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2.
Schizophr Res ; 255: 189-194, 2023 05.
Article in English | MEDLINE | ID: mdl-37003238

ABSTRACT

OBJECTIVE: Adversarial hearings in hospital commitment and de novo treatment proceedings, or court hearings, delay psychiatric treatment in many jurisdictions. In Massachusetts, the "treatment over objection" process requires a court petition. For state hospital patients, the delay to treatment is an initial 34 day waiting period in addition to continuances of court hearings that extend treatment delays. This study examined the frequency of adverse medical events due to delayed court hearings within a forensic state hospital in the US. METHODS: The study reviewed all (n = 355) treatment petitions filed by a Massachusetts forensic hospital from 2015 and 2016. The incidence and nature of adverse events (e.g. patient/staff assaults, milieu disruptions) and acute medical symptoms (e.g. catatonia, acute psychosis), before and after the Court granted a petition for treatment, were analyzed by two raters. Adverse events included patient and staff assaults, acute psychiatric symptoms, and milieu problems. RESULTS: 82.6 % of treatment petitions led to involuntary treatment, 16.6 % were withdrawn by the medical petition filer, and only 0.8 % petitions were denied by the judge. Adversarial hearings occasioned an average delay of 41 days from treatment petition filing to receipt of standing treatment in addition to statute required delays. Once treatment was court-approved, all types of adverse events were significantly reduced. CONCLUSIONS: Results established that the court treatment hearing scheme exacerbates health and safety risks to patients with serious mental illness. Increasing physician and court personnel awareness of these risks is likely key to enhancing a patient-focused, rights-oriented approach to these matters. This and other recommendations is proposed for jurisdictions that deal with this problem around the world.


Subject(s)
Commitment of Mentally Ill , Psychotic Disorders , Humans , Hospitals, Psychiatric
3.
J Am Chem Soc ; 142(1): 251-256, 2020 01 08.
Article in English | MEDLINE | ID: mdl-31804820

ABSTRACT

Weakly coordinating anions (WCAs) are generally tailored to act as spectators with little or no function. Here we describe the implementation of strongly coordinating dianionic carboranyl N-heterocyclic carbenes (NHCs) to create organometallic -ate complexes of Au(I) that serve both as WCAs and functional catalysts. These organometallic WCAs can be utilized to form both heterobimetallic (Au(I)-/Ag(I)+; Au(I)-/Ir(I)+) and organometallic/main group ion pairs (Au(I)-/(CPh3+ or SiEt3+). Because parent unfunctionalized dianionic carboranyl NHC complex 3 is unstable in most solvents when paired with CPh3+, novel synthesis methodology was devised to create polyhalogenated carboranyl NHCs, which show superior stability toward electrophilic substitution and cyclometalation chemistry. Additionally, the WCAs containing polyhalogenated carboranyl NHCs are among the most active catalysts reported for the hydroamination of alkynes. This investigation has also produced the first examples of a low-coordinate Au(III) center with two cis accessible coordination sites and the first true dianionic carbene. These studies pave the way for the design of functional ion pairs that have the potential to participate in tandem or cooperative small-molecule activation and catalysis.

4.
Trends Mol Med ; 26(2): 150-169, 2020 02.
Article in English | MEDLINE | ID: mdl-31706840

ABSTRACT

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.


Subject(s)
Cognition Disorders/genetics , Cognition/physiology , Down Syndrome/genetics , Animals , Brain/pathology , Chromosomes, Human, Pair 21/genetics , Disease Models, Animal , Humans , Phenotype , Pluripotent Stem Cells/pathology
5.
ACS Appl Mater Interfaces ; 10(8): 6825-6830, 2018 Feb 28.
Article in English | MEDLINE | ID: mdl-29405694

ABSTRACT

Electrochemical systems offer a versatile means for creating adaptive devices. However, the utility of electrochemical deposition is inherently limited by the properties of the electrolyte. The development of ionic liquids enables electrodeposition in high-vacuum environments and presents opportunities for creating electrochemically adaptive and regenerative spacecraft components. In this work, we developed a silver-rich, boron cluster ionic liquid (BCIL) for reversible electrodeposition of silver films. This air and moisture stable electrolyte was used to deposit metallic films in an electrochemical cell to tune the emissivity of the cell in situ, demonstrating a proof-of-concept design for spacecraft thermal control.

6.
Chem Commun (Camb) ; 51(25): 5359-62, 2015 Mar 28.
Article in English | MEDLINE | ID: mdl-25387660

ABSTRACT

The syntheses of unsymmetrical N-heterocyclic carbenes (NHCs) that contain a single N-bound icosahedral carborane anion substituent are reported. Both anionic C-2 and doubly deprotonated dianionic C-2/C-5 NHC lithium complexes are isolated. The latter species is formed selectively, which reveals a surprising directing effect conveyed by icosahedral carborane anion substituents.

7.
Pharm Dev Technol ; 19(4): 438-53, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23617261

ABSTRACT

OBJECTIVE: The purpose of this work was to prepare a stable paclitaxel nanosuspension and test it for potential use as a targeted chemotherapeutic. Different particle coatings were employed to assess their impact on cellular uptake in vitro. In vivo work was then performed to demonstrate efficacy in tumor-bearing mouse models. MATERIALS AND METHOD: Paclitaxel nanosuspensions were prepared using a homogenization process and coated with excipients. Surface charge was measured by zeta potential, potency by high-performance liquid chromatography, and solubility using an in-line UV probe. Cellular uptake studies were performed via flow cytometry. In vivo experiments were performed to determine residence time, maximum tolerated dose, and the efficacy of paclitaxel nanosuspensions (Paclitaxel-NS). RESULTS: A stable paclitaxel nanosuspension was prepared and coated with various excipients. Studies in mice showed that the nanosuspension was well-tolerated and at least as effective as the IV Taxol control in prolonging mouse survival in a head and neck cancer model as well as an ovarian cancer model with a lower overall drug dose than the traditional IV administration route. CONCLUSIONS: The paclitaxel nanosuspension is suitable for cellular uptake. The nanosuspension was effective in prolonging life in two separate xenograft orthotopic murine cancer models through two separate routes of administration.


Subject(s)
Antineoplastic Agents/chemistry , Nanoparticles/chemistry , Paclitaxel/chemistry , Suspensions/chemistry , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cells, Cultured , Excipients/chemistry , Female , Humans , Leukocytes, Mononuclear/drug effects , Mice , NIH 3T3 Cells , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacology , Suspensions/pharmacology
8.
J Comp Neurol ; 522(1): 186-203, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-23817783

ABSTRACT

Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and mitogen-activated protein kinase (MAPK) signaling pathways. In the adult mouse brain, RGS14 mRNA and protein are found almost exclusively in hippocampal CA2 neurons. We have shown that RGS14 is a natural suppressor of CA2 synaptic plasticity and hippocampal-dependent learning and memory. However, the protein distribution and spatiotemporal expression patterns of RGS14 in mouse brain during postnatal development are unknown. Here, using a newly characterized monoclonal anti-RGS14 antibody, we demonstrate that RGS14 protein immunoreactivity is undetectable at birth (P0), with very low mRNA expression in the brain. However, RGS14 protein and mRNA are upregulated during early postnatal development, with protein first detected at P7, and both increasing over time until reaching highest sustained levels throughout adulthood. Our immunoperoxidase data demonstrate that RGS14 protein is expressed in regions outside of hippocampal CA2 during development including the primary olfactory areas, the anterior olfactory nucleus and piriform cortex, and the olfactory associated orbital and entorhinal cortices. RGS14 is also transiently expressed in neocortical layers II/III and V during postnatal development. Finally, we show that RGS14 protein is first detected in the hippocampus at P7, with strongest immunoreactivity in CA2 and fasciola cinerea and sporadic immunoreactivity in CA1; labeling intensity in hippocampus increases until adulthood. These results show that RGS14 mRNA and protein are upregulated throughout postnatal mouse development, and RGS14 protein exhibits a dynamic localization pattern that is enriched in hippocampus and primary olfactory cortex in the adult mouse brain.


Subject(s)
Brain/growth & development , Brain/metabolism , RGS Proteins/metabolism , Animals , Antibodies, Monoclonal , Cerebral Cortex/growth & development , Cerebral Cortex/metabolism , Female , Hippocampus/growth & development , Hippocampus/metabolism , Immunoblotting , Immunoenzyme Techniques , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RGS Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
9.
Chembiochem ; 12(4): 633-40, 2011 Mar 07.
Article in English | MEDLINE | ID: mdl-21305681

ABSTRACT

The elucidation of signalling pathways relies heavily upon the identification of protein kinase substrates. Recent investigations have demonstrated the efficacy of chemical genetics using ATP analogues and modified protein kinases for specific substrate labelling. Here we combine N(6) -(cyclohexyl)ATPγS with an analogue-sensitive cdk2 variant to thiophosphorylate its substrates and demonstrate a pH-dependent, chemoselective, one-step alkylation to facilitate the detection or isolation of thiophosphorylated peptides.


Subject(s)
Chlorides/chemistry , Cyclin-Dependent Kinase 2/chemistry , Cysteine/chemistry , Peptides/chemistry , Phosphorus Compounds/chemistry , Alkylation , Cyclin-Dependent Kinase 2/genetics , Electrophoresis, Polyacrylamide Gel , Hydrogen-Ion Concentration , Peptides/genetics , Signal Transduction , Substrate Specificity
10.
Anal Bioanal Chem ; 399(2): 651-62, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20949261

ABSTRACT

This article addresses the identification and quantification of the chemical species resulting in resonances at 2.17 and 2.25 ppm in the (1)H nuclear magnetic resonance (NMR) spectrum of pharmaceutical-grade heparin sodium. The NMR signals in question were first confirmed to arise from chemical moieties covalently attached to the heparin molecule through NMR diffusion experiments as well as chemical treatment of heparin active pharmaceutical ingredient (API) containing the resonances. The material responsible for the extra NMR signals was then demonstrated by NMR spiking studies to be something other than oversulfated chondroitin sulfate and was finally identified as an O-acetylation product of heparin through (13)C labeling experiments with subsequent NMR analysis. The extent of O-acetylation was quantified using three orthogonal techniques: (1)H NMR, ion chromatography, and headspace gas chromatography/mass spectrometry. The results of this work showed good agreement between the three quantitative methods developed to analyze the signals in the United States Pharmacopeia-specified region of 2.12-3.00 ppm for heparin API.


Subject(s)
Anticoagulants/chemistry , Heparin/chemistry , Magnetic Resonance Spectroscopy/methods , Acetylation , Chondroitin Sulfates/analysis , Nitrous Acid/chemistry , Polymerization
11.
Org Biomol Chem ; 8(6): 1445-54, 2010 Mar 21.
Article in English | MEDLINE | ID: mdl-20204220

ABSTRACT

Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from 1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group is compatible with O-phosphorylation of the primary alcohol, as demonstrated by the successful preparation of the tetrafluorinated naphthyl-C-nucleotide.


Subject(s)
Nucleosides/chemistry , Nucleosides/chemical synthesis , Oxygen/chemistry , Butanols/chemistry , Halogenation , Phosphorylation , Stereoisomerism , Substrate Specificity
12.
Bioorg Med Chem Lett ; 19(14): 3804-7, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19410453

ABSTRACT

We hereby present a simple yet novel chemical synthesis of a family of gamma-modified ATPs bearing functional groups on the gamma-phosphate that are amenable to further derivatization by highly selective chemical manipulations (e.g., click chemistry, Staudinger ligations). A preliminary screen of these compounds as phosphate donors with a typical wild type protein kinase (cdk2) and one of its known substrates p27(kip1) is also presented.


Subject(s)
Adenosine Triphosphate/analogs & derivatives , Protein Kinase Inhibitors/chemical synthesis , Adenosine Triphosphate/chemical synthesis , Adenosine Triphosphate/pharmacology , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p27/chemistry , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
13.
Chembiochem ; 10(9): 1519-26, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19437469

ABSTRACT

Chemical genetic studies with enlarged ATP binding sites and unnatural ATP analogues have been applied to protein kinases for characterisation and substrate identification. Although this system is becoming widely used, there are limited data available about the kinetic profile of the modified system. Here we describe a detailed comparison of the wild-type cdk2 and the mutant gatekeeper kinase to assess the relative efficiencies of these kinases with ATP and unnatural ATP analogues. Our data demonstrate that mutation of the kinase alters neither the substrate specificity nor the phosphorylation site specificity. We find comparable K(M)/V(max) values for mutant cdk2 and wild-type kinase. Furthermore, F80G cdk2 is efficiently able to compensate for a defective cdk in a biological setting.


Subject(s)
Adenosine Triphosphate/analogs & derivatives , Cyclin-Dependent Kinase 2/chemistry , Cyclin-Dependent Kinase 2/genetics , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Amino Acid Substitution , Binding Sites , CDC28 Protein Kinase, S cerevisiae/metabolism , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Humans , Kinetics , Mutant Proteins/genetics , Mutant Proteins/metabolism , Oncogene Proteins/metabolism , Phosphorylation , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Retinoblastoma Protein/metabolism , Signal Transduction , Substrate Specificity
14.
J Am Chem Soc ; 131(4): 1589-97, 2009 Feb 04.
Article in English | MEDLINE | ID: mdl-19125651

ABSTRACT

Poly-beta-peptides are attractive for biomedical applications because the backbone is similar enough to that of proteins for biocompatibility, but the backbone is sufficiently unnatural that these polymers evade proteolytic degradation. Prior investigations of poly-beta-peptides have been hindered by two principal limitations: (1) most known examples are insoluble, and (2) the range of accessible side chain functionality has been quite limited (mostly simple hydrocarbon units). The present study describes innovations in poly-beta-peptide synthesis that enable the preparation of diversely functionalized examples and provide the basis for broad exploration of the properties and applications of these nylon-3 materials. We describe several beta-lactams with a protected amino group in their side chain that readily undergo ring-opening polymerization (ROP). These monomers are available in large quantities via N-chlorosulfonylisocyanate (CSI) cycloaddition reactions with functionalized alkenes; previously CSI reactions have been limited to alkenes with hydrocarbon substituents. Postpolymerization deprotection of the amino groups leads to water-soluble poly-beta-peptides. In addition, we introduce a simple co-initiation strategy that allows placement of a wide variety of functional groups at the N-termini of poly-beta-peptide chains. ROP involving the new beta-lactams and co-initiation strategy exhibits characteristics of a controlled polymerization and enables the preparation of amphiphilic block copolymers. We have recently shown that cationic copoly-beta-peptides made available by these innovations mimic the selective antibacterial activity of host-defense peptides; the results described here provide the foundation for further exploration of this valuable activity and for the pursuit of other biological applications such as DNA/siRNA delivery and tissue engineering.


Subject(s)
Peptides/chemistry , beta-Lactams/chemical synthesis , Imides/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , beta-Lactams/chemistry
15.
Future Med Chem ; 1(7): 1233-41, 2009 Oct.
Article in English | MEDLINE | ID: mdl-21426100

ABSTRACT

The protein kinase superfamily is one of the most important families of enzymes in molecular biology. Protein kinases typically catalyze the transfer of the γ-phosphate from ATP to a protein substrate (a highly ubiquitous cellular reaction), thereby controlling key areas of cell regulation. Deregulation of protein kinases is known to contribute to many human diseases, and selective inhibitors of protein kinases are a major area of interest in medicinal chemistry. However, a detailed understanding of many kinase pathways is currently lacking. Before we can effectively design medicinally relevant selective kinase inhibitors, it is necessary to understand the role played by a given kinase in specific signal-transduction cascades and to decipher its protein targets. Here, we describe recent advances towards dissecting protein kinase function through the use of chemical genetics.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinases/physiology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/pharmacology , Humans , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Kinases/chemistry , Protein Kinases/metabolism , Signal Transduction , Substrate Specificity
16.
J Mol Biol ; 379(1): 38-50, 2008 May 23.
Article in English | MEDLINE | ID: mdl-18440552

ABSTRACT

Flexible sequence-random polymers containing cationic and lipophilic subunits that act as functional mimics of host-defense peptides have recently been reported. We used bacteria and lipid vesicles to study one such polymer, having an average length of 21 residues, that is active against both Gram-positive and Gram-negative bacteria. At low concentrations, this polymer is able to permeabilize model anionic membranes that mimic the lipid composition of Escherichia coli, Staphylococcus aureus, or Bacillus subtilis but is ineffective against model zwitterionic membranes, which explains its low hemolytic activity. The polymer is capable of binding to negatively charged vesicles, inducing segregation of anionic lipids. The appearance of anionic lipid-rich domains results in formation of phase-boundary defects through which leakage can occur. We had earlier proposed such a mechanism of membrane disruption for another antimicrobial agent. Experiments with the mutant E. coli ML-35p indicate that permeabilization is biphasic: at low concentrations, the polymer permeabilizes the outer and inner membranes; at higher polymer concentrations, permeabilization of the outer membrane is progressively diminished, while the inner membrane remains unaffected. Experiments with wild-type E. coli K12 show that the polymer blocks passage of solutes into the intermembrane space at high concentrations. Cell membrane integrity in E. coli K12 and S. aureus exhibits biphasic dependence on polymer concentration. Isothermal titration calorimetry indicates that the polymer associates with the negatively charged lipopolysaccharide of Gram-negative bacteria and with the lipoteichoic acid of Gram-positive bacteria. We propose that this polymer has two mechanisms of antibacterial action, one predominating at low concentrations of polymer and the other predominating at high concentrations.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cell Membrane/drug effects , Escherichia coli/drug effects , Staphylococcus aureus/drug effects , beta-Lactams/pharmacology , Anti-Bacterial Agents/chemistry , Antimicrobial Cationic Peptides/chemistry , Biological Transport/drug effects , Calorimetry , Cations/chemistry , Cations/pharmacology , Cell Membrane/metabolism , Escherichia coli/metabolism , Liposomes/chemistry , Liposomes/metabolism , Microbial Sensitivity Tests , Nitrophenylgalactosides/metabolism , Permeability , Phospholipids/chemistry , Staphylococcus aureus/metabolism , beta-Lactams/chemistry
18.
ACS Chem Biol ; 2(5): 299-314, 2007 May 22.
Article in English | MEDLINE | ID: mdl-17518431

ABSTRACT

Protein kinases catalyze the transfer of the gamma-phosphate of ATP to a protein substrate and thereby profoundly alter the properties of the phosphorylated protein. The identification of the substrates of protein kinases has proven to be a very difficult task because of the multitude of structurally related protein kinases present in cells, their apparent redundancy of function, and the lack of absolute specificity of small-molecule inhibitors. Here, we review approaches that utilize chemical genetics to determine the functions and substrates of protein kinases, focusing on the design of ATP analogues and protein kinase binding site mutants.


Subject(s)
Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/chemical synthesis , Combinatorial Chemistry Techniques , Protein Engineering , Protein Kinases , Animals , Binding Sites , Humans , Models, Molecular , Phosphorylation , Protein Binding , Protein Kinases/chemistry , Protein Kinases/genetics , Protein Kinases/metabolism , Substrate Specificity
19.
Mol Pharmacol ; 69(1): 45-55, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16195468

ABSTRACT

Heterologous expression of alpha(1D)-adrenergic receptors (alpha(1D)-ARs) in most cell types results in intracellular retention and little or no functionality. We showed previously that heterodimerization with alpha(1B)-ARs promotes surface localization of alpha(1D)-ARs. Here, we report that the alpha(1B)-/alpha(1D)-AR interaction has significant effects on the pharmacology and signaling of the receptors, in addition to the effects on trafficking described previously. Upon coexpression of alpha(1B)-ARs and epitope-tagged alpha(1D)-ARs in both human embryonic kidney 293 and DDT(1)MF-2 cells, alpha(1D)-AR binding sites were not detectable with the alpha(1D)-AR selective antagonist 8-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY 7378), despite the ability to detect alpha(1D)-AR protein using confocal microscopy, immunoprecipitation, and a luminometer cell-surface assay. However, the alpha(1B)-AR-selective mutant F18A conotoxin showed a striking biphasic inhibition in alpha(1B)/alpha(1D)-AR-expressing cells, revealing that alpha(1D)-ARs were expressed but did not bind BMY 7378 with high affinity. Studies of norepinephrine-stimulated inositol phosphate formation showed that maximal responses were greatest in alpha(1B)/alpha(1D)-AR-coexpressing cells. Stable coexpression of an uncoupled mutant alpha(1B)-AR (Delta12) with alpha(1D)-ARs resulted in increased responses to norepinephrine. However, Schild plots for inhibition of norepinephrine-stimulated inositol phosphate formation showed a single low-affinity site for BMY 7378. Thus, our findings suggest that alpha(1B)/alpha(1D)-AR heterodimers form a single functional entity with enhanced functional activity relative to either subtype alone and a novel pharmacological profile. These data may help to explain why alpha(1D)-ARs are often pharmacologically undetectable in native tissues when they are coexpressed with alpha(1B)-ARs.


Subject(s)
Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Antagonists , Adrenergic alpha-Antagonists/pharmacology , Binding Sites , Cell Line , Dimerization , Humans , Piperazines/pharmacology , Radioligand Assay , Receptors, Adrenergic, alpha-1/chemistry
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