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Find video protocols related to scientific articles indexed in Pubmed.
PDE5 inhibitors enhance Celecoxib killing in multiple tumor types.
J. Cell. Physiol.
PUBLISHED: 09-15-2014
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The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1?/XBP1 enhanced killing whereas knock down of eIF2?/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
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Pharmacological characterization of TMEM16A currents.
Channels (Austin)
PUBLISHED: 03-20-2014
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Recent studies have shown that transmembrane protein 16 A (TMEM16A) is a subunit of calcium-activated chloride channels (CACCs). Pharmacological agents have been used to probe the functional role of CACCs, however their effect on TMEM16A currents has not been systematically investigated. In the present study, we characterized the voltage and concentration-dependent effects of 2 traditional CACC inhibitors (niflumic acid and anthracene-9-carboxcylic acid) and 2 novel CACC / TMEM16A inhibitors (CACCinhA01 and T16AinhA01) on TMEM16A currents. The whole cell patch clamp technique was used to record TMEM16A currents from HEK 293 cells that stably expressed human TMEM16A. Niflumic acid, A-9-C, CACCinhA01 and T16AinhA01 inhibited TMEM16A currents with IC 50 values of 12, 58, 1.7 and 1.5 µM, respectively, however, A-9-C and niflumic acid were less efficacious at negative membrane potentials. A-9-C and niflumic acid reduced the rate of TMEM16A tail current deactivation at negative membrane potentials and A-9-C (1 mM) enhanced peak TMEM16A tail current amplitude. In contrast, the inhibitory effects of CACCinhA01 and T16AinhA01 were independent of voltage and they did not prolong the rate of TMEM16A tail current deactivation. The effects of niflumic acid and A-9-C on TMEM16A currents were similar to previous observations on CACCs in vascular smooth muscle, strengthening the hypothesis that they are encoded by TMEM16A. However, CACCinhA01 and T16AinhA01 were more potent inhibitors of TMEM16A channels and their effects were not diminished at negative membrane potentials making them attractive candidates to interrogate the functional role of TMEM16A channels in future studies.
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Airmen with mild traumatic brain injury (mTBI) at increased risk for subsequent mishaps.
J Safety Res
PUBLISHED: 02-18-2014
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Little is known regarding long-term performance decrements associated with mild Traumatic Brain Injury (mTBI). The goal of this study was to determine if individuals with an mTBI may be at increased risk for subsequent mishaps.
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Sesterterpene glycinyl-lactams: a new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia.
Org. Biomol. Chem.
PUBLISHED: 06-11-2013
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Bioassay guided fractionation of three southern Australian marine sponges of the genus Psammocinia, selected for their ability to modulate glycine-gated chloride channel receptors (GlyRs), yielded the rare marine sesterterpenes (-)-ircinianin (1) and (-)-ircinianin sulfate (2), along with the new biosynthetically related metabolites (-)-ircinianin lactam A (3), (-)-ircinianin lactam A sulfate (4), (-)-oxoircinianin (5), (-)-oxoircinianin lactam A (6) and (-)-ircinianin lactone A (7). Acetylation of 1 returned (-)-ircinianin acetate (8). Whole cell patch-clamp electrophysiology on 1-8 established 3 as an exceptionally potent and selective ?3 GlyR potentiator, and 6 as a selective ?1 GlyR potentiator. The discovery and characterization of sesterterpenes 1-8, and in particular the glycinyl-lactams 3 and 6, provide valuable new insights into GlyR pharmacology. These insights have the potential to inform and inspire the development of new molecular tools to probe GlyR distribution and function, and therapeutics to treat a wide array of GlyR mediated diseases and disorders.
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A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.
Clin. Cancer Res.
PUBLISHED: 04-03-2013
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Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC).
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A multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first-line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC).
Cancer Chemother. Pharmacol.
PUBLISHED: 03-13-2013
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Platinum-based doublets are standard of care for advanced non-small-cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC.
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Risk for addiction-related disorders following mild traumatic brain injury in a large cohort of active-duty U.S. airmen.
Am J Psychiatry
PUBLISHED: 02-23-2013
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Military personnel are at increased risk for traumatic brain injury (TBI) from combat and noncombat exposures. The sequelae of moderate to severe TBI are well described, but little is known regarding long-term performance decrements associated with mild TBI. Furthermore, while alcohol and drug use are well known to increase risk for TBI, little is known regarding the reverse pattern. The authors sought to assess possible associations between mild TBI and addiction-related disorders in active-duty U.S. military personnel.
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Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel.
J. Biol. Chem.
PUBLISHED: 10-27-2011
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Ivermectin is an anthelmintic drug that works by activating glutamate-gated chloride channel receptors (GluClRs) in nematode parasites. GluClRs belong to the Cys-loop receptor family that also includes glycine receptor (GlyR) chloride channels. GluClRs and A288G mutant GlyRs are both activated by low nanomolar ivermectin concentrations. The crystal structure of the Caenorhabditis elegans ? GluClR complexed with ivermectin has recently been published. Here, we probed ivermectin sensitivity determinants on the ?1 GlyR using site-directed mutagenesis and electrophysiology. Based on a mutagenesis screen of transmembrane residues, we identified Ala288 and Pro230 as crucial sensitivity determinants. A comparison of the actions of selamectin and ivermectin suggested the benzofuran C05-OH was required for high efficacy. When taken together with docking simulations, these results supported a GlyR ivermectin binding orientation similar to that seen in the GluClR crystal structure. However, whereas the crystal structure shows that ivermectin interacts with the ? GluClR via H-bonds with Leu218, Ser260, and Thr285 (? GluClR numbering), our data indicate that H-bonds with residues homologous to Ser260 and Thr285 are not important for high ivermectin sensitivity or direct agonist efficacy in A288G ?1 GlyRs or three other GluClRs. Our data also suggest that van der Waals interactions between the ivermectin disaccharide and GlyR M2-M3 loop residues are unimportant for high ivermectin sensitivity. Thus, although our results corroborate the ivermectin binding orientation as revealed by the crystal structure, they demonstrate that some of the binding interactions revealed by this structure do not pertain to other highly ivermectin-sensitive Cys-loop receptors.
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Aircraft type and other risk factors for spinal disorders: data from 19,673 military cockpit aircrew.
Aviat Space Environ Med
PUBLISHED: 09-10-2010
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Many assume that exposure to flight in high-performance aircraft (HPA) or rotary wing aircraft (RWA) increases the risk of spinal disorders compared to other fixed wing aircraft (FWA). However, this association has yet to be confirmed. This study explores the relationship between flight in different aircraft and the development of lumbar and cervical spine disorders.
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Civil engineering airman at increased risk for injuries and injury-related musculoskeletal disorders.
Am. J. Ind. Med.
PUBLISHED: 09-08-2010
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With the advent of electronic records, the opportunity to conduct research on workplace-related injuries and musculoskeletal disorders has increased dramatically. The purpose of this study was to examine the United States Air Force Civil Engineering career field to determine if they are negatively impacted by their work environment. Specifically, the objective of this study was to determine if enlisted Civil Engineering Airmen (n?=?25,385) were at increased risk for injury or injury-related musculoskeletal disorders compared to enlisted Information Management/Communications Airmen (n?=?28,947).
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Fatigue and stimulant use in military fighter aircrew during combat operations.
Aviat Space Environ Med
PUBLISHED: 08-05-2010
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Fatigue in military aviation is a significant safety and operational problem resulting in diminished alertness and performance. Research demonstrates that stimulant medications maintain alertness and performance in sleep-deprived aircrew. However, these studies control many of the variables present during combat operations. Few studies have evaluated fatigue or the factors and effects associated with stimulant use in fighter aircrew during combat operations.
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Darbepoetin alfa 300 or 500 ?g once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia.
Am. J. Hematol.
PUBLISHED: 07-28-2010
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This study evaluated efficacy and safety of darbepoetin alfa administered every 3 weeks (Q3W) at fixed doses of 300 or 500 ?g with or without intravenous (IV) iron in treating anemia in patients receiving multicycle chemotherapy. This Phase 2, double-blind, 2 × 2 factorial study randomized patients to one of four treatment arms; darbepoetin alfa 300 ?g (n = 62), darbepoetin alfa 300 ?g plus IV iron (n = 60), darbepoetin alfa 500 ?g (n = 60), or darbepoetin alfa 500 ?g plus IV iron (n = 60). Patients had nonmyeloid malignancies, hemoglobin levels ?10 g dL(-1), and no iron deficiency. Primary endpoint was achievement of target hemoglobin (?11 g dL(-1)). Secondary endpoints included incidence of transfusions and change in Functional Assessment of Cancer Therapy Fatigue (FACT-F) score from baseline to end of study. Safety was evaluated by incidence of adverse events. No evidence of a statistically significant interaction between darbepoetin alfa dose received and IV iron usage was observed, therefore, results are provided separately comparing darbepoetin alfa doses and comparing IV iron usage groups. Similar proportions of patients receiving darbepoetin alfa 300 or 500 ?g achieved target hemoglobin (75 and 78%, respectively); Kaplan-Meier median time to target hemoglobin was 10 and 8 weeks, respectively. More patients receiving IV iron (82%) than not receiving IV iron (72%) achieved hemoglobin target. Adverse events profiles were similar for darbepoetin alfa treatment groups. Transient anaphylactoid reactions were reported in two patients receiving IV iron. Darbepoetin alfa at 300 ?g Q3W and 500 ?g Q3W showed similar benefit, while added IV iron improved treatment response in these patients.
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Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties.
Bioconjug. Chem.
PUBLISHED: 04-28-2010
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Membrane receptors for steroid hormones are currently a subject of considerable debate. One approach to selectively target these putative receptors has been to couple ligands to substances that restrict cell permeability. Using this approach, an analogue of the estrogen receptor ligand 4-hydroxytamoxifen was attached to fluorescent dyes with differing degrees of predicted cell permeability. The conjugates bound to estrogen receptor in vitro, but all three conjugates, including one predicted to be cell-impermeable, inhibited estradiol-induced transcriptional activation. Fluorescence microscopy revealed cytoplasmic localization for all three conjugates. We further characterized a 4-hydroxytamoxifen analogue conjugated to a BODIPY fluorophore in breast cancer cell lines. Those experiments suggested a similar, but not identical, mode of action to 4-hydroxytamoxifen, as the fluorescent conjugate was equally effective at inhibiting proliferation of both tamoxifen-sensitive and tamoxifen-resistant breast cancer cell lines. While these findings point to significant complicating factors in designing steroid hormone mimics targeted to the plasma membrane, the results also reveal a possible new direction for designing estrogen receptor modulators.
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Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae.
Bioorg. Med. Chem.
PUBLISHED: 02-08-2010
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Screening an extract library of >2500 southern Australian and Antarctic marine invertebrates and algae for modulators of glycine receptor (GlyR) chloride channels identified three Irciniidae sponges that yielded new examples of a rare class of glycinyl lactam sesterterpene, ircinialactam A, 8-hydroxyircinialactam A, 8-hydroxyircinialactam B, ircinialactam C, ent-ircinialactam C and ircinialactam D. Structure-activity relationship (SAR) investigations revealed a new pharmacophore with potent and subunit selective modulatory properties against alpha1 and alpha3 GlyR isoforms. Such GlyR modulators have potential application as pharmacological tools, and as leads for the development of GlyR targeting therapeutics to treat chronic inflammatory pain, epilepsy, spasticity and hyperekplexia.
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Lack of effect of casopitant on the pharmacokinetics of docetaxel in patients with cancer.
Cancer Chemother. Pharmacol.
PUBLISHED: 01-29-2010
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The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel.
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Illness and injury risk and healthcare utilization, United States Air Force battlefield airmen and security forces, 2000-2005.
Mil Med
PUBLISHED: 09-29-2009
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To study the illness and injury risk and healthcare utilization of male U.S. Air Force (USAF) battlefield airmen in comparison to male USAF security forces.
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High Throughput Techniques for Discovering New Glycine Receptor Modulators and their Binding Sites.
Front Mol Neurosci
PUBLISHED: 07-23-2009
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The inhibitory glycine receptor (GlyR) is a member of the Cys-loop receptor family that mediates inhibitory neurotransmission in the central nervous system. These receptors are emerging as potential drug targets for inflammatory pain, immunomodulation, spasticity and epilepsy. Antagonists that specifically inhibit particular GlyR isoforms are also required as pharmacological probes for elucidating the roles of particular GlyR isoforms in health and disease. Although a substantial number of both positive and negative GlyR modulators have been identified, very few of these are specific for the GlyR over other receptor types. Thus, the potential of known compounds as either therapeutic leads or pharmacological probes is limited. It is therefore surprising that there have been few published studies describing attempts to discover novel GlyR isoform-specific modulators. The first aim of this review is to consider various methods for efficiently screening compounds against these receptors. We conclude that an anion sensitive yellow fluorescent protein is optimal for primary screening and that automated electrophysiology of cells stably expressing GlyRs is useful for confirming hits and quantitating the actions of identified compounds. The second aim of this review is to demonstrate how these techniques are used in our laboratory for the purpose of both discovering novel GlyR-active compounds and characterizing their binding sites. We also describe a reliable, cost effective method for transfecting HEK293 cells in single wells of a 384-well plate using nanogram quantities of plasmid DNA.
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The M4 transmembrane segment contributes to agonist efficacy differences between alpha1 and alpha3 glycine receptors.
Mol. Membr. Biol.
PUBLISHED: 07-20-2009
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To date there are few compounds known to pharmacologically discriminate between alpha1 and alpha3 subunit-containing glycine receptors (GlyRs). The present study stemmed from an observation that the glycinergic agonists, taurine and beta-alanine, act with much lower agonist efficacy at alpha3 GlyRs than at alpha1 GlyRs. We sought to understand the structural basis of this difference to provide insights relevant to the development of alpha3-specific modulators as leads for the development of new anti-inflammatory analgesics. Using chimeras of alpha1 and alpha3 subunits, we identified the structurally divergent M4 transmembrane segment and C-terminal tail as a specific determinant of the efficacy difference. Because mutation of individual non-conserved M4 residues had little influence on agonist efficacies, the reduced agonist efficacy at alpha3 GlyRs is most likely a distributed effect of all non-conserved M4 residues. Given the lack of contact between M4 and other transmembrane segments, the efficacy differences are probably mediated by differential interactions with the surrounding lipid environment. This may explain why GlyR agonist efficacies differ among expression systems where membrane lipid composition is not conserved. It may also explain why GlyR agonist efficacy increases at high expression densities, as this would increase the propensity of receptors to cluster thereby inducing M4 segments of neighboring receptors to interact. This strong influence of M4 primary structure on partial agonist efficacy suggests that the relatively poorly conserved alpha3 GlyR M4 segment may be a promising domain to target in the search for alpha3 GlyR-specific modulators.
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Dihydropyridine inhibition of the glycine receptor: subunit selectivity and a molecular determinant of inhibition.
Neuropharmacology
PUBLISHED: 04-03-2009
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The dihydropyridines (DHPs), nifedipine and nicardipine, modulate native glycine receptors (GlyRs) at micromolar concentrations. Nicardipine has a biphasic potentiating and inhibitory effect, whereas nifedipine causes inhibition only. The present study sought to investigate (1) the molecular mechanism by which these compounds inhibit recombinant GlyRs, and (2) their potential utility as subunit-selective inhibitors of alpha1, alpha1beta, alpha3 and alpha3beta GlyRs. The rate of onset of inhibition in the open state was accelerated by pre-application of DHP in the closed state, with the degree of acceleration proportional to the concentration of pre-applied DHP. This implies a non-inhibitory binding site close to the DHP inhibitory site. DHP inhibition was use-dependent and independent of glycine concentration, consistent with a pore-blocking mode of action. DHP sensitivity was abolished by the G2A mutation, providing a strong case for a DHP binding site in the pore. Nifedipine exhibited an approximately 10-fold higher inhibitory potency at alpha1-containing relative to alpha3-containing receptors, whereas nicardipine was only weakly selective for alpha1-containing GlyRs. The differential sensitivities of nifedipine and nicardipine for different GlyR isoforms suggest that DHPs may be a useful resource to screen as pharmacological tools for selectively inhibiting different synaptic GlyR isoforms.
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Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study.
Support Care Cancer
PUBLISHED: 03-31-2009
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Aprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types.
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Review of the efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in a range of tumor types.
Cancer Treat. Rev.
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Chemotherapy regimens differ according to the tumor type being treated and are associated with varying degrees of emetogenic potential. Since the distribution of risk factors for chemotherapy-induced nausea and vomiting differs across tumor types, it is important to understand the efficacy of antiemetic regimens in multiple patient populations. To characterize treatment response in patients with various malignancies (e.g., breast, gastrointestinal, genitourinary, and lung) treated with either highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) regimens, a pooled analysis of patient-level data from 4 large randomized trials was performed (N=2813). Patients receiving an antiemetic regimen containing aprepitant, ondansetron, and dexamethasone were compared with patients receiving an active-control antiemetic regimen containing ondansetron plus dexamethasone. In all tumor types analyzed, complete responses were observed in a higher proportion of HEC-treated patients receiving aprepitant compared with active-control patients (genitourinary [61.5% vs 40.6%, P<0.001], gastrointestinal [68.2% vs 44.7%, P=0.013], and lung cancers [73.5% vs 52.8%, P<0.001]). For MEC-treated patients, complete response rates were also higher for aprepitant patients than active-control patients for all tumor types, with a significant difference noted among patients with breast cancer (54.9% vs 43.9%, P<0.0001). The proportion of patients with no vomiting was higher in both HEC- and MEC-treated patients. While results of previous studies provide support for the use of antiemetic regimens that include aprepitant, a selective 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone, this analysis demonstrates the consistent efficacy of aprepitant as part of an antiemetic regimen across different tumor types and chemotherapy regimens.
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Stoichiometry and subunit arrangement of ?1? glycine receptors as determined by atomic force microscopy.
Biochemistry
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The glycine receptor is an anion-permeable member of the Cys-loop ion channel receptor family. Synaptic glycine receptors predominantly comprise pentameric ?1? subunit heteromers. To date, attempts to define the subunit stoichiometry and arrangement of these receptors have not yielded consistent results. Here we introduced FLAG and six-His epitopes into ?1 and ? subunits, respectively, and imaged single antibody-bound ?1? receptors using atomic force microscopy. This permitted us to infer the number and relative locations of the respective subunits in functional pentamers. Our results indicate an invariant 2?1:3? stoichiometry with a ?-?-?-?-? subunit arrangement.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.