190 results on '"Baker RW"'
Search Results
2. Evaluation of Therapeutics for Advanced-Stage Heart Failure and Other Severely-Debilitating or Life-Threatening Diseases
- Author
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Prescott, JS, primary, Andrews, PA, additional, Baker, RW, additional, Bogdanffy, MS, additional, Fields, FO, additional, Keller, DA, additional, Lapadula, DM, additional, Mahoney, NM, additional, Paul, DE, additional, Platz, SJ, additional, Reese, DM, additional, Stoch, SA, additional, and DeGeorge, JJ, additional
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- 2017
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3. PHP30 2006 DRUG PAYMENTS IN THE HOSPITAL OUTPATIENT PROSPECTIVE PAYMENT SYSTEM: REIMBURSEMENT IMPLICATIONS
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Baker, JJ, primary and Baker, RW, additional
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- 2004
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4. PMH16 OLANZAPINE VERSUS RISPERIDONE IN THE TREATMENT OF BIPOLAR I DISORDER: DETERMINANTS OF CHANGE IN SEVERITY OF BIPOLAR ILLNESS RATINGS
- Author
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Brown, E, primary, Ahmed, S, additional, Schuh, L, additional, and Baker, RW, additional
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- 2004
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5. PMH14 INCIDENCE OF HYPERLIPIDEMIA DURING TREATMENT OF SCHIZOPHRENIA: FINDINGS IN A CLAIMS DATABASE
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Zhao, Z, primary, Ascher-Svanum, H, additional, Baker, RW, additional, and Cavazzoni, P, additional
- Published
- 2002
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6. Seizures during clozapine therapy
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Baker Rw and Conley Rr
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Psychiatry and Mental health ,business.industry ,Anesthesia ,Medicine ,Clozapine therapy ,business - Published
- 1991
7. Efficacy versus effectiveness
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Hogarty Ge, Baker Rw, and Nina R. Schooler
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Psychiatry and Mental health ,medicine.medical_specialty ,Treatment Outcome ,business.industry ,Mental Disorders ,Internal medicine ,Managed Care Programs ,Treatment outcome ,medicine ,Humans ,business ,Randomized Controlled Trials as Topic - Published
- 1997
8. Further study of neuroleptic malignant syndrome
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Chengappa Kn and Baker Rw
- Subjects
Neuroleptic malignant syndrome ,Psychiatry and Mental health ,medicine.medical_specialty ,business.industry ,medicine ,medicine.disease ,business ,Psychiatry - Published
- 1995
9. Explaining chronic obstructive pulmonary disease (COPD): perceptions of the role played by smoking.
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Hansen EC, Walters J, and Baker RW
- Subjects
OBSTRUCTIVE lung diseases ,HEALTH of cigarette smokers ,SMOKING ,QUALITATIVE research ,SMOKING cessation ,SMOKING in the workplace ,CHRONIC diseases -- Social aspects - Published
- 2007
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10. Use of tamoxifen in the control of canine mammary neoplasia
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Baker Rw
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Text mining ,General Veterinary ,business.industry ,Cancer research ,Medicine ,General Medicine ,business ,Tamoxifen ,medicine.drug - Published
- 1994
11. Coupling between a glacier and a soft bed: I. A relation between effective pressure and local sheer stress determined from till elasticity
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Iverson, Nr, Baker, Rw, Hooke, Rl, Hanson, B., and Peter Jansson
- Subjects
010506 paleontology ,010504 meteorology & atmospheric sciences ,01 natural sciences ,0105 earth and related environmental sciences ,Earth-Surface Processes - Abstract
To predict the distribution of motion beneath glaciers on soft beds, the strength of the coupling between the ice and the bed and its variation with effective pressure must be known. A record of shear strain, acquired with a tiltmeter emplaced in till beneath Storglaciären, Sweden, indicates that fluctuations in water pressure cause variations in the local shear stress on the bed and that the bed deforms elastically in response to these variations. To estimate the shear stress from the elastic component of the total shear strain, the shear modulus of the till was measured in relaxation tests conducted in the laboratory with a ring-shear device. After accounting for the elastic compliance of the device, these tests yielded shear moduli of about 1000 and 1800 kPa at confining pressures of 85 and 280 kPa, respectively. These values are comparable to those of other granular materials undergoing recoverable shear strains of the same magnitude. The local shear stress on the till, calculated by applying the measured shear moduli to the tilt record, scales with Pe1.7, where Pe is the effective pressure. This relation implies that as Pe decreases at the ice/till interface, shear stresses on the till are reduced and concentrated elsewhere on the bed, perhaps where the till is absent or the glacier is frozen to the bed. When compared with the strength of the till determined from ring-shear tests, this relation also accounts for the lack of permanent deformation at depth in the bed during periods of low Pe and indicates that most basal motion was by sliding or ploughing.
12. Effects of olanzapine alone and olanzapine/fluoxetine combination on health-related quality in patients with bipolar depression: secondary analyses of a double-blind, placebo-controlled, randomized clinical trial.
- Author
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Shi L, Namjoshi MA, Swindle R, Yu X, Risser R, Baker RW, and Tohen M
- Abstract
BACKGROUND: Improving patients' health-related quality of life (HRQOL) could be a treatment goal for bipolar depression. OBJECTIVES: The objectives of these secondary analyses of a previous report were to determine the benefits of olanzapine alone and olanzapine-fluoxetine combination (OFC) for improving HRQOL in patients with bipolar depression using both a generic and a depression-specific HRQOL instrument, and to examine the association between the 2 HRQOL instruments and the construct validity of the depression-specific HRQOL instrument. METHODS: This was a double-blind, placebo-controlled, 83-site, international, randomized trial. Adults with bipolar I disorder, most recent episode depressed (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), were randomly assigned to receive olanzapine (6-20 mg/d), OFC (6/25, 12/25, or 12/50 mg/d), or placebo for 8 weeks. HRQOL improvement was calculated as last-observation-carried-forward changes in dimension and component summary scores on Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and total score on the Quality of Life in Depression Scale (QLDS). Results: Patients were assigned to receive olanzapine (n = 377), OFC (n = 86), or placebo (n = 370) for 8 weeks. Of 833 enrolled patients, 454 discontinued (olanzapine, 232/377 [61.5%]; OFC, 31/86 [36.0%]; and placebo, 191/370 [51.6%]). Compared with placebo, olanzapine-treated patients exhibited greater improvements on SF-36 mental component summary (MCS) score ( P=0.002) and 3 of 8 SF-36 dimension scores (mental health [P=0.015], role-emotional [P=0.046], and social functioning [P=0.006). OFC-treated patients exhibited greater improvements on MCS score ( P<0.001) vs both placebo and olanzapine), 5 SF-36 dimension scores (general health perception (P<0.001) vs placebo; (P<0.001) vs olanzapinel, mental health [ P=0.001] vs both placebo and olanzapine], role-emotional [ P<0.001] vs placebo; [P=0.007] vs olanzapine], social functioning [ P=0.001] vs placebo; [P=0.032] vs olanzapine], and vitality [P=0.002] vs placebo; [P=0.011] vs olanzapine]), and QLDS total score ( P<0.001] vs both placebo and olanzapine). Changes in SF-36 scores of mental health, social functioning, role-emotional, and vitality were highly correlated to changes in the QLDS total score (all p < -0.5). CONCLUSIONS: Based on these analyses, patients with bipolar depression receiving olanzapine or OFC for 8 weeks had greater improvement in HRQOL than those receiving placebo. OFC treatment was associated with greater improvement in HRQOL than olanzapine alone. The correlation results support the construct validity of the QLDS. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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13. A structure-based mechanism for initiation of AP-3 coated vesicle formation.
- Author
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Begley M, Aragon M, and Baker RW
- Abstract
Adaptor protein complex 3 (AP-3) mediates cargo sorting from endosomes to lysosomes and lysosome-related organelles. Recently, it was shown that AP-3 is in a constitutively open, active conformation compared to the related AP-1 and AP-2 coat complexes, which are inactive until undergoing large conformational changes upon membrane recruitment. How AP-3 is regulated is therefore an open question. To understand the mechanism of AP-3 membrane recruitment and activation, we reconstituted the core of human AP-3 and determined multiple structures in the soluble and membrane-bound states using electron cryo-microscopy (cryo-EM). Similar to yeast AP-3, human AP-3 is in a constitutively open conformation, with the cargo-binding domain of the μ3 subunit conformationally free. To reconstitute AP-3 activation by the small GTPase Arf1, we used lipid nanodiscs to build Arf1-AP-3 complexes on membranes and determined three structures that show the stepwise conformational changes required for formation of AP-3 coated vesicles. First, membrane-recruitment is driven by one of two predicted Arf1 binding sites on AP-3. In this conformation, AP-3 is flexibly tethered to the membrane and its cargo binding domain remains conformationally dynamic. Second, cargo binding causes AP-3 to adopt a fixed position and rigidifies the complex, which stabilizes binding for a second Arf1 molecule. Finally, binding of the second Arf1 molecule provides the template for AP-3 dimerization, providing a glimpse into the first step of coat polymerization. We propose coat polymerization only occurs after cargo engagement, thereby linking cargo sorting with assembly of higher order coat structures. Additionally, we provide evidence for two amphipathic helices in AP-3, suggesting that AP-3 contributes to membrane deformation during coat assembly. In total, these data provide evidence for the first stages of AP-3 mediated vesicle coat assembly., Competing Interests: Competing interests: Authors declare that they have no competing interests
- Published
- 2024
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14. FacZ is a GpsB-interacting protein that prevents aberrant division-site placement in Staphylococcus aureus.
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Bartlett TM, Sisley TA, Mychack A, Walker S, Baker RW, Rudner DZ, and Bernhardt TG
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- Humans, Cell Division, Cell Membrane, Cell Movement, Staphylococcus aureus genetics, Staphylococcal Infections prevention & control
- Abstract
Staphylococcus aureus is a Gram-positive pathogen responsible for antibiotic-resistant infections. To identify vulnerabilities in cell envelope biogenesis that may overcome resistance, we enriched for S. aureus transposon mutants with defects in cell surface integrity or cell division by sorting for cells that stain with propidium iodide or have increased light-scattering properties, respectively. Transposon sequencing of the sorted populations identified more than 20 previously uncharacterized factors impacting these processes. Cells inactivated for one of these proteins, factor preventing extra Z-rings (FacZ, SAOUHSC_01855), showed aberrant membrane invaginations and multiple FtsZ cytokinetic rings. These phenotypes were suppressed in mutants lacking the conserved cell-division protein GpsB, which forms an interaction hub bridging envelope biogenesis factors with the cytokinetic ring in S. aureus. FacZ was found to interact directly with GpsB in vitro and in vivo. We therefore propose that FacZ is an envelope biogenesis factor that antagonizes GpsB function to prevent aberrant division events in S. aureus., (© 2024. The Author(s).)
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- 2024
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15. Author Correction: Structure and dynamics of the ASB9 CUL-RING E3 Ligase.
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Lumpkin RJ, Baker RW, Leschziner AE, and Komives EA
- Published
- 2023
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16. Significant cell uptake of Gd(III)-diphenylphosphoryl-diphenylphosphonium complexes: evidence for a new conformationally-dependent tumour cell targeting vector.
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Hall AJ, Robertson AG, Baker RW, Hill LR, and Rendina LM
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- Humans, Gadolinium pharmacology, Gadolinium chemistry, Neoplasms pathology
- Abstract
The synthesis, characterisation, and tumour cell uptake of six novel Gd(III)-diphenylphosphoryl-diphenylphosphonium complexes are reported. The propyl-linked Gd(III) complexes can accumulate inside human glioma cells at prodigious levels, approaching 1200%, over the parent triphenylphosphonium salts. DFT and quantum chemical topology analyses support a new type of conformationally-dependent tumour cell targeting vector.
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- 2023
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17. Lipid nanodiscs as a template for high-resolution cryo-EM structures of peripheral membrane proteins.
- Author
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S Cannon K, Sarsam RD, Tedamrongwanish T, Zhang K, and Baker RW
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- Models, Molecular, Membrane Proteins chemistry, Cryoelectron Microscopy methods, Lipid Bilayers chemistry, Nanostructures chemistry
- Abstract
Peripheral membrane proteins are ubiquitous throughout cell biology and are required for a variety of cellular processes such as signal transduction, membrane trafficking, and autophagy. Transient binding to the membrane has a profound impact on protein function, serving to induce conformational changes and alter biochemical and biophysical parameters by increasing the local concentration of factors and restricting diffusion to two dimensions. Despite the centrality of the membrane in serving as a template for cell biology, there are few reported high-resolution structures of peripheral membrane proteins bound to the membrane. We analyzed the utility of lipid nanodiscs to serve as a template for cryo-EM analysis of peripheral membrane proteins. We tested a variety of nanodiscs and we report a 3.3 Å structure of the AP2 clathrin adaptor complex bound to a 17-nm nanodisc, with sufficient resolution to visualize a bound lipid head group. Our data demonstrate that lipid nanodiscs are amenable to high-resolution structure determination of peripheral membrane proteins and provide a framework for extending this analysis to other systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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18. Identification of FacZ as a division site placement factor in Staphylococcus aureus .
- Author
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Bartlett TM, Sisley TA, Mychack A, Walker S, Baker RW, Rudner DZ, and Bernhardt TG
- Abstract
Staphylococcus aureus is a gram-positive pathogen responsible for life-threatening infections that are difficult to treat due to antibiotic resistance. The identification of new vulnerabilities in essential processes like cell envelope biogenesis represents a promising avenue towards the development of anti-staphylococcal therapies that overcome resistance. To this end, we performed cell sorting-based enrichments for S. aureus mutants with defects in envelope integrity and cell division. We identified many known envelope biogenesis factors as well as a large collection of new factors with roles in this process. Mutants inactivated for one of the hits, the uncharacterized SAOUHSC_01855 protein, displayed aberrant membrane invaginations and multiple FtsZ cytokinetic ring structures. This factor is broadly distributed among Firmicutes, and its inactivation in B. subtilis similarly caused division and membrane defects. We therefore renamed the protein FacZ (Firmicute-associated coordinator of Z-rings). In S. aureus , inactivation of the conserved cell division protein GpsB suppressed the division and morphological defects of facZ mutants. Additionally, FacZ and GpsB were found to interact directly in a purified system. Thus, FacZ is a novel antagonist of GpsB function with a conserved role in controlling division site placement in S. aureus and other Firmicutes.
- Published
- 2023
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19. Allosteric regulation of exocyst: Discrete activation of tethering by two spatial signals.
- Author
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Miller BK, Rossi G, Hudson S, Cully D, Baker RW, and Brennwald P
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- Animals, Allosteric Regulation, Cytoplasm metabolism, Saccharomyces cerevisiae metabolism, Vesicular Transport Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Exocytosis physiology, Saccharomyces cerevisiae Proteins metabolism, rab GTP-Binding Proteins metabolism
- Abstract
The exocyst imparts spatial control during exocytic vesicle tethering through its interactions with proteins and lipids on the vesicle and the plasma membrane. One such interaction is with the vesicle tether Sro7, although the outcome of this interaction is poorly understood. Here, we describe how Sro7 binding to the Exo84 subunit results in activation of the exocyst complex which leads to an increase in avidity for the Rab GTPase Sec4 and an increase in exocyst-mediated vesicle tethering. Gain-of-function (GOF) mutations in Exo84 that mimic Sro7 activation replicate these biochemical changes and result in allosteric changes within the complex. Direct comparison of GOF mutants which mimic Sro7- and Rho/Cdc42-activation of the exocyst reveals distinct mechanisms and outcomes. We propose a model by which these two activation pathways reside within the same tethering complex but remain insulated from one another. Structural modeling suggests a related mechanism for Sro7 activation of the exocyst in yeast and Ral GTPase activation of the exocyst in animal cells., (© 2023 Miller et al.)
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- 2023
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20. Structural basis of an endocytic checkpoint that primes the AP2 clathrin adaptor for cargo internalization.
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Partlow EA, Cannon KS, Hollopeter G, and Baker RW
- Subjects
- Adaptor Protein Complex 2 chemistry, Animals, Cell Membrane metabolism, Endocytosis, Mice, Adaptor Proteins, Vesicular Transport metabolism, Clathrin metabolism
- Abstract
Clathrin-mediated endocytosis (CME) is the main route of internalization from the plasma membrane. It is known that the heterotetrameric AP2 clathrin adaptor must open to simultaneously engage membrane and endocytic cargo, yet it is unclear how transmembrane cargos are captured to catalyze CME. Using cryogenic-electron microscopy, we discover a new way in which mouse AP2 can reorganize to expose membrane- and cargo-binding pockets, which is not observed in clathrin-coated structures. Instead, it is stimulated by endocytic pioneer proteins called muniscins, which do not enter vesicles. Muniscin-engaged AP2 is primed to rearrange into the vesicle-competent conformation on binding the tyrosine cargo internalization motif (YxxΦ). We propose adaptor priming as a checkpoint to ensure cargo internalization., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2022
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21. Functional characterization of NPM1-TYK2 fusion oncogene.
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Kuravi S, Baker RW, Mushtaq MU, Saadi I, Lin TL, Vivian CJ, Valluripalli A, Abhyankar S, Ganguly S, Cui W, Elenitoba-Johnson KSJ, Welch DR, Jensen RA, Saunthararajah Y, McGuirk JP, and Balusu R
- Abstract
Gene fusions are known to drive many human cancers. Therefore, the functional characterization of newly discovered fusions is critical to understanding the oncobiology of these tumors and to enable therapeutic development. NPM1-TYK2 is a novel fusion identified in CD30 + lymphoproliferative disorders, and here we present the functional evaluation of this fusion gene as an oncogene. The chimeric protein consists of the amino-terminus of nucleophosmin 1 (NPM1) and the carboxyl-terminus of tyrosine kinase 2 (TYK2), including the kinase domain. Using in vitro lymphoid cell transformation assays and in vivo tumorigenic xenograft models we present direct evidence that the fusion gene is an oncogene. NPM1 fusion partner provides the critical homodimerization needed for the fusion kinase constitutive activation and downstream signaling that are responsible for cell transformation. As a result, our studies identify NPM1-TYK2 as a novel fusion oncogene and suggest that inhibition of fusion homodimerization could be a precision therapeutic approach in cutaneous T-cell lymphoma patients expressing this chimera., (© 2022. The Author(s).)
- Published
- 2022
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22. Structure Analysis of Proteins and Peptides by Difference Circular Dichroism Spectroscopy.
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Arakawa T, Tokunaga M, Kita Y, Niikura T, Baker RW, Reimer JM, and Leschziner AE
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- Circular Dichroism, Protein Structure, Secondary, Sodium Dodecyl Sulfate, Peptides, Trifluoroethanol
- Abstract
Difference circular dichroism (CD) spectroscopy was used here to characterize changes in structure of flexible peptides upon altering their environments. Environmental changes were introduced by binding to a large target structure, temperature shift (or concentration increase) or so-called membrane-mimicking solvents. The first case involved binding of a largely disordered peptide to its target structure associated with chromatin remodeling, leading to a transition into a highly helical structure. The second example was a short 8HD (His-Asp) repeat peptide that can bind metal ions. Both Zn and Ni at μM concentrations resulted in different type of changes in secondary structure, suggesting that these metal ions provide different environments for the peptide to assume unique secondary structures. The third case is related to a few short neuroprotective peptides that were largely disordered in aqueous solution. Increased temperature resulted in induction of significant, though small, β-sheet structures. Last example was the induction of non-helical structures for short neuroprotective peptides by membrane-mimicking solvents, including trifluoroethanol, dodecylphosphocholine and sodium dodecylsulfate. While these agents are known to induce α-helix, none of the neuropeptides underwent transition to a typical helical structure. However, trifluoroethanol did induce α-helix for the first peptide involved in chromatin remodeling described above in the first example., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2021
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23. Selective delivery of remarkably high levels of gadolinium to tumour cells using an arsonium salt.
- Author
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Windsor MSA, Busse M, Morrison DE, Baker RW, Hill LR, and Rendina LM
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- Antineoplastic Agents metabolism, Arsenicals metabolism, Cell Line, Tumor, Chelating Agents metabolism, Chelating Agents toxicity, Gadolinium metabolism, Humans, Precision Medicine methods, Antineoplastic Agents chemistry, Arsenicals chemistry, Chelating Agents chemistry, Gadolinium chemistry
- Abstract
The use of a triphenylarsonium vector for tumour cell-targeting leads to a dramatic increase in Gd
3+ uptake in human glioblastoma multiforme cells by up to an order of magnitude over the isosteric triarylphosphonium analogue, with significant implications for 'theranostic' applications involving delivery of this important lanthanoid metal ion to tumour cells.- Published
- 2021
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24. Structural insights into assembly and function of the RSC chromatin remodeling complex.
- Author
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Baker RW, Reimer JM, Carman PJ, Turegun B, Arakawa T, Dominguez R, and Leschziner AE
- Subjects
- Amino Acid Sequence, Carrier Proteins metabolism, Cell Cycle Proteins metabolism, Chromosomal Proteins, Non-Histone metabolism, Cryoelectron Microscopy, Nuclear Proteins metabolism, Nucleosomes metabolism, Saccharomyces cerevisiae genetics, Chromatin metabolism, Chromatin Assembly and Disassembly physiology, DNA-Binding Proteins metabolism, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Transcription Factors metabolism
- Abstract
SWI/SNF chromatin remodelers modify the position and spacing of nucleosomes and, in humans, are linked to cancer. To provide insights into the assembly and regulation of this protein family, we focused on a subcomplex of the Saccharomyces cerevisiae RSC comprising its ATPase (Sth1), the essential actin-related proteins (ARPs) Arp7 and Arp9 and the ARP-binding protein Rtt102. Cryo-EM and biochemical analyses of this subcomplex shows that ARP binding induces a helical conformation in the helicase-SANT-associated (HSA) domain of Sth1. Surprisingly, the ARP module is rotated 120° relative to the full RSC about a pivot point previously identified as a regulatory hub in Sth1, suggesting that large conformational changes are part of Sth1 regulation and RSC assembly. We also show that a conserved interaction between Sth1 and the nucleosome acidic patch enhances remodeling. As some cancer-associated mutations dysregulate rather than inactivate SWI/SNF remodelers, our insights into RSC complex regulation advance a mechanistic understanding of chromatin remodeling in disease states.
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- 2021
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25. Structure and dynamics of the ASB9 CUL-RING E3 Ligase.
- Author
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Lumpkin RJ, Baker RW, Leschziner AE, and Komives EA
- Subjects
- Allosteric Regulation, Creatine Kinase ultrastructure, Cullin Proteins chemistry, Cullin Proteins metabolism, Elongin ultrastructure, Humans, Models, Molecular, Protein Binding, Protein Subunits chemistry, Protein Subunits metabolism, Structure-Activity Relationship, Substrate Specificity, Suppressor of Cytokine Signaling Proteins ultrastructure, Ubiquitin-Protein Ligases chemistry, Ubiquitin-Protein Ligases metabolism, Creatine Kinase metabolism, Cryoelectron Microscopy, Elongin metabolism, Suppressor of Cytokine Signaling Proteins chemistry, Suppressor of Cytokine Signaling Proteins metabolism
- Abstract
The Cullin 5 (CUL5) Ring E3 ligase uses adaptors Elongins B and C (ELOB/C) to bind different SOCS-box-containing substrate receptors, determining the substrate specificity of the ligase. The 18-member ankyrin and SOCS box (ASB) family is the largest substrate receptor family. Here we report cryo-EM data for the substrate, creatine kinase (CKB) bound to ASB9-ELOB/C, and for full-length CUL5 bound to the RING protein, RBX2, which binds various E2s. To date, no full structures are available either for a substrate-bound ASB nor for CUL5. Hydrogen-deuterium exchange (HDX-MS) mapped onto a full structural model of the ligase revealed long-range allostery extending from the substrate through CUL5. We propose a revised allosteric mechanism for how CUL-E3 ligases function. ASB9 and CUL5 behave as rigid rods, connected through a hinge provided by ELOB/C transmitting long-range allosteric crosstalk from the substrate through CUL5 to the RBX2 flexible linker.
- Published
- 2020
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26. LIS1 promotes the formation of activated cytoplasmic dynein-1 complexes.
- Author
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Htet ZM, Gillies JP, Baker RW, Leschziner AE, DeSantis ME, and Reck-Peterson SL
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- Animals, Carrier Proteins metabolism, HEK293 Cells, Humans, Mice, Microtubules metabolism, Protein Binding physiology, Recombinant Proteins metabolism, 1-Alkyl-2-acetylglycerophosphocholine Esterase metabolism, Cytoplasmic Dyneins metabolism, Dynactin Complex metabolism, Microtubule-Associated Proteins metabolism
- Abstract
Cytoplasmic dynein-1 is a molecular motor that drives nearly all minus-end-directed microtubule-based transport in human cells, performing functions that range from retrograde axonal transport to mitotic spindle assembly
1,2 . Activated dynein complexes consist of one or two dynein dimers, the dynactin complex and an 'activating adaptor', and they show faster velocity when two dynein dimers are present3-6 . Little is known about the assembly process of this massive ~4 MDa complex. Here, using purified recombinant human proteins, we uncover a role for the dynein-binding protein LIS1 in promoting the formation of activated dynein-dynactin complexes that contain two dynein dimers. Complexes activated by proteins representing three families of activating adaptors-BicD2, Hook3 and Ninl-all show enhanced motile properties in the presence of LIS1. Activated dynein complexes do not require sustained LIS1 binding for fast velocity. Using cryo-electron microscopy, we show that human LIS1 binds to dynein at two sites on the motor domain of dynein. Our research suggests that LIS1 binding at these sites functions in multiple stages of assembling the motile dynein-dynactin-activating adaptor complex.- Published
- 2020
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27. A structural mechanism for phosphorylation-dependent inactivation of the AP2 complex.
- Author
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Partlow EA, Baker RW, Beacham GM, Chappie JS, Leschziner AE, and Hollopeter G
- Subjects
- Cryoelectron Microscopy, Phosphorylation, Protein Binding, Adaptor Protein Complex 2 chemistry, Adaptor Protein Complex 2 metabolism, Adaptor Proteins, Vesicular Transport chemistry, Adaptor Proteins, Vesicular Transport metabolism, Caenorhabditis elegans Proteins chemistry, Caenorhabditis elegans Proteins metabolism, Protein Processing, Post-Translational
- Abstract
Endocytosis of transmembrane proteins is orchestrated by the AP2 clathrin adaptor complex. AP2 dwells in a closed, inactive state in the cytosol, but adopts an open, active conformation on the plasma membrane. Membrane-activated complexes are also phosphorylated, but the significance of this mark is debated. We recently proposed that NECAP negatively regulates AP2 by binding open and phosphorylated complexes (Beacham et al., 2018). Here, we report high-resolution cryo-EM structures of NECAP bound to phosphorylated AP2. The site of AP2 phosphorylation is directly coordinated by residues of the NECAP PHear domain that are predicted from genetic screens in C. elegans . Using membrane mimetics to generate conformationally open AP2, we find that a second domain of NECAP binds these complexes and cryo-EM reveals both domains of NECAP engaging closed, inactive AP2. Assays in vitro and in vivo confirm these domains cooperate to inactivate AP2. We propose that phosphorylation marks adaptors for inactivation., Competing Interests: EP, RB, GB, JC, AL, GH No competing interests declared, (© 2019, Partlow et al.)
- Published
- 2019
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28. Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association.
- Author
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Jiao J, He M, Port SA, Baker RW, Xu Y, Qu H, Xiong Y, Wang Y, Jin H, Eisemann TJ, Hughson FM, and Zhang Y
- Subjects
- Amino Acid Sequence, Animals, Exocytosis, Humans, Membrane Fusion, Munc18 Proteins genetics, Munc18 Proteins metabolism, Mutation, Protein Binding, Rats, SNARE Proteins genetics, Sequence Homology, Amino Acid, Synaptosomal-Associated Protein 25 genetics, Synaptosomal-Associated Protein 25 metabolism, Syntaxin 1 genetics, Syntaxin 1 metabolism, Vesicle-Associated Membrane Protein 2 genetics, Vesicle-Associated Membrane Protein 2 metabolism, Neurons metabolism, SNARE Proteins metabolism
- Abstract
Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved., Competing Interests: JJ, MH, SP, RB, YX, HQ, YX, YW, HJ, TE, FH, YZ No competing interests declared, (© 2018, Jiao et al.)
- Published
- 2018
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29. Salivary levels of total huntingtin are elevated in Huntington's disease patients.
- Author
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Corey-Bloom J, Haque AS, Park S, Nathan AS, Baker RW, and Thomas EA
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Huntingtin Protein metabolism, Huntington Disease metabolism, Saliva metabolism
- Abstract
Patients with Huntington's disease (HD), an autosomal-dominant neurodegenerative disease, show substantial variability in age-of-onset, symptom severity and course of illness, warranting the need for biomarkers to anticipate and monitor these features. The HD gene encodes the disease protein huntingtin (Htt), a potentially useful biomarker for this disease. In the current study, we determined whether total Htt protein (normal plus mutant; "tHtt") could be reliably measured in human saliva, a body fluid that is much more accessible compared to cerebral spinal fluid or even blood, and whether salivary levels of tHtt were clinically meaningful. We collected 146 saliva samples from manifest HD patients, early-premanifest individuals, late-premanifest patients, gene-negative family members and normal controls. We found that tHtt protein could be reliably and stably detected in human saliva and that tHtt levels were significantly increased in saliva from HD individuals compared to normal controls. Salivary tHtt showed no gender effects, nor were levels correlated with total protein levels in saliva. Salivary tHtt was significantly positively correlated with age, but not age-of-onset or CAG-repeat length. Importantly, salivary tHtt was significantly correlated with several clinical measures, indicating relevance to disease symptom onset and/or severity. Measurements of salivary tHtt offer significant promise as a relevant, non-invasive disease biomarker for HD, and its use could be implemented into clinical applications.
- Published
- 2018
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30. Repeat-Specific Functions for the C-Terminal Domain of RNA Polymerase II in Budding Yeast.
- Author
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Babokhov M, Mosaheb MM, Baker RW, and Fuchs SM
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Genes, Suppressor, Inositol metabolism, Mutation genetics, Phenotype, Protein Domains, Repetitive Sequences, Amino Acid, Saccharomyces cerevisiae Proteins metabolism, Serine metabolism, RNA Polymerase II chemistry, RNA Polymerase II metabolism, Saccharomycetales enzymology
- Abstract
The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae , the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD., (Copyright © 2018 Babokhov et al.)
- Published
- 2018
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31. Actin-related proteins regulate the RSC chromatin remodeler by weakening intramolecular interactions of the Sth1 ATPase.
- Author
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Turegun B, Baker RW, Leschziner AE, and Dominguez R
- Abstract
The catalytic subunits of SWI/SNF-family and INO80-family chromatin remodelers bind actin and actin-related proteins (Arps) through an N-terminal helicase/SANT-associated (HSA) domain. Between the HSA and ATPase domains lies a conserved post-HSA (pHSA) domain. The HSA domain of Sth1, the catalytic subunit of the yeast SWI/SNF-family remodeler RSC, recruits the Rtt102-Arp7/9 heterotrimer. Rtt102-Arp7/9 regulates RSC function, but the mechanism is unclear. We show that the pHSA domain interacts directly with another conserved region of the catalytic subunit, protrusion-1. Rtt102-Arp7/9 binding to the HSA domain weakens this interaction and promotes the formation of stable, monodisperse complexes with DNA and nucleosomes. A crystal structure of Rtt102-Arp7/9 shows that ATP binds to Arp7 but not Arp9. However, Arp7 does not hydrolyze ATP. Together, the results suggest that Rtt102 and ATP stabilize a conformation of Arp7/9 that potentiates binding to the HSA domain, which releases intramolecular interactions within Sth1 and controls DNA and nucleosome binding., Competing Interests: Competing interests: The authors declare that they have no competing financial interests.
- Published
- 2018
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32. Chaperoning SNARE assembly and disassembly.
- Author
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Baker RW and Hughson FM
- Subjects
- Animals, Humans, Molecular Chaperones metabolism, SNARE Proteins metabolism
- Abstract
Intracellular membrane fusion is mediated in most cases by membrane-bridging complexes of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). However, the assembly of such complexes in vitro is inefficient, and their uncatalysed disassembly is undetectably slow. Here, we focus on the cellular machinery that orchestrates assembly and disassembly of SNARE complexes, thereby regulating processes ranging from vesicle trafficking to organelle fusion to neurotransmitter release. Rapid progress is being made on many fronts, including the development of more realistic cell-free reconstitutions, the application of single-molecule biophysics, and the elucidation of X-ray and high-resolution electron microscopy structures of the SNARE assembly and disassembly machineries 'in action'.
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- 2016
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33. Clozapine and risperidone in moderately refractory schizophrenia: a 6-month randomized double-blind comparison.
- Author
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Schooler NR, Marder SR, Chengappa KN, Petrides G, Ames D, Wirshing WC, McMeniman M, Baker RW, Parepally H, Umbricht D, and Kane JM
- Subjects
- Brief Psychiatric Rating Scale, Comorbidity, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Drug Resistance, Humans, Psychotic Disorders diagnosis, Psychotic Disorders psychology, Schizophrenia diagnosis, Treatment Outcome, Clozapine adverse effects, Clozapine therapeutic use, Psychotic Disorders drug therapy, Risperidone adverse effects, Risperidone therapeutic use, Schizophrenia drug therapy, Schizophrenic Psychology
- Abstract
Objective: Clozapine remains the only medication indicated for refractory schizophrenia. As new antipsychotic drugs become available, their efficacy compared to clozapine, particularly in moderately ill patients, is of great clinical interest. We compared risperidone, the first of these, to clozapine in partially responsive patients. Further, since participation of patients usually excluded from clinical trials is increasingly important, we broadened inclusion to a wider patient population., Methods: We compared clozapine (n = 53) to risperidone (n = 54) in a randomized, double-blind, 29-week trial in schizophrenia patients (diagnosed using DSM-IV) at 3 research outpatient clinics. Randomization was stratified by "narrow" or "broad" inclusion criteria. The study was conducted between December 1995 and October 1999. Time to treatment discontinuation for lack of efficacy and time to 20% improvement in the Brief Psychiatric Rating Scale psychotic symptom cluster were the primary outcome measures., Results: There were no differences in all-cause discontinuation; clozapine-treated participants were significantly less likely to discontinue for lack of efficacy (15%) than risperidone-treated participants (38%) (Wilcoxon χ(2)1 = 6.10, P = .01). Clozapine resulted in significantly more global improvement (F2,839 = 6.07, P < .01) and asociality improvement (F2,315 = 6.64, P < .01) than risperidone. There was no difference in proportions meeting an a priori criterion of psychosis improvement (risperidone: 57%; clozapine: 71%). Significant adverse effect differences in salivation (F1 = 4.05, P < .05) (F1 = 12.13, P < .001), sweating (F1 = 5.07, P < .05), and tachycardia (F1 = 6.51, P < .05) favored risperidone., Conclusions: Clozapine-treated partially responsive patients were less likely to discontinue treatment for lack of efficacy and improved more globally than those treated with risperidone, although psychotic symptoms did not differ. These findings suggest that clozapine should not be restricted to the most severely ill, treatment-refractory patients; it should be considered as an alternative for patients who have some response to other antipsychotics, but still experience troubling symptoms., (© Copyright 2016 Physicians Postgraduate Press, Inc.)
- Published
- 2016
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34. A direct role for the Sec1/Munc18-family protein Vps33 as a template for SNARE assembly.
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Baker RW, Jeffrey PD, Zick M, Phillips BP, Wickner WT, and Hughson FM
- Subjects
- Crystallography, X-Ray, Membrane Proteins chemistry, Membrane Proteins metabolism, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins chemistry, Saccharomyces cerevisiae Proteins ultrastructure, Synaptosomal-Associated Protein 25 chemistry, Synaptosomal-Associated Protein 25 metabolism, Vesicular Transport Proteins chemistry, Vesicular Transport Proteins ultrastructure, Munc18 Proteins metabolism, Qa-SNARE Proteins metabolism, R-SNARE Proteins metabolism, Saccharomyces cerevisiae Proteins metabolism, Vesicular Transport Proteins metabolism
- Abstract
Fusion of intracellular transport vesicles requires soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and Sec1/Munc18-family (SM) proteins. Membrane-bridging SNARE complexes are critical for fusion, but their spontaneous assembly is inefficient and may require SM proteins in vivo. We report x-ray structures of Vps33, the SM subunit of the yeast homotypic fusion and vacuole protein-sorting (HOPS) complex, bound to two individual SNAREs. The two SNAREs, one from each membrane, are held in the correct orientation and register for subsequent complex assembly. Vps33 and potentially other SM proteins could thus act as templates for generating partially zipped SNARE assembly intermediates. HOPS was essential to mediate SNARE complex assembly at physiological SNARE concentrations. Thus, Vps33 appears to catalyze SNARE complex assembly through specific SNARE motif recognition., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
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35. Crystal Structures of the Sec1/Munc18 (SM) Protein Vps33, Alone and Bound to the Homotypic Fusion and Vacuolar Protein Sorting (HOPS) Subunit Vps16*.
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Baker RW, Jeffrey PD, and Hughson FM
- Subjects
- Amino Acid Sequence, Chaetomium, Conserved Sequence, Crystallography, X-Ray, Models, Molecular, Protein Binding, Protein Domains, SNARE Proteins metabolism, Fungal Proteins chemistry, Fungal Proteins metabolism, Protein Subunits metabolism
- Abstract
Intracellular membrane fusion requires the regulated assembly of SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) proteins anchored in the apposed membranes. To exert the force required to drive fusion between lipid bilayers, juxtamembrane SNARE motifs zipper into four-helix bundles. Importantly, SNARE function is regulated by additional factors, none more extensively studied than the SM (Sec1/Munc18-like) proteins. SM proteins interact with both individual SNAREs and SNARE complexes, likely chaperoning SNARE complex formation and protecting assembly intermediates from premature disassembly by NSF. Four families of SM proteins have been identified, and representative members of two of these families (Sec1/Munc18 and Sly1) have been structurally characterized. We report here the 2.6 Å resolution crystal structure of an SM protein from the third family, Vps33. Although Vps33 shares with the first two families the same basic three-domain architecture, domain 1 is displaced by 15 Å, accompanied by a 40° rotation. A unique feature of the Vps33 family of SM proteins is that its members function as stable subunits within a multi-subunit tethering complex called HOPS (homotypic fusion and vacuolar protein sorting). Integration into the HOPS complex depends on the interaction between Vps33 and a second HOPS subunit, Vps16. The crystal structure of Vps33 bound to a C-terminal portion of Vps16, also at 2.6 Å resolution, reveals the structural basis for this interaction. Despite the extensive interface between the two HOPS subunits, the conformation of Vps33 is only subtly affected by binding to Vps16.
- Published
- 2013
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36. Influence of combinatorial histone modifications on antibody and effector protein recognition.
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Fuchs SM, Krajewski K, Baker RW, Miller VL, and Strahl BD
- Subjects
- Amino Acid Sequence, Antibody Affinity, Methylation, Models, Molecular, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Antibodies metabolism, Histones immunology, Histones metabolism, Protein Processing, Post-Translational physiology
- Abstract
Increasing evidence suggests that histone posttranslational modifications (PTMs) function in a combinatorial fashion to regulate the diverse activities associated with chromatin. Yet how these patterns of histone PTMs influence the adapter proteins known to bind them is poorly understood. In addition, how histone-specific antibodies are influenced by these same patterns of PTMs is largely unknown. Here we examine the binding properties of histone-specific antibodies and histone-interacting proteins using peptide arrays containing a library of combinatorially modified histone peptides. We find that modification-specific antibodies are more promiscuous in their PTM recognition than expected and are highly influenced by neighboring PTMs. Furthermore, we find that the binding of histone-interaction domains from BPTF, CHD1, and RAG2 to H3 lysine 4 trimethylation is also influenced by combinatorial PTMs. These results provide further support for the histone code hypothesis and raise specific concerns with the quality of the currently available modification-specific histone antibodies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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37. Polymerizable cationic micelles form cylinders at intermediate conversions.
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Chatjaroenporn K, Baker RW, FitzGerald PA, and Warr GG
- Abstract
The structural evolution of micelles of the polymerizable surfactant omega-methacryloyloxyundecyltrimethylammonium bromide (MUTAB) during UV-initiated polymerization in aqueous micellar solution has been followed by small-angle neutron scattering. Although the micelles are short spheroids both before and after polymerization, a significant, distinct population of rodlike micelles develops during the reaction, which accounts for as much as 40 vol % of the micellized surfactant and coexists with the spheroids and dissolved monomer. These coexisting micelle populations are shown to remain in dynamic equilibrium throughout the reaction and can be understood by treating it as a ternary mixture of surfactant, amphiphilic polyelectrolyte, and water.
- Published
- 2010
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38. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.
- Author
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Marder SR, Sorsaburu S, Dunayevich E, Karagianis JL, Dawe IC, Falk DM, Dellva MA, Carlson JL, Cavazzoni PA, and Baker RW
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antipsychotic Agents administration & dosage, Antipsychotic Agents therapeutic use, Benzodiazepines administration & dosage, Benzodiazepines therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder mortality, Bipolar Disorder psychology, Child, Databases as Topic statistics & numerical data, Fatal Outcome, Female, Humans, Injections, Intramuscular, Male, Middle Aged, Olanzapine, Risk Factors, Schizophrenia drug therapy, Schizophrenia mortality, Schizophrenic Psychology, Treatment Outcome, Adverse Drug Reaction Reporting Systems statistics & numerical data, Antipsychotic Agents adverse effects, Benzodiazepines adverse effects, Psychomotor Agitation drug therapy
- Abstract
Objective: Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented., Method: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment., Results: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs., Conclusions: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously., (Copyright 2010 Physicians Postgraduate Press, Inc.)
- Published
- 2010
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39. Structure changes in micelles and adsorbed layers during surfactant polymerization.
- Author
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Chatjaroenporn K, Baker RW, FitzGerald PA, and Warr GG
- Abstract
We have studied the self-assembled structures formed by the cationic surfactant 11-(methacryloyloxy)undecyltrimethylammonium bromide (MUTAB) using small angle neutron scattering as it undergoes UV-initiated polymerization in bulk solution, and the subsequent adsorbed structures at the mica/solution interface using atomic force microscopy. MUTAB forms spheroidal aggregates in aqueous solution with an axial ratio of 2-3 both before and after polymerization, as previously reported in numerous studies. However, at intermediate conversions the micelles surprisingly form elongated structures up to 200 A long. Except for the unpolymerized MUTAB, which forms a featureless adsorbed layer, the micelle structures are largely retained after adsorption: structures are elongated at 50% conversion and globular at 100% conversion. These results demonstrate that the structure of the unpolymerized micelle is not simply kinetically-trapped during polymerization, but undergoes extensive reorganization as the reaction proceeds. This has implications for attempts to capture micellar structure by polymerization and use it to template nanostructured materials or for encapsulation.
- Published
- 2009
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40. ATRMec1 phosphorylation-independent activation of Chk1 in vivo.
- Author
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Chen Y, Caldwell JM, Pereira E, Baker RW, and Sanchez Y
- Subjects
- Amino Acid Substitution, Checkpoint Kinase 1, DNA Damage drug effects, DNA Replication drug effects, Enzyme Activation physiology, Hydroxyurea pharmacology, MAP Kinase Kinase 1 genetics, Nucleic Acid Synthesis Inhibitors pharmacology, Phosphorylation drug effects, Phosphorylation physiology, Point Mutation, Protein Kinases genetics, Protein Structure, Tertiary physiology, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins genetics, DNA Damage physiology, DNA Replication physiology, MAP Kinase Kinase 1 metabolism, Protein Kinases metabolism, Saccharomyces cerevisiae enzymology, Saccharomyces cerevisiae Proteins metabolism
- Abstract
The conserved protein kinase Chk1 is a player in the defense against DNA damage and replication blocks. The current model is that after DNA damage or replication blocks, ATR(Mec1) phosphorylates Chk1 on the non-catalytic C-terminal domain. However, the mechanism of activation of Chk1 and the function of the Chk1 C terminus in vivo remains largely unknown. In this study we used an in vivo assay to examine the role of the C terminus of Chk1 in the response to DNA damage and replication blocks. The conserved ATR(Mec1) phosphorylation sites were essential for the checkpoint response to DNA damage and replication blocks in vivo; that is, that mutation of the sites caused lethality when DNA replication was stalled by hydroxyurea. Despite this, loss of the ATR(Mec1) phosphorylation sites did not change the kinase activity of Chk1 in vitro. Furthermore, a single amino acid substitution at an invariant leucine in a conserved domain of the non-catalytic C terminus restored viability to cells expressing the ATR(Mec1) phosphorylation site-mutated protein and relieved the requirement of an upstream mediator for Chk1 activation. Our findings show that a single amino acid substitution in the C terminus, which could lead to an allosteric change in Chk1, allows it to bypass the requirement of the conserved ATR(Mec1) phosphorylation sites for checkpoint function.
- Published
- 2009
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41. Clinical, functional, and economic ramifications of early nonresponse to antipsychotics in the naturalistic treatment of schizophrenia.
- Author
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Ascher-Svanum H, Nyhuis AW, Faries DE, Kinon BJ, Baker RW, and Shekhar A
- Subjects
- Adult, Ambulatory Care economics, Cost-Benefit Analysis, Double-Blind Method, Female, Follow-Up Studies, Hospitalization economics, Humans, Male, Middle Aged, Olanzapine, Psychiatric Status Rating Scales, Schizophrenia diagnosis, Treatment Failure, United States, Activities of Daily Living psychology, Antipsychotic Agents economics, Antipsychotic Agents therapeutic use, Benzodiazepines economics, Benzodiazepines therapeutic use, Drug Costs statistics & numerical data, Risperidone economics, Risperidone therapeutic use, Schizophrenia drug therapy, Schizophrenia economics, Schizophrenic Psychology, Social Adjustment
- Abstract
Objective: Early nonresponse to antipsychotics appears to predict subsequent nonresponse to treatment when assessed in randomized controlled trials of predominately acute inpatients treated for schizophrenia. This study assessed the predictive accuracy of early nonresponse to treatment and its clinical, functional, and economic ramifications in the naturalistic treatment of predominately chronic outpatients treated for schizophrenia., Methods: This post hoc analysis used data from a 1-year, randomized, open-label study of olanzapine, risperidone, and typical antipsychotics in the treatment of schizophrenia. If clinically warranted, patients could switch antipsychotics following 8 weeks of treatment. Patients completing 8 weeks of treatment (n = 443 of 664 enrollees) were included. Patients with early response (> or = 20% improvement from baseline on the Positive and Negative Syndrome Scale at 2 weeks) were compared with early nonresponders on symptom remission, functionality, perceptions of medication influence, and total health care costs at 8 weeks., Results: Early response/nonresponse at 2 weeks predicted subsequent response/nonresponse at 8 weeks with a high level of accuracy (72%) and specificity (89%). After 8 weeks, early nonresponders were less likely to achieve symptom remission (P < .001), improved less on functional domains (P < .05), perceived medication as less beneficial (P = .004), and incurred total heath care costs over twice that of early responders ($4349 vs $2102, P = .010)., Conclusions: In the usual care of schizophrenia patients, early nonresponse appears to reliably predict subsequent nonresponse to continued treatment with the same medication to be associated with poorer outcomes and higher health care costs. Identifying early nonresponders may minimize prolonging exposure to suboptimal or ineffective treatment strategies.
- Published
- 2008
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42. Initial symptoms of manic relapse in manic or mixed-manic bipolar disorder: post hoc analysis of patients treated with olanzapine or lithium.
- Author
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Houston JP, Lipkovich IA, Ahl J, Rotelli MD, Baker RW, and Bowden CL
- Subjects
- Acute Disease, Adult, Benzodiazepines therapeutic use, Bipolar Disorder psychology, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Olanzapine, Prognosis, Prospective Studies, Psychiatric Status Rating Scales, Secondary Prevention, Antimanic Agents therapeutic use, Antipsychotic Agents therapeutic use, Bipolar Disorder diagnosis, Bipolar Disorder drug therapy, Lithium Carbonate therapeutic use
- Abstract
Unlabelled: A post hoc analysis of Young Mania Rating Scale (YMRS) item scores was conducted to identify symptoms that may predict impending relapse using prospectively collected data from a double-blind, randomized relapse prevention study of patients treated with olanzapine (N=200, 5-20 mg/d) versus lithium (N=201, 300-1800 mg/d)., Methods: Relapses (YMRS > or = 15, or hospitalization) included in this analysis occurred 3-52 weeks after randomization. Repeated measures logistic regression of increases (> or = 1) in YMRS item scores prior to the visit that preceded relapse was used to estimate the odds of relapse., Results: A total of 31 patients relapsed during the first 3-16 weeks of the study (olanzapine, n=12; lithium, n=19). YMRS items that increased most frequently within a 2-week period preceding relapse were (olanzapine vs. lithium, respectively): increased motor activity/energy (58.3%, 21.1%), irritability (33.3%, 31.6%), decreased need for sleep (25.0%, 10.5%), increased speech (25.0%, 10.5%), and elevated mood (25.0%, 15.8%). YMRS items with significant odds ratios (OR) that predicted relapse in patients treated with olanzapine or lithium, respectively, were: increased motor activity/energy (OR, 35.7; OR, 7.8), irritability (OR, 9.5; OR, 7.8), elevated mood (OR, 8.1; OR, 4.2), and increased sexual interest (OR, 13.7; OR, 7.7)., Conclusions: Early recognition of symptom exacerbation in bipolar mania, particularly increased motor activity-energy may permit clinical interventions to help avert relapse.
- Published
- 2007
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43. Outcomes for Latin American versus White patients suffering from acute mania in a randomized, double-blind trial comparing olanzapine and haloperidol.
- Author
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Tamayo JM, Mazzotti G, Tohen M, Gattaz WF, Zapata R, Castillo JJ, Fahrer RD, González-Pinto AM, Vieta E, Azorin JM, Brown E, Brunner E, Rovner J, Bonett-Perrin E, and Baker RW
- Subjects
- Acute Disease, Aged, Antipsychotic Agents administration & dosage, Antipsychotic Agents adverse effects, Antipsychotic Agents therapeutic use, Benzodiazepines administration & dosage, Benzodiazepines adverse effects, Benzodiazepines therapeutic use, Bipolar Disorder ethnology, Bipolar Disorder psychology, Cholesterol blood, Diagnostic and Statistical Manual of Mental Disorders, Double-Blind Method, Fasting blood, Female, Haloperidol administration & dosage, Haloperidol adverse effects, Haloperidol therapeutic use, Hospitalization statistics & numerical data, Humans, Male, Middle Aged, Olanzapine, Remission Induction, Time Factors, Treatment Outcome, Weight Gain drug effects, Bipolar Disorder drug therapy, Hispanic or Latino psychology, White People psychology
- Abstract
Data from a published double-blind randomized trial comparing olanzapine versus haloperidol in acute mania were used to address the response and tolerability of Latin American patients. Primary efficacy end point was the remission rate (Young Mania Rating Scale score
- Published
- 2007
- Full Text
- View/download PDF
44. Olanzapine versus risperidone in the treatment of manic or mixed States in bipolar I disorder: a randomized, double-blind trial.
- Author
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Perlis RH, Baker RW, Zarate CA Jr, Brown EB, Schuh LM, Jamal HH, and Tohen M
- Subjects
- Adult, Aged, Akathisia, Drug-Induced etiology, Antipsychotic Agents adverse effects, Appetite drug effects, Benzodiazepines adverse effects, Benzodiazepines therapeutic use, Bipolar Disorder classification, Dizziness chemically induced, Double-Blind Method, Female, Headache chemically induced, Humans, Least-Squares Analysis, Male, Middle Aged, Olanzapine, Risperidone adverse effects, Sleep Stages, Treatment Outcome, Antipsychotic Agents therapeutic use, Bipolar Disorder drug therapy, Risperidone therapeutic use
- Abstract
Objective: To compare olanzapine and risperidone in the treatment of nonpsychotic acute manic or mixed episodes., Method: This 3-week, randomized, controlled, double-blind, parallel multicenter study compared olanzapine (5-20 mg/day; N = 165) and risperidone (1-6 mg/day; N = 164) among hospital inpatients who met DSM-IV criteria for bipolar I disorder, manic or mixed episode, without psychotic features. The study was conducted at 30 sites in the United States between July 2001 and June 2002. The primary outcome measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary measures included the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness scale, and the Cognitive Test for Delirium (CTD). Quality of life (Short Form Health Survey [SF-12]), psychological well-being (Psychological General Well-Being [PGWB] inventory), and sexual functioning were also compared., Results: Mean modal doses for olanzapine and risperidone were 14.7 mg/day and 3.9 mg/day, respectively. Between treatments, there was no difference in mean change in the YMRS, MADRS, CTD, PGWB, or SF-12 measures or in remission or response rates. Significantly more olanzapine-treated patients completed the study compared with risperidone patients (78.7% vs. 67.0%; p = .019). Olanzapine-treated patients had greater HAM-D-21 (p = .040) and CGI-BP (p = .026) score improvement across the study. Olanzapine-treated patients experienced greater elevations in liver function enzymes (p < .05) and increase in weight (2.5 kg vs. 1.6 kg; p = .004), while risperidone-treated patients were more likely to experience prolactin elevation (51.73 ng/mL vs. 8.23 ng/mL; p < .001) and sexual dysfunction (total score increase of 1.75 vs. 0.64; p = .049)., Conclusion: Both olanzapine and risperidone treatment yielded similar improvements in mania. The olanzapine group had significantly greater improvements in secondary measures of severity and depressive symptoms and better study completion rates but experienced more weight gain.
- Published
- 2006
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45. Clinical relevance of depressive symptom improvement in bipolar I depressed patients.
- Author
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Williamson D, Brown E, Perlis RH, Ahl J, Baker RW, and Tohen M
- Subjects
- Benzodiazepines administration & dosage, Benzodiazepines therapeutic use, Bipolar Disorder diagnosis, Bipolar Disorder drug therapy, Depression diagnosis, Depression drug therapy, Diagnostic and Statistical Manual of Mental Disorders, Double-Blind Method, Drug Administration Schedule, Drug Therapy, Combination, Fluoxetine administration & dosage, Fluoxetine therapeutic use, Humans, Olanzapine, Selective Serotonin Reuptake Inhibitors administration & dosage, Severity of Illness Index, Surveys and Questionnaires, Treatment Outcome, Bipolar Disorder epidemiology, Depression epidemiology, Selective Serotonin Reuptake Inhibitors therapeutic use
- Abstract
Background: Gaps remain between rating scale changes obtained in a clinical trial and what those results mean in clinical practice., Objective: To better understand the relevance of results from a clinical trial we examined the relationship between rating scale measures and the clinicians' assessment of illness severity., Methods: Data from a randomized double-blind 8-week study of bipolar I depression were examined post hoc in patients who received placebo (PLA, n = 355), olanzapine (n = 351) (OLZ, 5 to 20 mg/d), or olanzapine-fluoxetine combination (n = 82) (OFC, 6 and 25, 6 and 50, or 12 and 50 mg/d). Principal components analysis identified related symptoms (factors) from Montgomery-Asberg Depression Rating Scale (MADRS) item scores. Regression analysis examined baseline to endpoint changes in factor scores and Clinical Global Impression (CGI) scores. Mixed-effects model repeated measures analysis assessed differences between treatment groups., Results: MADRS factors identified were: sadness, negative thoughts, detachment, and neurovegetative symptoms. Factor and CGI scores were significantly reduced from baseline to endpoint (LOCF) in the combination therapy group as compared with placebo (p < .01). Changes in factor scores were highly correlated (p < .001) with changes in the CGI. Over 80% of this treatment effect was attributable to indirect effects of improvements in the MADRS factors, the remaining difference could not be explained even when changes in the YMRS and HAMA scores were included in the analytical model., Conclusions: The changes in MADRS factors were closely aligned with the clinician's assessment of overall depression severity, which may suggest a high degree of clinical relevance for differences observed between treatments.
- Published
- 2006
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46. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine.
- Author
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Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, Baker RW, Chou JC, and Bowden CL
- Subjects
- Acute Disease, Adult, Antipsychotic Agents adverse effects, Benzodiazepines adverse effects, Benzodiazepines therapeutic use, Bipolar Disorder psychology, Double-Blind Method, Female, Humans, Male, Obesity chemically induced, Olanzapine, Placebos, Secondary Prevention, Time Factors, Treatment Outcome, Weight Gain drug effects, Antipsychotic Agents therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder prevention & control
- Abstract
Objective: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder., Method: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score
or =15, HAM-D score > or =15, or hospitalization)., Results: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2)., Conclusions: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode. - Published
- 2006
- Full Text
- View/download PDF
47. The in utero passage of meconium by very low birth weight infants: a marker for adverse outcomes.
- Author
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Henry JA, Baker RW, and Yanowitz TD
- Subjects
- Amniotic Fluid chemistry, Biomarkers analysis, Biopsy, Needle, Female, Follow-Up Studies, Gestational Age, Humans, Immunohistochemistry, Infant Mortality trends, Infant, Newborn, Infant, Premature, Diseases mortality, Male, Perinatal Care, Placenta pathology, Predictive Value of Tests, Pregnancy, Probability, Prospective Studies, Retrospective Studies, Risk Assessment, Sensitivity and Specificity, Tissue Culture Techniques, Infant, Premature, Diseases diagnosis, Infant, Very Low Birth Weight, Meconium metabolism, Placenta metabolism, Placental Circulation, Pregnancy Outcome
- Abstract
Objectives: To determine the incidence of in utero meconium passage and the rate of associated complications among VLBW infants., Study Design: Retrospective review of medical records and prospective evaluation of placental samples from 431 VLBW infants who survived >24 h. Cases with histologic evidence of meconium were re-examined and hemosiderin excluded by a negative iron stain. Statistical analysis included chi2, logistic regression, Student's t-test and Kruskal-Wallis., Results: The 70 infants (16.2%) who had placental evidence of in utero meconium passage were younger, weighed less, and more likely to be delivered by C-section (P = 0.006), intubated in the delivery room (P = 0.02), receive chest compressions (P = 0.003), require volume resuscitation (P = 0.001) and develop grade III-IV intraventricular hemorrhages (P = 0.011) than were control infants., Conclusion: Microscopic evaluation of the placental membranes reveals that the in utero passage of meconium occurs in about 16% of premature infants and is associated with adverse perinatal outcomes, including the need for resuscitation at delivery and an increased risk for grade III-IV intraventricular hemorrhages.
- Published
- 2006
- Full Text
- View/download PDF
48. Variability in cerebral oxygen delivery is reduced in premature neonates exposed to chorioamnionitis.
- Author
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Yanowitz TD, Potter DM, Bowen A, Baker RW, and Roberts JM
- Subjects
- Female, Humans, Infant, Newborn, Male, Pregnancy, Regression Analysis, Spectroscopy, Near-Infrared, Brain metabolism, Chorioamnionitis metabolism, Infant, Premature, Oxygen metabolism
- Abstract
Premature infants exposed to chorioamnionitis are at increased risk for periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH), lesions that may result from inflammation and/or fluctuations in cerebral blood flow. The effect of chorioamnionitis on near-infrared spectroscopy (NIRS) measures of cerebral oxygen delivery has not been evaluated previously. Forty-nine infants born at 25-31 6/7 wk gestation underwent NIRS examination on d 1, 2, 3, and 7 of life. Variability in NIRS tracings was analyzed by partitioning each tracing into three components: long-term, intermediate, and short-term variability; the latter two components were analyzed. Chorioamnionitis-exposed infants manifest reduced intermediate variability in cerebral oxygenated and deoxygenated Hb but not total Hb. Infants with severe IVH/PVL had the lowest intermediate variability on d 1. Short-term variability was similar between chorioamnionitis-exposed and unexposed infants, and between infants with versus without severe IVH or PVL. We conclude that intermediate-term variability in NIRS cerebral oxygen delivery is reduced in chorioamnionitis-exposed infants. We speculate that intermediate variability represents the important time frame for evaluating the pathogenesis of perinatal brain injury. Further studies are needed to determine how these findings relate to cerebral blood flow autoregulation and oxygen utilization in premature infants.
- Published
- 2006
- Full Text
- View/download PDF
49. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials.
- Author
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Perlis RH, Brown E, Baker RW, and Nierenberg AA
- Subjects
- Adult, Ambulatory Care, Antipsychotic Agents therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder psychology, Cohort Studies, Depressive Disorder, Major drug therapy, Depressive Disorder, Major psychology, Diagnosis, Differential, Drug Therapy, Combination, Female, Humans, Logistic Models, Male, Models, Statistical, Multicenter Studies as Topic statistics & numerical data, Psychiatric Status Rating Scales statistics & numerical data, ROC Curve, Randomized Controlled Trials as Topic statistics & numerical data, Recurrence, Sensitivity and Specificity, Bipolar Disorder diagnosis, Depressive Disorder, Major diagnosis
- Abstract
Objective: Failure to recognize bipolar disorder in patients who experience a major depressive episode may lead to inappropriate treatment and poorer outcomes. Clinical features that could distinguish bipolar from unipolar depression would facilitate more appropriate treatment selection., Method: The authors used data from nonpsychotic outpatients participating in three large multicenter clinical trials conducted in the United States for the treatment of major depressive episodes to compare 477 subjects with a diagnosis of bipolar disorder and 1,074 with major depressive disorder., Results: Bipolar depression was associated with family history of bipolar disorder, an earlier age at onset, a greater previous number of depressive episodes, and eight individual symptom items on the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale. Fears were more common in patients with bipolar disorder, whereas sadness; insomnia; intellectual (cognitive), somatic (muscular), respiratory, genitourinary complaints; and depressed behavior were more common in patients with unipolar depression. A logistic regression model correctly classified 86.9% of the subjects., Conclusions: Bipolar depression and major depressive disorder exhibit subtle differences in presentation, which may help guide the initial diagnosis.
- Published
- 2006
- Full Text
- View/download PDF
50. Influenza vaccine for patients with chronic obstructive pulmonary disease.
- Author
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Poole PJ, Chacko E, Wood-Baker RW, and Cates CJ
- Subjects
- Aged, Humans, Influenza Vaccines adverse effects, Influenza, Human prevention & control, Randomized Controlled Trials as Topic, Vaccines, Attenuated adverse effects, Vaccines, Attenuated therapeutic use, Vaccines, Inactivated adverse effects, Vaccines, Inactivated therapeutic use, Influenza Vaccines therapeutic use, Lung Diseases, Obstructive complications
- Abstract
Background: Influenza vaccinations are currently recommended in the care of people with COPD, but these recommendations are based largely on evidence from observational studies with very few randomised controlled trials (RCTs) reported. Influenza infection causes excess morbidity and mortality in COPD patients but there is also the potential for influenza vaccination to cause adverse effects or not to be cost effective., Objectives: To evaluate the evidence from RCTs for a treatment effect of influenza vaccination in COPD subjects. Outcomes of interest were exacerbation rates, hospitalisations, mortality, lung function and adverse effects., Search Strategy: We searched the Cochrane Airways Group Specialised Register of trials, and reference lists of articles. References were also provided by a number of drug companies we contacted., Selection Criteria: RCTs that compared live or inactivated virus vaccines with placebo, either alone or with another vaccine in persons with COPD. Studies of people with asthma were excluded., Data Collection and Analysis: Two reviewers extracted data. All entries were double checked. Study authors and drug companies were contacted for missing information., Main Results: Eleven trials were included but only six of these were specifically performed in COPD patients. The others were conducted on elderly and high-risk individuals, some of whom had chronic lung disease. Inactivated vaccine in COPD patients resulted in a significant reduction in the total number of exacerbations per vaccinated subject compared with those who received placebo (weighted mean difference (WMD) -0.37, 95% confidence interval -0.64 to -0.11, P = 0.006). This was due to the reduction in "late" exacerbations occurring after three or four weeks (WMD -0.39, 95% CI -0.61 to -0.18, P = 0.0004). In Howells 1961, the number of patients experiencing late exacerbations was also significantly less (odds ratio 0.13, 95% CI 0.04 to 0.45, P = 0.002). Both Howells 1961 and Wongsurakiat 2004 found that inactivated influenza vaccination reduced influenza -related respiratory infections (WMD 0.19, 95% CI 0.07 to 0.48, P = 0.0005). In both COPD patient and in elderly patients (only a minority of whom had COPD), there was a significant increase in the occurrence of local adverse reactions in vaccinees, but the effects were generally mild and transient. There was no evidence of an effect of intranasal live attenuated virus when this was added to inactivated intramuscular vaccination. The studies are too small to have detected any effect on mortality. An updated search conducted in September 2001 did not yield any further studies. A search in 2003 yielded two further reports of the same eligible study Gorse 2003. A search in 2004 yielded two reports of the another eligible study Wongsurakiat 2004. The author informed us of another report of the same study Wongsurakiat 2004/2., Authors' Conclusions: It appears, from the limited number of studies performed, that inactivated vaccine reduces exacerbations in COPD patients. The size of effect was similar to that seen in large observational studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination, and due to influenza. There is a mild increase in transient local adverse effects with vaccination, but no evidence of an increase in early exacerbations.
- Published
- 2006
- Full Text
- View/download PDF
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