Differential Effects of Endocannabinoids on Amyloid-Beta Aggregation and Toxicity.

The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid ß (Aß) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aß aggregation and protect cells against Aß toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aß42 aggregation. They were able to provide protection against Aß42 induced cytotoxicity via receptor-mediated and non-receptor-mediated mechanisms in CB1-CHO and HT22 cells, respectively. The aggregation kinetic experiments demonstrate the anti-Aß aggregation activity of some endocannabinoids (AEA, noladin). These data demonstrate the potential role and application of endocannabinoids in AD pathology and treatment.

Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aß) Self-Aggregation Inhibitors.

Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-ß (Aß) deposition. Targeting the Aß pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Aß40 aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment. The CAP-gemini surfactants (18-7N(p1-4)-18) were evaluated as potential Aß40 peptide aggregation inhibitors by a fluorescence kinetic assay and for their binding interactions with Aß40 dimers by molecular docking studies. In vitro Aß40 peptide aggregation inhibition studies showed that the 18-7N(p3)-18 and 18-7N(p1)-18 ligands inhibit Aß40 peptide aggregation and prevent the formation of higher order structures. CDOCKER energies and CDOCKER interaction energies demonstrated that the CAP-gemini surfactants formed more stable complexes in the Aß40 dimer assembly and underwent both polar and nonpolar interactions compared to CAP peptides alone. Also, 18-7N(p3)-18 showed a significantly lower CDOCKER energy compared to that of the unmodified gemini surfactant 18-7NH-18 (p < 0.0001) and 18-7N(p4)-18 (p < 0.001), 18-7N(p1)-18, and 18-7N(p2)-18. Similarly, 18-7N(p3)-18 showed a significantly lower CDOCKER interaction energy compared to that of 18-7NH-18, 18-7N(p4)-18 (p < 0.0001), and 18-7N(p2)-18 (p < 0.001), while 18-7N(p3)-18 and 18-7N(p1)-18 showed similar CDOCKER interaction energies. These studies suggest that a combination of both hydrophobic and electrostatic interactions contributes to the anti-Aß40 aggregation activity of CAP-gemini surfactants. CAP-gemini surfactants showed 10-fold better Aß40 peptide aggregation inhibition compared to previously reported values and could provide a new opportunity for glaucoma treatment as dual-functional gene carriers.

Impact of COVID-19 infection among myasthenia gravis patients- a Cerner Real-World DataTM study.

BACKGROUND: Myasthenia gravis (MG) is an auto-immune disease, and the mainstay of therapy is immunomodulation. Such patients are at high risk of acquiring any infections. Hence, we sought to determine the impact of the current global pandemic COVID-19 infection in MG patients. METHODS: For our study, we used Cerner Real-World DataTM that was provided through Cerner's HealtheDataLab research tool. We ran a database query from January 2019 to July 2020 in our study and identified myasthenia patients with and without COVID-19 infection. To extract these patients' data, we used ICD 9-CM, ICD-10, and SNOMED-CT codes. We reported the data using means, range, and prevalence rates, and the p-values were calculated using the two-sample t-test and Pearson's chi-squared test. RESULTS: In the COVID-19 data set, a total of twenty-seven myasthenia patients were identified with a positive COVID-19 infection, and four were diagnosed with an exacerbation. The male to female ratio was equal and one unknown gender (3.7%) with a mean (± SD) age of 64.33 ± 18.42 years. This study group was compared with a non-COVID-19 data set in which a total of sixty-four myasthenia patients were identified, and twenty-three had an exacerbation. Among the 13 hospitalized patients in the two groups, the mean length of hospitalization for the myasthenia patients in the COVID-19 data set was 8.28 days (n = 7), and the non-COVID-19 set was 4.33 days (n = 6), and it was statistically significant (p-value= 0.007). CONCLUSIONS: The mean length of hospital stay is prolonged in myasthenia patients who tested positive for COVID-19.

Interactions of polyunsaturated fatty acids with amyloid peptides Aß40 and Aß42.

Polyunsaturated fatty acids (PUFAs) are reported to exert beneficial effects in Alzheimer's disease. Some PUFAs are known to reduce amyloid-beta (Aß) toxicity by promoting its degradation and clearance. Studies on the direct interactions of PUFAs with Aß peptides are limited and contradictory. In this study, we report the interactions of fatty acids docosahexaenoic acid (DHA), eicosatetraenoic acid (EPA), α-linolenic acid (ALA), arachidonic acid (ARA), linoleic acid (LNA) and oleic acid (OA) with Aß peptides by carrying out fluorescence based aggregation kinetic experiments, transmission electron microscopy and molecular docking studies. Our investigations demonstrate that all the fatty acids tested exhibit anti-aggregation properties by preventing both Aß40 and Aß42 fibrillogenesis (∼16-84% inhibition). OA and DHA were identified as excellent inhibitors of Aß40 or Aß42 fibrillogenesis respectively (∼84% and 81% inhibition at 25 µM). Molecular docking studies conducted, using the dimer and oligomer models of Aß40 peptide, suggest that these fatty acids interact in the aggregation prone Phe19-Ala21 and the ß-turn region (Asp23-Lys28) whereas a similar study with Aß42 dimer and oligomer models, indicate that the fatty acids were oriented in a hydrophobic region (Gln15, Leu16, Leu17 and Leu34). These results, suggest that DHA, EPA, ALA, ARA, LNA and OA are capable of directly interacting with both Aß40 and Aß42 peptides. These studies will have implications in developing potential therapeutics for Alzheimer's disease.

The effects of heat and freeze-thaw cycling on naloxone stability.

PURPOSE: The availability of take home naloxone (THN) was increased for Canadians in 2016, including access to kits via pharmacies. Unlike typical over-the-counter (OTC) and prescription drugs, THN kits may be stored in non-standard conditions, including in vehicles, backpacks, and out of doors. To evaluate whether these non-standard storage conditions affect stability, we investigated the impact of heat and freeze-thaw cycling on naloxone hydrochloride stability. METHODS: To assess the effect of heat, naloxone hydrochloride ampoules were exposed to 80 °C in a temperature-controlled oven for 8 h followed by 16 h at room temperature. To assess the effect of freeze-thaw cycles, naloxone hydrochloride ampoules were exposed to - 20 °C for 16 h followed by 8 h at 4 °C. The impact of these conditions on naloxone hydrochloride stability was evaluated each day for 1 week and after 2 and 4 weeks. The concentration of remaining naloxone hydrochloride was quantified using high-performance liquid chromatography (HPLC). Naloxone hydrochloride ampoules stored at room temperature served as the experimental control. RESULTS: Naloxone hydrochloride ampoules exhibit no changes in drug concentration following exposure to heat or freeze-thaw cycles for up to 28 days compared to ampoules maintained at room temperature (as indicated in the product monograph). CONCLUSIONS: Naloxone hydrochloride remains chemically stable following exposure to heat or freeze-thaw cycles after 28 days. If THN kits are stored in non-standard conditions (for up to 28 days) the active naloxone is likely to remain stable. Despite this, pharmacists should continue to emphasize the importance of appropriate storage of THN kits to ensure optimal efficacy should naloxone administration be required in an emergency situation.

Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles.

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.

Droplet Microfluidic System with On-Demand Trapping and Releasing of Droplet for Drug Screening Applications.

96-Well plate has been the traditional method used for screening drug compounds libraries for potential bioactivity. Although this method has been proven successful in testing dose-response analysis, the microliter consumption of expensive reagents and hours of reaction and analysis time call for innovative methods for improvements. This work demonstrates a droplet microfluidic platform that has the potential to significantly reduce the reagent consumption and shorten the reaction and analysis time by utilizing nanoliter-sized droplets as a replacement of wells. This platform is evaluated by applying it to screen drug compounds that inhibit the tau-peptide aggregation, a phenomena related to Alzheimer's disease. In this platform, sample reagents are first dispersed into nanolitre-sized droplets by an immiscible carrier oil and then these droplets are trapped on-demand in the downstream of the microfluidic device. The relative decrease in fluorescence through drug inhibition is characterized using an inverted epifluorescence microscope. Finally, the trapped droplets are released on-demand after each test by manipulating the applied pressures to the channel network which allows continuous processing. The testing results agree well with that obtained from 96-well plates with much lower sample consumption (∼200 times lower than 96-well plate) and reduced reaction time due to increased surface volume ratio (2.5 min vs 2 h).

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.

Synthesis and characterization of asymmetrical gemini surfactants.

The effect of variation in the length of surfactant hydrocarbon tail groups was tested in a series of dissymmetric gemini surfactants (N1-alkyl N1,N1,N3,N3-tetramethyl-N3-(6-pyren-6yl)-hexyl)propane-1,3-diammonium dibromide designated as CmC3CnBr, with m = hexyl pyrene, and n = 8, 12, 14, 16, and 18. The aggregation properties of these surfactants have been investigated by means of 1H NMR, fluorescence spectroscopy, surface tension and electrical conductivity measurements. The critical micelle concentration (CMC) was determined using surface tension and confirmed using the specific conductance method. Krafft temperatures and the degree of micelle ionization (α) were obtained from specific conductance measurements. With an increase of the dissymmetry (m/n) ratio, the CMC decreased linearly and an increase in the Krafft temperatures was observed for all of the gemini surfactants. α values for the dissymmetric GS were higher than those of the m-3-m counterparts, which may be attributed to enhanced micelle-micelle interactions that arise from increased hydrophobicity of the hydrocarbon chains. The introduction of the bulky pyrenyl tail group resulted in much lower CMC values compared to their symmetrical counterparts affecting the packing of these surfactants at the air/water interface, which resulted in high-ordered structures (lamellar and inverted micelles). This in turn affected the thermodynamic parameters of the micellization.

DISPAQ: Distributed Profitable-Area Query from Big Taxi Trip Data.

One of the crucial problems for taxi drivers is to efficiently locate passengers in order to increase profits. The rapid advancement and ubiquitous penetration of Internet of Things (IoT) technology into transportation industries enables us to provide taxi drivers with locations that have more potential passengers (more profitable areas) by analyzing and querying taxi trip data. In this paper, we propose a query processing system, called Distributed Profitable-Area Query (DISPAQ) which efficiently identifies profitable areas by exploiting the Apache Software Foundation's Spark framework and a MongoDB database. DISPAQ first maintains a profitable-area query index (PQ-index) by extracting area summaries and route summaries from raw taxi trip data. It then identifies candidate profitable areas by searching the PQ-index during query processing. Then, it exploits a Z-Skyline algorithm, which is an extension of skyline processing with a Z-order space filling curve, to quickly refine the candidate profitable areas. To improve the performance of distributed query processing, we also propose local Z-Skyline optimization, which reduces the number of dominant tests by distributing killer profitable areas to each cluster node. Through extensive evaluation with real datasets, we demonstrate that our DISPAQ system provides a scalable and efficient solution for processing profitable-area queries from huge amounts of big taxi trip data.

Nanoparticle induced miscibility in LCST polymer blends: critically assessing the enthalpic and entropic effects.

The use of copolymer and polymer blends widened the possibility of creating materials with multilayered architectures. Hierarchical polymer systems with a wide array of micro and nanostructures are generated by thermally induced phase separation (TIPS) in partially miscible polymer blends. Various parameters like the interaction between the polymers, concentration, solvent/non-solvent ratio, and quenching temperature have to be optimized to obtain these micro/nanophase structures. Alternatively, the addition of nanoparticles is another strategy to design materials with desired hetero-phase structures. The dynamics of the polymer nanocomposite depends on the statistical ordering of polymers around the nanoparticle, which is dependent on the shape of the nanoparticle. The entropic loss due to deformation of polymer chains, like the repulsive interactions due to coiling and the attractive interactions in the case of swelling has been highlighted in this perspective article. The dissipative particle dynamics has been discussed and is correlated with the molecular dynamics simulation in the case of polymer blends. The Cahn-Hillard-Cook model on variedly shaped immobile fillers has shown difference in the propagation of the composition wave. The nanoparticle shape has a contributing effect on the polymer particle interaction, which can change the miscibility window in the case of these phase separating polymer blends. Quantitative information on the effect of spherical particles on the demixing temperature is well established and further modified to explain the percolation of rod shaped particles in the polymer blends. These models correlate well with the experimental observations in context to the dynamics induced by the nanoparticle in the demixing behavior of the polymer blend. The miscibility of the LCST polymer blend depends on the enthalpic factors like the specific interaction between the components, and the solubility product and the entropic losses occurring due to the formation of any favorable interactions. Hence, it is essential to assess the entropic and enthalpic interactions induced by the nanoparticles independently. The addition of nanoparticles creates heterogeneity in the polymer phase it is localized. This can be observed as an alteration in the relaxation behavior of the polymer. This changes the demixing behavior and the interaction parameter between the polymers. The compositional changes induced due to the incorporation of nanoparticles are also attributed as a reason for the altered demixing temperature. The particle shape anisotropy causes a direction dependent depletion, which changes the phase behavior of the blend. The polymer-grafted nanoparticles with varying grafting density show tremendous variation in the miscibility of the blend. The stretching of the polymer chains grafted on the nanoparticles causes an entropy penalty in the polymer blend. A comparative study on the different shaped particles is not available up to date for understanding these aspects. Hence, we have juxtaposed the various computational studies on nanoparticle dynamics, the shape effect of NPs on homopolymers and also the cases of various polymer blends without nanoparticles to sketch a complete picture on the effect of various particles on the miscibility of LCST blends.

Querying and Extracting Timeline Information from Road Traffic Sensor Data.

The escalation of traffic congestion in urban cities has urged many countries to use intelligent transportation system (ITS) centers to collect historical traffic sensor data from multiple heterogeneous sources. By analyzing historical traffic data, we can obtain valuable insights into traffic behavior. Many existing applications have been proposed with limited analysis results because of the inability to cope with several types of analytical queries. In this paper, we propose the QET (querying and extracting timeline information) system-a novel analytical query processing method based on a timeline model for road traffic sensor data. To address query performance, we build a TQ-index (timeline query-index) that exploits spatio-temporal features of timeline modeling. We also propose an intuitive timeline visualization method to display congestion events obtained from specified query parameters. In addition, we demonstrate the benefit of our system through a performance evaluation using a Busan ITS dataset and a Seattle freeway dataset.

Positively Charged Chitosan and N-Trimethyl Chitosan Inhibit Aß40 Fibrillogenesis.

Amyloid fibrils, formed by aggregation of improperly folded or intrinsically disordered proteins, are closely related with the pathology of a wide range of neurodegenerative diseases. Hence, there is a great deal of interest in developing molecules that can bind and inhibit amyloid formation. In this regard, we have investigated the effect of two positively charged polysaccharides, chitosan (CHT) and its quarternary derivative N-trimethyl chitosan chloride (TMC), on the aggregation of Aß40 peptide. Our aggregation kinetics and atomic force microscopy (AFM) studies show that both CHT and TMC exhibit a concentration-dependent inhibiting activity on Aß40 fibrillogenesis. Systematic pH-dependent studies demonstrate that the attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues in Aß40 play a key role in this inhibiting activity. The stronger inhibiting activity of TMC than CHT further suggests the importance of charge density of the polymer chain in interacting with Aß40 and blocking the fibril formation. The possible interactions between CHT/TMC and Aß40 are also revealed at the atomic level by molecular docking simulation, showing that the Aß40 monomer could be primarily stabilized by electrostatic interactions with charged amines of CHT and quaternary amines of TMC, respectively. Binding of CHT/TMC on the central hydrophobic core region of Aß40 peptide may be responsible for blocking the propagation of the nucleus to form fibrillar structures. These results suggest that incorporation of sugar units such as d-glucosamine and N-trimethyl-d-glucosamine into polymer structural template may serve as a new strategy for designing novel antiamyloid molecules.

Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein.

The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00µM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01µM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63µM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23µM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500µM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).

In vitro COX-1 and COX-2 enzyme inhibitory activities of iridoids from Penstemon barbatus, Castilleja tenuiflora, Cresentia alata and Vitex mollis.

A group of sixteen iridoids isolated from plants used as anti-inflammatory remedies in Mexican folk medicine were evaluated for their potential to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. From these assays, loganic acid (10) was identified as the most promising compound with both COX-1 (36.0 ± 0.6%) and COX-2 (80.8 ± 4.0%) inhibition at 10 µM. Compound 10 shows a better inhibition against the COX-2 enzyme. Other iridoids tested in the present study showed weak or no inhibition against these enzymes. Furthermore, herein are presented key interactions of iridoid 10 with COX-1 and COX-2 enzymes through molecular docking studies. These studies suggest that 10 exhibits anti-inflammatory activity due to COX inhibition.

A-ring substituted 17ß-arylsulfonamides of 17ß-aminoestra-1,3,5(10)-trien-3-ol as highly potent reversible inhibitors of steroid sulfatase.

Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER(+) breast cancer. A series of 4-substituted 17ß-arylsulfonamides of 17ß-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a Ki(app) value of 1 nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 3'-Br, 3'-CF3, 4-NO2-3'-Br and 4-NO2-3'-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9-3.4 µM.

An alternative database approach for management of SNOMED CT and improved patient data queries.

OBJECTIVE: SNOMED CT is the international lingua franca of terminologies for human health. Based in Description Logics (DL), the terminology enables data queries that incorporate inferences between data elements, as well as, those relationships that are explicitly stated. However, the ontologic and polyhierarchical nature of the SNOMED CT concept model make it difficult to implement in its entirety within electronic health record systems that largely employ object oriented or relational database architectures. The result is a reduction of data richness, limitations of query capability and increased systems overhead. The hypothesis of this research was that a graph database (graph DB) architecture using SNOMED CT as the basis for the data model and subsequently modeling patient data upon the semantic core of SNOMED CT could exploit the full value of the terminology to enrich and support advanced data querying capability of patient data sets. METHODS: The hypothesis was tested by instantiating a graph DB with the fully classified SNOMED CT concept model. The graph DB instance was tested for integrity by calculating the transitive closure table for the SNOMED CT hierarchy and comparing the results with transitive closure tables created using current, validated methods. The graph DB was then populated with 461,171 anonymized patient record fragments and over 2.1 million associated SNOMED CT clinical findings. Queries, including concept negation and disjunction, were then run against the graph database and an enterprise Oracle relational database (RDBMS) of the same patient data sets. The graph DB was then populated with laboratory data encoded using LOINC, as well as, medication data encoded with RxNorm and complex queries performed using LOINC, RxNorm and SNOMED CT to identify uniquely described patient populations. RESULTS: A graph database instance was successfully created for two international releases of SNOMED CT and two US SNOMED CT editions. Transitive closure tables and descriptive statistics generated using the graph database were identical to those using validated methods. Patient queries produced identical patient count results to the Oracle RDBMS with comparable times. Database queries involving defining attributes of SNOMED CT concepts were possible with the graph DB. The same queries could not be directly performed with the Oracle RDBMS representation of the patient data and required the creation and use of external terminology services. Further, queries of undefined depth were successful in identifying unknown relationships between patient cohorts. CONCLUSION: The results of this study supported the hypothesis that a patient database built upon and around the semantic model of SNOMED CT was possible. The model supported queries that leveraged all aspects of the SNOMED CT logical model to produce clinically relevant query results. Logical disjunction and negation queries were possible using the data model, as well as, queries that extended beyond the structural IS_A hierarchy of SNOMED CT to include queries that employed defining attribute-values of SNOMED CT concepts as search parameters. As medical terminologies, such as SNOMED CT, continue to expand, they will become more complex and model consistency will be more difficult to assure. Simultaneously, consumers of data will increasingly demand improvements to query functionality to accommodate additional granularity of clinical concepts without sacrificing speed. This new line of research provides an alternative approach to instantiating and querying patient data represented using advanced computable clinical terminologies.

Multidetector CT evaluation of airway stents: what the radiologist should know.

Airway stents are increasingly used to treat symptomatic patients with obstructive tracheobronchial diseases who are not amenable to surgical resection or who have poor performance status, precluding them from resection. The most common conditions that are treated with tracheobronchial stents are primary lung cancer and metastatic disease. However, stents have also been used to treat patients with airway stenosis related to a variety of benign conditions, such as tracheobronchomalacia, relapsing polychondritis, postintubation tracheal stenosis, postoperative anastomotic stenosis, and granulomatous diseases. Additionally, airway stents can be used as a barrier method in the management of esophagorespiratory fistulas. Many types of stents are available from different manufacturers. Principally, they are classified as silicone; covered and uncovered metal; or hybrid, which are made of silicone and reinforced by metal rings. The advantages and disadvantages of each type of airway stent are carefully considered when choosing the most appropriate stent for each patient. Multidetector computed tomography plays an important role in determining the cause and assessing the location and extent of airway obstruction. Moreover, it is very accurate in its depiction of complications after airway stent placement.

N-Benzyl-2-chloro-quinazolin-4-amine.

The asymmetric unit of the title compound, C15H12ClN3, contains two independent mol-ecules. The quinazoline ring system in each is essentially planar, with maximum deviations of 0.025 (16) and 0.0171 (16) Å. The dihedral angles between quinazoline ring systems and the phenyl rings are 88.25 (8) and 85.28 (16)° in the two independent mol-ecules. In the crystal, alternating independent mol-ecules are linked by N-H⋯N hydrogen bonds, forming chains along [001].

Post-Translational Modifications in Tau and Their Roles in Alzheimer's Pathology.

Microtubule-Associated Protein Tau (also known as tau) has been shown to accumulate into paired helical filaments and neurofibrillary tangles, which are known hallmarks of Alzheimer's disease (AD) pathology. Decades of research have shown that tau protein undergoes extensive post-translational modifications (PTMs), which can alter the protein's structure, function, and dynamics and impact the various properties such as solubility, aggregation, localization, and homeostasis. There is a vast amount of information describing the impact and role of different PTMs in AD pathology and neuroprotection. However, the complex interplay between these PTMs remains elusive. Therefore, in this review, we aim to comprehend the key post-translational modifications occurring in tau and summarize potential connections to clarify their impact on the physiology and pathophysiology of tau. Further, we describe how different computational modeling methods have helped in understanding the impact of PTMs on the structure and functions of the tau protein. Finally, we highlight the tau PTM-related therapeutics strategies that are explored for the development of AD therapy.