at pH 4.3 revealed a single protein band migrating beyond lysozyme, with the dye front, suggesting that this protein was more basic than lysozyme (pI 10.5). The enzymatic and physical-chemical characteristics of this soluble enzyme were remarkably similar to a recently described phospholipase A(2) of rabbit polymorphonuclear leukocytes derived from glycogen-induced peritoneal exudates. The possible origin and physiological role of this soluble enzyme are discussed.
- Published
- 1978
- Full Text
- View/download PDF
4. Fra Nuuk til ...? Hvad betyder dansk for grønlændere?
- Author
-
Kristmannsson , Dr. Gauti, Weiss, Dr. Peter, Trondhjem, Naja Blytmann, Kristmannsson , Dr. Gauti, Weiss, Dr. Peter, and Trondhjem, Naja Blytmann
- Published
- 2005
5. Eine neue Schar periodischer Lösungen des ebenen Dreikörperproblems
- Author
-
Weiss, Dr. G., Arzberg (Oberfranken) and Weiss, Dr. G., Arzberg (Oberfranken)
6. Natural Cycle/Progesterone Fortified Protocol for Endometrial Preparation for Frozen/Thawed Embryo Transfer
- Author
-
Amir Weiss, Dr.
- Published
- 2019
7. Antibodies attenuate the capacity of dendritic cells to stimulate HIV-specific cytotoxic T lymphocytes
- Author
-
Sylvain Cardinaud, Wilfried Posch, Klaus Loacker, Cornelia Lass-Flörl, Manfred P. Dierich, Annelies Mühlbacher, Adam J. Fletcher, Asier Sáez-Cirión, Chiraz Hamimi, Doris Wilflingseder, Gianfranco Pancino, Paul Eichberger, Arnaud Moris, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulation des Infections Rétrovirales, Institut Pasteur [Paris] (IP), University College of London [London] (UCL), This work was supported by the Austrian Science Fund [FWF, P22165 and P24598 to DW]and the Tyrolean Science Fund [TWF, project: D-155140-016-011 to WP]. The authors thankProf. Olivier Lambotte, Prof. Laurence Weiss, Dr. Caroline Lascoux, Dr. Olivier Taulera,Katia Bourdic, Jeannine Delgado, Maria Manea and all the other physicians and nurses whocared for the patients whose samples were included in the study. Additionally, we want tothank Polymun Scientific, Donaustrasse 99, Klosterneuburg, Austria who provided allreagents for p24 ELISA . The reagents ARP118 (HIV-BaL), ARP513 (HIVIg pool) andARP177.8 (HIV-92UG037) were obtained from the Centre for AIDS Reagents, NIBSCHPA UK, supported by the EC FP6/7 Europrise Network of Excellence, and NGIN consortiaand the Bill and Melinda Gates GHRC-CAVD Project and were donated by Dr.S.Gartner,Dr.M.Popovic, Dr.R.Gallo (Courtesy of the NIH AIDS Research and Reference ReagentProgram [BaL]), Dr B. Wahren, The Swedish Institute for Infectious Disease Control,Stockholm, Sweden [HIVIg pool] and the WHO UN AIDS Network for HIV-isolation andcharacterization [92UG037]., Innsbruck Medical University [Austria] (IMU), Institut Pasteur [Paris], and Guibert, Marie-Genevieve
- Subjects
CD4-Positive T-Lymphocytes ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Cytotoxic ,T-Lymphocytes ,Immunology ,Antigen presentation ,Priming (immunology) ,HIV Infections ,Biology ,Antibodies, Viral ,Lymphocyte Activation ,Article ,Antibodies ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Antigen ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Viral ,Antigens ,Antigens, Viral ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Antigen Presentation ,virus diseases ,HIV ,Dendritic cell ,Complement System Proteins ,Dendritic Cells ,Molecular biology ,3. Good health ,Clone Cells ,Antibody opsonization ,CTL ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,CD8 ,T-Lymphocytes, Cytotoxic ,030215 immunology - Abstract
International audience; BACKGROUND: Control of HIV is suggested to depend on potent effector functions of the virus-specific CD8(+) T-cell response. Antigen opsonization can modulate the capture of antigen, its presentation, and the priming of specific CD8(+) T-cell responses. OBJECTIVE: We have previously shown that opsonization of retroviruses acts as an endogenous adjuvant for dendritic cell (DC)-mediated induction of specific cytotoxic T lymphocytes (CTLs). However, in some HIV-positive subjects, high levels of antibodies and low levels of complement fragments coat the HIV surface. METHODS: Therefore we analyzed the effect of IgG opsonization on the antigen-presenting capacity of DCs by using CD8(+) T-cell proliferation assays after repeated prime boosting, by measuring the antiviral activity against HIV-infected autologous CD4(+) T cells, and by determining IFN-γ secretion from HIV-specific CTL clones. RESULTS: We find that DCs exposed to IgG-opsonized HIV significantly decreased the HIV-specific CD8(+) T-cell response compared with the earlier described efficient CD8(+) T-cell activation induced by DCs loaded with complement-opsonized HIV. DCs exposed to HIV bearing high surface IgG levels after incubation in plasma from HIV-infected subjects acted as weak stimulators for HIV-specific CTL clones. In contrast, HIV opsonized with plasma from patients exhibiting high complement and low IgG deposition on the viral surface favored significantly higher activation of HIV-specific CD8(+) T-cell clones. CONCLUSION: Our ex vivo and in vitro observations provide the first evidence that IgG opsonization of HIV is associated with a decreased CTL-stimulatory capacity of DCs.
- Published
- 2012
- Full Text
- View/download PDF
8. Structure-based discovery of selective positive allosteric modulators of antagonists for the M 2 muscarinic acetylcholine receptor.
- Author
-
Korczynska M, Clark MJ, Valant C, Xu J, Moo EV, Albold S, Weiss DR, Torosyan H, Huang W, Kruse AC, Lyda BR, May LT, Baltos JA, Sexton PM, Kobilka BK, Christopoulos A, Shoichet BK, and Sunahara RK
- Subjects
- Allosteric Regulation, Allosteric Site, Animals, Humans, Kinetics, Ligands, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Molecular Docking Simulation, Muscarinic Agonists metabolism, Phosphorylation, Protein Binding, Rats, Receptor, Muscarinic M2 metabolism, Muscarinic Agonists chemistry, Receptor, Muscarinic M2 chemistry
- Abstract
Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M
2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N -methyl scopolamine (NMS). Structure-based optimization led to compound '628, which enhanced binding of NMS, and the drug scopolamine itself, with a cooperativity factor (α) of 5.5 and a KB of 1.1 μM, while sparing the endogenous agonist acetylcholine. NMR spectral changes determined for methionine residues reflected changes in the allosteric network. Moreover, '628 slowed the dissociation rate of NMS from the M2 mAChR by 50-fold, an effect not observed at the other four mAChR subtypes. The specific PAM effect of '628 on NMS antagonism was conserved in functional assays, including agonist stimulation of [35 S]GTPγS binding and ERK 1/2 phosphorylation. Importantly, the selective allostery between '628 and NMS was retained in membranes from adult rat hypothalamus and in neonatal rat cardiomyocytes, supporting the physiological relevance of this PAM/antagonist approach. This study supports the feasibility of discovering PAMs that confer subtype selectivity to antagonists; molecules like '628 can convert an armamentarium of potent but nonselective GPCR antagonist drugs into subtype-selective reagents, thus reducing their off-target effects., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)- Published
- 2018
- Full Text
- View/download PDF
9. Millisecond dynamics of RNA polymerase II translocation at atomic resolution.
- Author
-
Silva DA, Weiss DR, Pardo Avila F, Da LT, Levitt M, Wang D, and Huang X
- Subjects
- Amino Acid Sequence, Markov Chains, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Tertiary, RNA Polymerase II physiology, RNA Polymerase II ultrastructure, Sequence Alignment, Time Factors, Models, Chemical, Models, Molecular, RNA Polymerase II metabolism, Transcription, Genetic physiology
- Abstract
Transcription is a central step in gene expression, in which the DNA template is processively read by RNA polymerase II (Pol II), synthesizing a complementary messenger RNA transcript. At each cycle, Pol II moves exactly one register along the DNA, a process known as translocation. Although X-ray crystal structures have greatly enhanced our understanding of the transcription process, the underlying molecular mechanisms of translocation remain unclear. Here we use sophisticated simulation techniques to observe Pol II translocation on a millisecond timescale and at atomistic resolution. We observe multiple cycles of forward and backward translocation and identify two previously unidentified intermediate states. We show that the bridge helix (BH) plays a key role accelerating the translocation of both the RNA:DNA hybrid and transition nucleotide by directly interacting with them. The conserved BH residues, Thr831 and Tyr836, mediate these interactions. To date, this study delivers the most detailed picture of the mechanism of Pol II translocation at atomic level.
- Published
- 2014
- Full Text
- View/download PDF
10. SAMPL4 & DOCK3.7: lessons for automated docking procedures.
- Author
-
Coleman RG, Sterling T, and Weiss DR
- Subjects
- HIV enzymology, Ligands, Protein Binding, Thermodynamics, HIV Integrase metabolism, Molecular Docking Simulation, Software
- Abstract
The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: (1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, (2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, (3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking tools, not just DOCK 3.7, that could improve the state of the art. Future difficulties and projects will be discussed.
- Published
- 2014
- Full Text
- View/download PDF
11. Abundant Pericytes in the Venous Intima and the Vasa Venarum: Evidence for Their Key Role in Venous Thrombosis.
- Author
-
Nees S, Weiss DR, Partsch H, and Juchem G
- Published
- 2013
- Full Text
- View/download PDF
12. Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4.
- Author
-
Mysinger MM, Weiss DR, Ziarek JJ, Gravel S, Doak AK, Karpiak J, Heveker N, Shoichet BK, and Volkman BF
- Subjects
- Cell Line, Drug Discovery, Humans, Ligands, Molecular Structure, Proteins chemistry, Receptors, CXCR4 chemistry
- Abstract
G-protein-coupled receptors (GPCRs) are key signaling molecules and are intensely studied. Whereas GPCRs recognizing small-molecules have been successfully targeted for drug discovery, protein-recognizing GPCRs, such as the chemokine receptors, claim few drugs or even useful small molecule reagents. This reflects both the difficulties that attend protein-protein interface inhibitor discovery, and the lack of structures for these targets. Imminent structure determination of chemokine receptor CXCR4 motivated docking screens for new ligands against a homology model and subsequently the crystal structure. More than 3 million molecules were docked against the model and then against the crystal structure; 24 and 23 high-scoring compounds from the respective screens were tested experimentally. Docking against the model yielded only one antagonist, which resembled known ligands and lacked specificity, whereas the crystal structure docking yielded four that were dissimilar to previously known scaffolds and apparently specific. Intriguingly, several were potent and relatively small, with IC(50) values as low as 306 nM, ligand efficiencies as high as 0.36, and with efficacy in cellular chemotaxis. The potency and efficiency of these molecules has few precedents among protein-protein interface inhibitors, and supports structure-based efforts to discover leads for chemokine GPCRs.
- Published
- 2012
- Full Text
- View/download PDF
13. Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models.
- Author
-
Juchem G, Weiss DR, Knott M, Senftl A, Förch S, Fischlein T, Kreuzer E, Reichart B, Laufer S, and Nees S
- Subjects
- Actins metabolism, Arterioles drug effects, Arterioles immunology, Arterioles metabolism, Blood Platelets cytology, Blood Platelets drug effects, Blood Platelets metabolism, Capillaries drug effects, Capillaries immunology, Capillaries metabolism, Capillary Permeability drug effects, Cells, Cultured, Coronary Circulation drug effects, Dinoprostone pharmacology, Drug Synergism, Erythrocytes cytology, Erythrocytes drug effects, Erythrocytes metabolism, Hemostatics pharmacology, Humans, Interleukin-6 pharmacology, Interleukin-8 pharmacology, Leukotriene B4 pharmacology, Myocarditis immunology, Pericytes drug effects, Pericytes immunology, Pericytes metabolism, Platelet Activating Factor pharmacology, Thrombin pharmacology, Venules drug effects, Venules immunology, Venules metabolism, Blood Proteins pharmacology, Capillary Permeability immunology, Coronary Circulation immunology, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells metabolism, Inflammation Mediators pharmacology, Myocarditis metabolism
- Abstract
We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity (L(P)) was registered. L(P) of SC-PAO remained low under all conditions (3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)). In contrast, in the venular wall model, PGE(2), platelet-activating factor (PAF), leukotriene B(4) (LTB(4)), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in L(P) with synergistic support when combined. PAF and LTB(4) released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6-8 h by the presence of 50 μM quercetin glucuronide (QG). LTB(4) synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention.
- Published
- 2012
- Full Text
- View/download PDF
14. Isolation, bulk cultivation, and characterization of coronary microvascular pericytes: the second most frequent myocardial cell type in vitro.
- Author
-
Nees S, Weiss DR, Senftl A, Knott M, Förch S, Schnurr M, Weyrich P, and Juchem G
- Subjects
- Animals, Blood Coagulation, Cattle, Cell Communication, Cell Proliferation, Cell Survival, Cells, Cultured, Coculture Techniques, Coronary Vessels cytology, Cricetinae, Cryopreservation, Endothelial Cells physiology, Guinea Pigs, Humans, Mesocricetus, Mice, Microvessels cytology, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular physiology, Myocytes, Smooth Muscle physiology, Neovascularization, Physiologic, Phenotype, Rabbits, Rats, Rats, Sprague-Dawley, Sus scrofa, Time Factors, Cell Separation, Coronary Vessels physiology, Microvessels physiology, Pericytes physiology
- Abstract
Densely arranged pericytes engird the endothelial tube of all coronary microvessels. Since the experimental access to these abundant cells in situ is difficult, a prerequisite for broader investigation is the availability of sufficient numbers of fully differentiated pericytes in homogenous culture. To reach this goal, we applied strictly standardized cell isolation techniques, optimized culture methods and specific histological staining. Approximately 1,000-fold enriched pericytes were proteolytically detached from highly purified coronary microvascular networks (density gradient centrifugation) of eight mammalian species including human. Addition of species-autologous fetal or neonatal serum (10-20% vol/vol) was a precondition for longer term survival of homogenous pericyte cultures. This ensured optimal growth (doubling time <14 h) and full expression of pericyte-specific markers. In 3-mo, 10(10) pericytes (15 g) could be cultivated from 1 bovine heart. Pericytes could be stored in liquid N(2), recultured, and passaged repeatedly without loss of typical features. In cocultures with EC or vascular smooth muscle cells, pericytes transferred fluorescent calcein to each other and to EC via their antler-like extensions, organized angiogenetic sprouting of vessels, and rapidly activated coagulation factors X and II via tissue factor and prothrombinase. The interconnected pericytes of the coronary system are functionally closely correlated with the vascular endothelium and may play key roles in the adjustment of local blood flow, the regulation of angiogenic processes, and the induction of procoagulatory processes. Their successful bulk cultivation enables direct experimental access under defined in vitro conditions and the isolation of pericyte specific antigens for the production of specific antibodies.
- Published
- 2012
- Full Text
- View/download PDF
15. Wall structures of myocardial precapillary arterioles and postcapillary venules reexamined and reconstructed in vitro for studies on barrier functions.
- Author
-
Nees S, Juchem G, Eberhorn N, Thallmair M, Förch S, Knott M, Senftl A, Fischlein T, Reichart B, and Weiss DR
- Subjects
- Albumins metabolism, Arterioles cytology, Arterioles metabolism, Cell Separation, Cells, Cultured, Coculture Techniques, Coronary Vessels cytology, Culture Media, Electric Conductivity, Extracellular Matrix metabolism, Humans, Immunohistochemistry, Microscopy, Confocal, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Time Factors, Venules cytology, Venules metabolism, Capillary Permeability, Coronary Vessels metabolism, Endothelial Cells metabolism, Pericytes metabolism
- Abstract
The barrier functions of myocardial precapillary arteriolar and postcapillary venular walls (PCA or PCV, respectively) are of considerable scientific and clinical interest (regulation of blood flow and recruitment of immune defense). Using enzyme histochemistry combined with confocal microscopy, we reexamined the cell architecture of human PCA and PVC and reconstructed appropriate in vitro models for studies of their barrier functions. Contrary to current opinion, the PCA endothelial tube is encompassed not by smooth muscle cells but rather by a concentric layer of pericytes cocooned in a thick, microparticle-containing extracellular matrix (ECM) that contributes substantially to the tightness of the arteriolar wall. This core tube extends upstream into the larger arterioles, there additionally enwrapped by smooth muscle. PCV consist of an inner layer of large, contractile endothelial cells encompassed by a fragile, wide-meshed pericyte network with a weakly developed ECM. Pure pericyte and endothelial cell preparations were isolated from PCA and PCV and grown in sandwich cultures. These in vitro models of the PCA and PCV walls exhibited typical histological and functional features. In both plasma-like (PLM) and serum-containing (SCM) media, the PCA model (including ECM) maintained its low hydraulic conductivity (L(P) = 3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)) and a high selectivity index for transmural passage of albumin (SI(Alb) = 0.95 ± 0.02). In contrast, L(P) and SI(Alb) in the PCV model (almost no ECM) were 2.55 ± 0.32·10(-7)cm·s(-1)·cmH(2)O(-1) and 0.88 ± 0.03, respectively, in PLM, and 1.39 ± 0.10·10(-6)cm·s(-1)·cmH(2)O(-1) and 0.49 ± 0.04 in SCM. With the use of these models, systematic, detailed studies on the regulation of microvascular barrier properties now appear to be feasible.
- Published
- 2012
- Full Text
- View/download PDF
16. Optimized torsion-angle normal modes reproduce conformational changes more accurately than cartesian modes.
- Author
-
Bray JK, Weiss DR, and Levitt M
- Subjects
- Computer Simulation, Protein Conformation, Torque, Algorithms, Models, Chemical, Models, Molecular, Proteins chemistry, Proteins ultrastructure
- Abstract
We present what to our knowledge is a new method of optimized torsion-angle normal-mode analysis, in which the normal modes move along curved paths in Cartesian space. We show that optimized torsion-angle normal modes reproduce protein conformational changes more accurately than Cartesian normal modes. We also show that orthogonalizing the displacement vectors from torsion-angle normal-mode analysis and projecting them as straight lines in Cartesian space does not lead to better performance than Cartesian normal modes. Clearly, protein motion is more naturally described by curved paths in Cartesian space., (Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
17. Biomechanical investigation of a novel ratcheting arthrodesis nail.
- Author
-
McCormick JJ, Li X, Weiss DR, Billiar KL, and Wixted JJ
- Abstract
Background: Knee or tibiotalocalcaneal arthrodesis is a salvage procedure, often with unacceptable rates of nonunion. Basic science of fracture healing suggests that compression across a fusion site may decrease nonunion. A novel ratcheting arthrodesis nail designed to improve dynamic compression is mechanically tested in comparison to existing nails., Methods: A novel ratcheting nail was designed and mechanically tested in comparison to a solid nail and a threaded nail using sawbones models (Pacific Research Laboratories, Inc.). Intramedullary nails (IM) were implanted with a load cell (Futek LTH 500) between fusion surfaces. Constructs were then placed into a servo-hydraulic test frame (Model 858 Mini-bionix, MTS Systems) for application of 3 mm and 6 mm dynamic axial displacement (n = 3/group). Load to failure was also measured., Results: Mean percent of initial load after 3-mm and 6-mm displacement was 190.4% and 186.0% for the solid nail, 80.7% and 63.0% for the threaded nail, and 286.4% and 829.0% for the ratcheting nail, respectively. Stress-shielding (as percentage of maximum load per test) after 3-mm and 6-mm displacement averaged 34.8% and 28.7% (solid nail), 40.3% and 40.9% (threaded nail), and 18.5% and 11.5% (ratcheting nail), respectively. In the 6-mm trials, statistically significant increase in initial load and decrease in stress-shielding for the ratcheting vs. solid nail (p = 0.029, p = 0.001) and vs. threaded nail (p = 0.012, p = 0.002) was observed. Load to failure for the ratcheting nail; 599.0 lbs, threaded nail; 508.8 lbs, and solid nail; 688.1 lbs., Conclusion: With significantly increase of compressive load while decreasing stress-shielding at 6-mm of dynamic displacement, the ratcheting mechanism in IM nails may clinically improve rates of fusion.
- Published
- 2010
- Full Text
- View/download PDF
18. RNA polymerase II trigger loop residues stabilize and position the incoming nucleotide triphosphate in transcription.
- Author
-
Huang X, Wang D, Weiss DR, Bushnell DA, Kornberg RD, and Levitt M
- Subjects
- Hydrogen Bonding, Models, Molecular, Molecular Dynamics Simulation, Nucleotides chemistry, RNA Polymerase II chemistry, Nucleotides metabolism, RNA Polymerase II metabolism, Transcription, Genetic
- Abstract
A structurally conserved element, the trigger loop, has been suggested to play a key role in substrate selection and catalysis of RNA polymerase II (pol II) transcription elongation. Recently resolved X-ray structures showed that the trigger loop forms direct interactions with the beta-phosphate and base of the matched nucleotide triphosphate (NTP) through residues His1085 and Leu1081, respectively. In order to understand the role of these two critical residues in stabilizing active site conformation in the dynamic complex, we performed all-atom molecular dynamics simulations of the wild-type pol II elongation complex and its mutants in explicit solvent. In the wild-type complex, we found that the trigger loop is stabilized in the "closed" conformation, and His1085 forms a stable interaction with the NTP. Simulations of point mutations of His1085 are shown to affect this interaction; simulations of alternative protonation states, which are inaccessible through experiment, indicate that only the protonated form is able to stabilize the His1085-NTP interaction. Another trigger loop residue, Leu1081, stabilizes the incoming nucleotide position through interaction with the nucleotide base. Our simulations of this Leu mutant suggest a three-component mechanism for correctly positioning the incoming NTP in which (i) hydrophobic contact through Leu1081, (ii) base stacking, and (iii) base pairing work together to minimize the motion of the incoming NTP base. These results complement experimental observations and provide insight into the role of the trigger loop on transcription fidelity.
- Published
- 2010
- Full Text
- View/download PDF
19. Pericytes in the macrovascular intima: possible physiological and pathogenetic impact.
- Author
-
Juchem G, Weiss DR, Gansera B, Kemkes BM, Mueller-Hoecker J, and Nees S
- Subjects
- Animals, Cattle, Cell Culture Techniques methods, Cell Proliferation, Cell Separation methods, Cells, Cultured, Endothelium, Vascular cytology, Endothelium, Vascular physiology, Female, Humans, Models, Animal, Saphenous Vein cytology, Saphenous Vein physiology, Thromboplastin metabolism, Pericytes cytology, Pericytes physiology, Tunica Intima cytology, Tunica Intima physiology
- Abstract
The frequently observed de-endothelialization of venous coronary bypass grafts prepared using standard methods exposes subendothelial prothrombotic cells to blood components, thus endangering patients by inducing acute thromboembolic infarction or long-term proliferative stenosis. Our aim was to gain deeper histological and physiological insight into these relations. An intricate network of subendothelial cells, characterized by histological features specific for true pericytes, was detected even in healthy vessels and forms, coupled to the luminal endothelium, a second leaflet of the macrovascular intima. These cells, and particularly those in the venous intima, express enormous concentrations of tissue factor and can recruit additional amounts of up to the 25-fold concentration within 1 h during preincubation with serum (intimal pericytes of venous origin activate 30.71 +/- 4.07 pmol coagulation factor x.min(-1).10(-6) cells; n = 15). Moreover, decoupled from the endothelium, they proliferate rapidly (generation time, 15 +/- 2.1 h, n = 8). Central regions of atherosclerotic plaques, as well as of those of restenosed areas of coronary vein grafts, consist almost completely of these cells. In stark contrast with the prothrombogenicity of the intimal pericytes, intact luminal endothelium recruits high concentrations of thrombomodulin (CD 141) specifically within its intercellular junctions, activates Protein C rapidly (42 +/- 5.1 pmol/min.10(6) venous endothelial cells at thrombin saturation; n = 15), can thus actively prevent coagulatory processes, and never expresses histologically detectable and functionally active tissue factor. Given this strongly prothrombotic potential of the intimal pericytes and their overshooting growth behavior in endothelium-denuded vascular regions, they may play important roles in the development of atherosclerosis, thrombosis, and saphenous vein graft disease.
- Published
- 2010
- Full Text
- View/download PDF
20. Search for optimized conditions for sealing and storage of bypass vessels: influence of preservation solution and filling pressure on the degree of endothelialization.
- Author
-
Weiss DR, Juchem G, Eblenkamp M, Kemkes BM, Gansera B, Geier M, and Nees S
- Abstract
The aim of the present study was to develop methods for the rapid assessment of intimal quality of coronary bypass segments of venous origin, and to prevent endothelial damage by improved intraoperative handling of graft segments. Particular attention was paid to the influence of the composition of the preservation solution and the intravasal filling pressure on the degree of endothelialization. Intrava-sal exposure to Alcian blue at pH<3 resulted in highly specific staining of intimal regions with functionally or structurally damaged endothelium. Standardization of preparation, staining and image acquisition of the intimal surface of graft remnants and subsequent computer-aided planimetry of these images made it possible for the first time to perform rapid serial investigations for quality control of bypass grafts. Using saline as the rinsing and intraoperative storage medium resulted in the loss of more than 50% of the endothelium at intravasal pressures of 0-100 mmHg. Increasing the pressure resulted eventually in complete de-endothelialization. In contrast, grafts incubated in a customized plasma derivative tolerated pressures of up to 200 mmHg with no significant endothelial loss; and even after exposure to 1,000 mmHg (10 times the average mean arterial pressure!) more than 70% of the endothelium were intact and vital. These findings imply strongly that the quality of aortocoronary bypass grafts of venous origin can be improved substantially by the use of a plasma derivative solution for intraoperative preservation and by monitoring and controlling the intravasal pressures reached during sealing and storage.
- Published
- 2010
21. Extensive deendothelialization and thrombogenicity in routinely prepared vein grafts for coronary bypass operations: facts and remedy.
- Author
-
Weiss DR, Juchem G, Kemkes BM, Gansera B, and Nees S
- Abstract
The objective of this study was to gain deeper insight into the early reasons for saphenous vein graft disease and to find a practical approach to obviate it. Intraoperative storage of freshly explanted venous grafts (45 min, 20 degrees C; n=25 in each case) in saline, saline + 5% albumin, or HTK-solution and also in heparinized autologous blood was poorly tolerated by the endothelium. Large endothelial areas (mostly >75% of total surface) were detached already during brief non-pulsatile flushing just before the transplantation. Contact of deendothelialized areas in graft remnants with defined mixtures of coagulation factors or blood (n=11-17) caused rapid coagulatory processes via expression of tissue factor and assembly of prothrombinase in the subendothelium. Attached platelets and leukocytes accelerated the procoagulatory processes further, and endothelium-dependent anticoagulatory activities were significantly abolished. During pulsatile arterial flow, the resulting blood clots exacerbated the damage of the intima markedly, because they were flushed away tearing off further endothelium. In contrast, storage of venous grafts in a plasma preparation freed from isoagglutinins and coagulation factors preserved the endothelium, which resisted arterial flow and revealed anticoagulatory activity in the presence of antithrombin III and/or protein C. We conclude that gentle preparation and preservation of the vascular endothelium with a suitable storage solution during bypass surgery is a decisive first step to obviate saphenous vein graft disease.
- Published
- 2009
22. How hydrophobic buckminsterfullerene affects surrounding water structure.
- Author
-
Weiss DR, Raschke TM, and Levitt M
- Subjects
- Adsorption, Solubility, Surface Tension, Fullerenes chemistry, Hydrophobic and Hydrophilic Interactions, Water chemistry
- Abstract
The hydrophobic hydration of fullerenes in water is of significant interest as the most common Buckminsterfullerene (C60) is a mesoscale sphere; C60 also has potential in pharmaceutical and nanomaterial applications. We use an all-atom molecular dynamics simulation lasting hundreds of nanoseconds to determine the behavior of a single molecule of C60 in a periodic box of water, and compare this to methane. A C60 molecule does not induce drying at the surface; however, unlike a hard sphere methane, a hard sphere C60 solute does. This is due to a larger number of attractive Lennard-Jones interactions between the carbon atom centers in C60 and the surrounding waters. In these simulations, water is not uniformly arranged but rather adopts a range of orientations in the first hydration shell despite the spherical symmetry of both solutes. There is a clear effect of solute size on the orientation of the first hydration shell waters. There is a large increase in hydrogen-bonding contacts between waters in the C60 first hydration shell. There is also a disruption of hydrogen bonds between waters in the first and second hydration shells. Water molecules in the first hydration shell preferentially create triangular structures that minimize the net water dipole near the surface near both the methane and C60 surface, reducing the total energy of the system. Additionally, in the first and second hydration shells, the water dipoles are ordered to a distance of 8 A from the solute surface. We conclude that, with a diameter of approximately 1 nm, C60 behaves as a large hydrophobic solute.
- Published
- 2008
- Full Text
- View/download PDF
23. Five-year predictors of physical activity decline among adults in low-income communities: a prospective study.
- Author
-
Weiss DR, O'Loughlin JL, Platt RW, and Paradis G
- Abstract
Background: Obesity in North America is now endemic, and increased understanding of the determinants of physical inactivity is critical. This analysis identified predictors of declines in physical activity over 5 years among adults in low-income, inner-city neighbourhoods., Methods: Data on leisure time physical activity were collected in telephone interviews in 1992 and 1997 from 765 adults (47% of baseline respondents), as part of the evaluation of a community-based cardiovascular disease risk reduction program., Results: One-third of 527 participants who were physically active at baseline, were inactive in 1997. Predictors of becoming inactive included female sex (OR = 1.63 95% CI (1.09, 2.43)), older age (1.02 (1.01, 1.04)), higher BMI (1.57 (1.03, 2.40)), poor self-rated health (1.39 (1.05, 1.84)), lower self-efficacy for physical activity (1.46 (1.00, 2.14)), and not using a neighborhood facility for physical activity (1.61 (1.02, 2.14))., Conclusion: These results highlight the fact that a variety of variables play a role in determining activity level, from demographic variables such as age and sex, to psychosocial and environmental variables. In addition, these results highlight the important role that other health-related variables may play in predicting physical activity level, in particular the observed association between baseline BMI and the increased risk of becoming inactive over time. Lastly, these results demonstrate the need for multi-component interventions in low-income communities, which target a range of issues, from psychosocial factors, to features of the physical environment.
- Published
- 2007
- Full Text
- View/download PDF
24. Diabetic thoracic polyradiculopathy presenting as abdominal swelling.
- Author
-
Boulton AJ, Angus E, Ayyar DR, and Weiss DR
- Subjects
- Aged, Humans, Male, Thoracic Nerves, Abdomen, Diabetic Neuropathies diagnosis
- Published
- 1984
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.