ABSTRACT
Since being first published in 2018, the use of two-dimensional MXene in solar cells has attracted significant interest. This study presents, for the first time, the synthesis of an efficient hybrid electrocatalyst in the form of a nanocomposite (MXene/CoS)-SnO2 designed to function as a high-performance electron transfer layer (ETL). The study can be divided into three distinct parts. The first part involves the synthesis of single-layer Ti3C2Tx MXene nanosheets, followed by the preparation of a CoS solution. Subsequently, in the second part, the fabrication of MXene/CoS heterostructure nanocomposites is carried out, and a comprehensive characterization is conducted to evaluate the physical, structural, and optical properties. In the third part, the attention is on the crucial characterizations of the novel nanocomposite-electron transport layer (ETL) solution, significantly contributing to the evolution of perovskite solar cells. Upon optimising the composition, an exceptional power conversion efficiency of more than 17.69% is attained from 13.81% of the control devices with fill factor (FF), short-circuit current density (Jsc), and open-circuit voltage (Voc) were 66.51%, 20.74 mA/cm2, and 1.282 V. Therefore, this PCE is 21.93% higher than the control device. The groundbreaking MXene/CoS (2 mg mL-1) strategy reported in this research represents a promising and innovative avenue for the realization of highly efficient perovskite solar cells.
ABSTRACT
The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.
Subject(s)
Receptors, Adrenergic, alpha-1/genetics , Receptors, Adrenergic, beta-1/genetics , Urologic Diseases/genetics , Urologic Neoplasms/genetics , Adrenergic beta-Antagonists/therapeutic use , Epithelial-Mesenchymal Transition/drug effects , Humans , Male , Prostate/metabolism , Prostate/pathology , Signal Transduction/drug effects , Tumor Microenvironment/genetics , Urinary Tract/metabolism , Urinary Tract/pathology , Urologic Diseases/pathology , Urologic Neoplasms/pathologyABSTRACT
In this work, voltammetric study based on cetyltrimethylammonium bromide (CTAB) as an ion-pairing agent for the determination of iodine level in iodized table salt has been explored. CTAB was used as an intermediate compound between iodide (I-) and the electrode due to its ability to dissociate to produce cetyltrimethylammonium ions ([CTA]+). The [CTA]+ with a long hydrophobic alkyl chain can be directly adsorbed onto the surface of the working electrode, and this in turns coated the electrode with cationic charge and enhance the electrode ability to bind to iodide (I-) and other molecular iodine ions. A mixture of iodide and CTAB ([CTA]+I-) was prepared and potential of 1.0 V for 60.0 s was applied to pre-concentrate the solution on the working electrode causing the [CTA]+I- to oxidize to iodine (I2). The produced I2 immediately react with chloride ion (Cl-) from the electrolyte of hydrochloric acid (HCl) to produce I2Cl- and form ion-pair with CTA+ as [CTA]+I2Cl-. The linear calibration curve of the developed method towards iodide was in the concentration range of 0.5-4.0 mg/L with sensitivity of - 1.383 µA mg/L-1 cm-2 (R2 = 0.9950), limit of detection (LOD) of 0.3 mg/L and limit of quantification (LOQ) of 1.0 mg/L, respectively. The proposed method indicates good agreement with the standard method for iodine determination with recovery range from 95.0 to 104.3%. The developed method provided potential application as a portable on-site iodine detector.
ABSTRACT
Precise fluid height sensing in open-channel microfluidics has long been a desirable feature for a wide range of applications. However, performing accurate measurements of the fluid level in small-scale reservoirs (<1 mL) has proven to be an elusive goal, especially if direct fluid-sensor contact needs to be avoided. In particular, gravity-driven systems used in several microfluidic applications to establish pressure gradients and impose flow remain open-loop and largely unmonitored due to these sensing limitations. Here we present an optimized self-shielded coplanar capacitive sensor design and automated control system to provide submillimeter fluid-height resolution (â¼250 µm) and control of small-scale open reservoirs without the need for direct fluid contact. Results from testing and validation of our optimized sensor and system also suggest that accurate fluid height information can be used to robustly characterize, calibrate and dynamically control a range of microfluidic systems with complex pumping mechanisms, even in cell culture conditions. Capacitive sensing technology provides a scalable and cost-effective way to enable continuous monitoring and closed-loop feedback control of fluid volumes in small-scale gravity-dominated wells in a variety of microfluidic applications.
ABSTRACT
OBJECTIVE: The high prevalence of leptospirosis in humans is of great public health concern, particularly in tropical and subtropical regions. This study aimed to determine the seroprevalence of leptospiral antibodies and distribution of serovars, and to assess the usefulness of enzyme-linked immunosorbent assay (ELISA) as a screening method for leptospiral antibodies in a high-risk healthy community. METHODS: Cross-sectional study of 231 market workers and food handlers in wet markets and food premises from two localities in central Malaysia. Respondents' background information was obtained using a questionnaire. Serum samples were tested for leptospiral antibodies using ELISA and microscopic agglutination test (MAT). RESULTS: Seroprevalence of leptospirosis among healthy workers was 46.3%. Detection of seropositivity was higher by MAT (46%) than ELISA (15%). We observed high seropositivity among local workers (49%), food handlers (49.5%), females (60.8%) and those aged 34 years and older (46.3%). Local strain LEP175 was the predominant serovar, followed by WHO strain Patoc. CONCLUSION: Overall seroprevalence among healthy food handlers and market workers was high in this study. The workplace places susceptible individuals at risk of leptospirosis.
Subject(s)
Food Handling , Leptospira/isolation & purification , Leptospirosis/microbiology , Occupational Diseases/microbiology , Adult , Antibodies, Bacterial/blood , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Leptospirosis/epidemiology , Malaysia , Male , Middle Aged , Occupational Diseases/epidemiology , Occupational Exposure/statistics & numerical data , Seroepidemiologic StudiesABSTRACT
BACKGROUND: To determine effects of allogeneic human chondrocytes expressing TGF-ß1 (TG-C) on structural progression of MRI features of knee osteoarthritis over a 1 year period. METHODS: This phase II randomized controlled trial of TG-C included patients with moderate to advanced osteoarthritis. Patients were randomized to receive an intraarticular 3:1 mixture of non-transduced allogeneic human chondrocytes and TG-C or placebo. 3 T MRI was acquired for all patients at baseline and follow-up (3, 6 and 12 months). MRIs were assessed using the WORMS system including cartilage damage, bone marrow lesions (BMLs), meniscal damage/extrusion, Hoffa-, effusion-synovitis, and osteophytes. Analyses were performed on a whole knee level, compartmental level, and subregional level. Binary logistic regression with Generalized Estimating Equation was used to compare risks of progression, adjusting for baseline age and gender. Mann - Whitney - Wilcoxon tests were used to assess differences for continuous variables. RESULTS: Fifty-seven Patients were included in the TG-C group and 29 in the placebo group. At 12 months, knees in the TG-C group showed less progression of cartilage damage compared to placebo on a whole knee level (34.6% vs. 47.9%; adjusted RR 0.7, 95%CI [0.5-1.1], p = 0.077). Less progression of Hoffa-synovitis and effusion-synovitis was observed in the TG-C group compared to placebo (9.6% vs. 21.1%, adjusted RR 0.5, 95%CI [0.2,1.2], p = 0.115). No statistically significant differences were seen for BMLs, meniscal damage and osteophytes. CONCLUSIONS: Intraarticular treatment with TG-C showed fewer patients in the treated group with progression in structural OA features and other MRI-defined inflammatory markers such as Hoffa-synovitis and effusion-synovitis. However, no differences were observed in regard to progression of BMLs and meniscal damage, or hypertrophic osteophyte formation. TRIAL REGISTRATION: NCT01221441 .Registered 13th October, 2010.
Subject(s)
Cartilage, Articular/pathology , Chondrocytes/transplantation , Knee Joint/pathology , Osteoarthritis, Knee/therapy , Transforming Growth Factor beta1/metabolism , Aged , Cartilage, Articular/cytology , Cartilage, Articular/diagnostic imaging , Cell- and Tissue-Based Therapy/methods , Chondrocytes/metabolism , Disease Progression , Female , Follow-Up Studies , Humans , Injections, Intra-Articular , Knee Joint/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Osteoarthritis, Knee/diagnosis , Osteoarthritis, Knee/pathology , Osteophyte/diagnostic imaging , Osteophyte/pathology , Osteophyte/therapy , Placebos , Severity of Illness Index , Transduction, Genetic , Transforming Growth Factor beta1/genetics , Transplantation, HomologousABSTRACT
OBJECTIVE: To analyze the impact of the presence of shaggy aorta on 30 day morbidity and mortality and long-term survival in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS: This retrospective observational study included 447 consecutive patients who underwent AAA repair between January 2009 and December 2012. The study included 209 patients (47%) having open surgical repair (OSR) and 238 patients (53%) having endovascular aneurysm repair (EVAR). RESULTS: Of the 447 patients having elective AAA repair, 48 patients (11%) had shaggy aorta. Both the OSR (p = .005) and EVAR group (p = .007) demonstrated a higher 30 day morbidity and mortality in patients with shaggy aorta. On multivariate regression analysis, patients with shaggy aorta had 4.1 fold (95% CI = 1.7-9.7; p = .002) increase in 30 day morbidity and mortality. According to the Kaplan-Meier analysis, patients with shaggy aorta had significantly decreased long-term overall survival in comparison with the non-shaggy group (log-rank test; p = .005), and this resulted from comorbidities. CONCLUSIONS: Shaggy aorta is a prominent risk factor associated with 30 day morbidity and mortality. Poor long-term survival was expected in patients with shaggy aorta.
Subject(s)
Aortic Aneurysm, Abdominal/surgery , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Aged , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/mortality , Aortography/methods , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/mortality , Chi-Square Distribution , Computed Tomography Angiography , Endovascular Procedures/adverse effects , Endovascular Procedures/mortality , Female , Humans , Kaplan-Meier Estimate , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Proportional Hazards Models , Retrospective Studies , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Several biomarkers of esophageal squamous cell carcinoma (ESCC) have been explored to improve the prognosis of this disease. One of these, the 47-kDa heat shock protein (HSP47), has been screened as a potential biomarker by genomic profiling and is known to be overexpressed in some malignant diseases. In this study, we explored the role and evaluated the prognostic value of HSP47 expression in ESCC. The function of this protein was analyzed by assaying proliferation, wound healing, and colony formation in an HSP47-knockdown ESCC line. The prognostic implication of HSP47 expression was analyzed by immunohistochemical staining in 157 surgical specimens. HSP47 expression level and other clinical variables were analyzed using multivariate Cox proportional hazards models. Silencing of the HSP47 gene in the ESCC cell line inhibited cell proliferation and colony formation. HSP47 was highly expressed in ESCC tissue samples, compared with normal esophageal tissues. The level of immunohistochemical staining of HSP47 and pathologic stage were significantly correlated with overall and recurrence-free survival, as shown by multivariate analysis (P = 0.014 and 0.044, respectively). We found that overexpression of HSP47 is associated with poor prognosis in patients with ESCC and that this is consistent with the function of HSP47 in terms of increased cell proliferation and colony formation. These results suggest that HSP47 is a potential prognostic biomarker for ESCC and merits further research for novel diagnostic and therapeutic applications.
Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , HSP47 Heat-Shock Proteins/metabolism , Aged , Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Disease-Free Survival , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Esophagus/metabolism , Esophagus/pathology , Female , Gene Knockdown Techniques , Gene Silencing/physiology , Humans , Immunohistochemistry , Male , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local/genetics , Neoplasm Staging , Neoplastic Stem Cells/metabolism , Prognosis , Proportional Hazards ModelsABSTRACT
Electrical discharge using a capacitance of 450 µF at 7.0 and 8.0 kJ input energies was applied to mechanical alloyed Ti5Si3 powder without applying any external pressure. A solid bulk of nanostructured Ti5Si3 with no compositional deviation was obtained in times as short as 159 µsec by the discharge. During an electrical discharge, the heat generated is the required parameter possibly to melt the Ti5Si3 particles and the pinch force can pressurize the melted powder without allowing the formation of pores. Followed rapid cooling preserved the nanostructure of consolidated Ti5Si3 compact. Three stepped processes during an electrical discharge for the formation of nanostructured Ti5Si3 compact are proposed: (a) a physical breakdown of the surface oxide of Ti5Si3 powder particles, (b) melting and condensation of Ti5Si3 powder by the heat and pinch pressure, respectively, and (c) rapid cooling for the preservation of nanostructure. Complete conversion yielding a single phase Ti5Si3 is primarily dominated by the solid-liquid mechanism.
ABSTRACT
BACKGROUND: Maintenance of water balance in the stratum corneum (SC) is determined by the content of intercellular lipids and natural moisturizing factors (NMFs) in corneocytes. AIM: To investigate the association between the NMFs and (pro)filaggrin and the proteases responsible for the processing of (pro)filaggrin to NMFs in the SC of hydrated and dry skin areas of healthy human subjects. METHODS: The SC hydration state and the transepidermal water loss (TEWL) were measured using a Corneometer and a Tewameter, respectively. Proteases, (pro)filaggrin and NMFs were extracted from SC samples obtained by tape-stripping of the tested skin. Expression levels of (pro)filaggrin were determined by dot blotting and western blotting, and total NMFs by ultra-high performance liquid chromatography. Expression of the proteases caspase-14, calpain-1 and bleomycin hydrolase was measured by western blotting. RESULTS: The levels of (pro)filaggrin were not significantly different between hydrated and dry skin, whereas the level of total NMFs was significantly reduced in dry skin. A negative correlation between (pro)filaggrin and NMFs was found in dry skin (Pearson correlation coefficient r = - 0.57, *P < 0.05). Bleomycin hydrolase expression was significantly decreased in the SC of dry skin. CONCLUSIONS: These results suggest that the low hydration state of dry skin may be due to the reduction in (pro)filaggrin degradation caused by decreased bleomycin hydrolase expression.
Subject(s)
Cysteine Endopeptidases/metabolism , Epidermis/metabolism , Intermediate Filament Proteins/metabolism , Adult , Calpain/metabolism , Caspase 14/metabolism , Chromatography, High Pressure Liquid , Epidermis/physiology , Female , Filaggrin Proteins , Humans , Male , Middle Aged , Water Loss, Insensible/physiologyABSTRACT
Glucosamine (GlcN), like N-acetylglucosamine (GlcNAc), is salvaged into the hexosamine pathway and is converted to UDP-GlcNAc. Golgi N-glycan branching enzymes produce N-glycans, using UDP-GlcNAc as a substrate, which attach to the T cell receptor (TCR) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). These findings suggest that GlcN exerts the immunoregulation through TCR signalling, which could be involved not only in cytokine production but also activated T cell apoptosis. In fact, a preliminary study showed that GlcN reduced the number of CD3+ T cells of NC/Nga mice with AD-like skin lesions. Therefore, whether apoptosis of T cells would be one of the potential molecular mechanisms of GlcN-induced immunosuppression was investigated. Cultured human primary along with Jurkat T cells and purified T cells from NC/Nga mice with or without Df-induced AD-like skin lesion were used for the study. Glucosamine treatment increased the number of T cells expressing ß1,6GlcNAc-branched N-glycans, with reduced ZAP-70 phosphorylation and enhanced CTLA-4 expression. Glucosamine treatment reduced the number of activated T cells from both the human primary and Jurkat cells and the dermatitis-induced mice. The expression of FasL and activated caspases, particularly caspase-3, was increased, whereas the phosphorylation of PI3K, Akt and NF-κB was decreased by GlcN treatment. Therefore, in addition to down-regulating TCR signalling and promoting CTLA-4 expression, GlcN may also suppress T cell function by enhancing apoptosis of activated T cells, through both extrinsic and intrinsic apoptotic signalling pathways, which were regulated by the inhibition of PI3K/Akt and NF-κB phosphorylation.
Subject(s)
Apoptosis/drug effects , Glucosamine/pharmacology , Receptors, Antigen, T-Cell/physiology , T-Lymphocytes/drug effects , Animals , CTLA-4 Antigen/analysis , Humans , Jurkat Cells , Lymphocyte Activation , Male , Mice , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , T-Lymphocytes/immunology , ZAP-70 Protein-Tyrosine Kinase/antagonists & inhibitors , ZAP-70 Protein-Tyrosine Kinase/metabolismABSTRACT
This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PK-PD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.6-20.5), 1.9%/h, 7.3% (5.4-9.3), and -0.5% (-2.6 to 1.6), 8.7% (7.3-10.1), 2.5%/h, 6.0% (4.1-7.2) for microemulsion propofol, and -9.3% (-11.6 to -6.9), 20.1% (18.2-22.0), 5.1%/h, 7.6% (6.1-9.1) and 5.6% (4.1-7.1), 8.0% (6.9-9.3), 4.7%/h, 4.1% (3.1-5.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PK-PD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration.
Subject(s)
Anesthetics, Intravenous/pharmacokinetics , Dogs/blood , Emulsions/chemistry , Propofol/pharmacokinetics , Triglycerides/chemistry , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/chemistry , Animals , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Female , Infusion Pumps/veterinary , Male , Propofol/administration & dosage , Propofol/chemistry , Reproducibility of ResultsABSTRACT
Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed-effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living-donor liver transplantation (LDLT). Fentanyl was continuously infused at the rate of 200-400 µg/h throughout the operation. The time course of the fentanyl plasma concentration levels was best described in terms of a two-compartment model. Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V(1)) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) × 42.5, 113.0, and 189.0, respectively, × (body weight/69)(1.3); peripheral volume of distribution (V(2)) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 × (cardiac output (CO)/6.7)(2.5), 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Demography , Fentanyl/pharmacokinetics , Linear Models , Liver Transplantation , Living Donors , Adult , Analgesics, Opioid/adverse effects , Analgesics, Opioid/therapeutic use , Ascitic Fluid , Computer Simulation , Fentanyl/adverse effects , Fentanyl/therapeutic use , Humans , Hypertension, Portal/complications , Liver/drug effects , Liver/surgery , Metabolic Clearance Rate/drug effects , Middle Aged , Models, BiologicalABSTRACT
Defects are one of the most important factors influencing the optical properties of groups III-V nitride semiconductor materials and thereby their applicability to light-emitting diodes. In this paper, we demonstrate that it is possible to estimate the presence of defects in InGaN laser diodes by performing pump-probe measurements and observing the induced absorptions. We have confirmed that the induced absorption originates from defects by performing experiments in which the pump intensity is varied. We believe that our method provides a powerful tool for evaluating the optical quality of InGaN materials before processing them into device fabrications.
Subject(s)
Equipment Failure Analysis/methods , Gallium/chemistry , Indium/chemistry , Lasers, Semiconductor , Photometry/methods , ProtonsABSTRACT
BACKGROUND AND PURPOSE: Recently, we reported that 12(S)-HPETE (12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)-HPETE might act as an agonist of the low-affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)-HPETE-induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4'-[[pentanoyl (phenyl) amino]methyl]-1,1'-biphenyl-2-carboxylic acid) and 12(S)-HETE (12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid). EXPERIMENTAL APPROACH: A video recording was used to determine whether the BLT2 receptor agonists caused itch-associated scratching in ICR mice. Selective antagonists and several chemicals were used. KEY RESULTS: Both 12(S)-HETE and compound A dose dependently induced scratching in the ICR mice. The dose-response curve for compound A showed peaks at around 0.005-0.015 nmol per site. Compound A- and 12(S)-HETE-induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6-[6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl]-1,5-hexanediol, the BLT1 receptor antagonist) and LY255283 (1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone, the BLT2 receptor antagonist) on the BLT2 agonist-induced scratching. LY255283 suppressed compound A- and 12(S)-HETE-induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A-induced scratching than it did to suppress the 12(S)-HETE-induced scratching. One of the BLT(2) receptor agonists, 12(R)-HETE (12(R)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid), also induced scratching in the ICR mice. CONCLUSIONS AND IMPLICATIONS: Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)-lipoxygenase-product-induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.
Subject(s)
Arachidonate 12-Lipoxygenase/metabolism , Behavior, Animal , Pruritus/metabolism , Receptors, Leukotriene B4/metabolism , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/metabolism , Animals , Antipruritics/pharmacology , Behavior, Animal/drug effects , Capsaicin/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Fatty Alcohols/pharmacology , Glycols/pharmacology , Male , Mice , Mice, Inbred ICR , Naltrexone/pharmacology , Pruritus/chemically induced , Pruritus/prevention & control , Receptors, Leukotriene B4/drug effects , Signal Transduction/drug effects , Tetrazoles/pharmacology , Video RecordingABSTRACT
The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Revisiting of aerosol gene delivery may provide an alternative for safe and effective treatment for lung cancer. In this study, imidazole ring-containing urocanic acid-modified chitosan (UAC) designed in the previous study was used as a gene carrier. The potential effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) on Akt-related signals and cell cycle regulation were evaluated. Aerosols of UAC-PTEN were delivered into K-ras(LA1) lung cancer model mice through the nose-only inhalation system twice a week for total 4 weeks. Delivered PTEN suppressed lung tumor development significantly through nuclear complex formation between PTEN and p53, suppressing Akt-related signals as well as cell cycle regulation. Together, our results suggest that aerosol delivery of UAC-PTEN may be compatible with noninvasive in vivo gene therapy.
Subject(s)
Chitosan/pharmacology , Genes, ras , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , PTEN Phosphohydrolase/therapeutic use , Urocanic Acid/pharmacology , Administration, Inhalation , Aerosols , Animals , Disease Models, Animal , Gene Deletion , Genetic Vectors , Male , Mice , PTEN Phosphohydrolase/administration & dosage , PTEN Phosphohydrolase/geneticsABSTRACT
In biometrical genetic analyses of binary traits, the use of family data overcomes some limitations of twin studies, particularly in terms of sample size and types of genetic or environmental factors that can be estimated. However, because of computational problems, recent methods in the application of generalized linear mixed models for family data structure have limited the ability to handle large data sets with general covariates. In this paper, we investigate the use of the hierarchical likelihood approach to the analysis of binary traits from family data. In a simulation study, the method is shown to be highly accurate for the estimation of both the variance components and fixed regression parameters, even for small family sizes. For illustration, we analyze a real data set of familial aggregation of preeclampsia, a pregnancy-induced hypertension. When possible, the analysis is compared with the exact maximum likelihood approach.
Subject(s)
Analysis of Variance , Cytogenetic Analysis/methods , Genotype , Pre-Eclampsia/genetics , Quantitative Trait Loci/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Likelihood Functions , Linear Models , Models, Genetic , PregnancyABSTRACT
Some musical chords sound pleasant, or consonant, while others sound unpleasant, or dissonant. Helmholtz's psychoacoustic theory of consonance and dissonance attributes the perception of dissonance to the sensation of "beats" and "roughness" caused by interactions in the auditory periphery between adjacent partials of complex tones comprising a musical chord. Conversely, consonance is characterized by the relative absence of beats and roughness. Physiological studies in monkeys suggest that roughness may be represented in primary auditory cortex (A1) by oscillatory neuronal ensemble responses phase-locked to the amplitude-modulated temporal envelope of complex sounds. However, it remains unknown whether phase-locked responses also underlie the representation of dissonance in auditory cortex. In the present study, responses evoked by musical chords with varying degrees of consonance and dissonance were recorded in A1 of awake macaques and evaluated using auditory-evoked potential (AEP), multiunit activity (MUA), and current-source density (CSD) techniques. In parallel studies, intracranial AEPs evoked by the same musical chords were recorded directly from the auditory cortex of two human subjects undergoing surgical evaluation for medically intractable epilepsy. Chords were composed of two simultaneous harmonic complex tones. The magnitude of oscillatory phase-locked activity in A1 of the monkey correlates with the perceived dissonance of the musical chords. Responses evoked by dissonant chords, such as minor and major seconds, display oscillations phase-locked to the predicted difference frequencies, whereas responses evoked by consonant chords, such as octaves and perfect fifths, display little or no phase-locked activity. AEPs recorded in Heschl's gyrus display strikingly similar oscillatory patterns to those observed in monkey A1, with dissonant chords eliciting greater phase-locked activity than consonant chords. In contrast to recordings in Heschl's gyrus, AEPs recorded in the planum temporale do not display significant phase-locked activity, suggesting functional differentiation of auditory cortical regions in humans. These findings support the relevance of synchronous phase-locked neural ensemble activity in A1 for the physiological representation of sensory dissonance in humans and highlight the merits of complementary monkey/human studies in the investigation of neural substrates underlying auditory perception.