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1
Nakaminami, Masamitsu, Tsutomu Tokuma, Kazuhiko Matsumoto, Sachinori Sakashita, Toshimichi Moriwaki, and Keiichi Nakamoto. "Optimal Structure Design Methodology for Compound Multiaxis Machine Tools - II - Investigation of Basic Structure -." International Journal of Automation Technology 1, no. 2 (November 5, 2007): 87–93. http://dx.doi.org/10.20965/ijat.2007.p0087.
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Compound multiaxis machine tools are used to machine high-value-added parts through integrating milling and turning. Compound machine tools are generally structured based on a conventional NC lathe by incorporating Y axis and automatic tool changer (ATC) components for milling. Due to complexity of the structure and functional versatility required for a compound machine tool, accuracy, productivity, and return on investment (ROI) must be improved over conventional NC lathes and machining centers. In the sections that follow, we discuss design methodology for compound multiaxis machine tools, focusing on the design of an optimal basic structure for high accuracy and high productivity. We propose a box in box structure, a movable column-Y axis, and a boring machine structure. We analyzed static rigidity, dynamic features, and movement accuracy of machine structures theoretically using FEM for three proposed structures. We found that the box in box structure is suitable for compound multiaxis machine tools to achieve high accuracy and high productivity.
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Sun, Xing Wei, Wan Tao Liu, You Jun Zhang, and Ke Wang. "The Influence of Following Error of Servo System on Machining Precision for NC Machine Tool." Advanced Materials Research 118-120 (June 2010): 841–45. http://dx.doi.org/10.4028/www.scientific.net/amr.118-120.841.
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The characteristic of servo system is an important data to influence the mechanical working properties of NC machine tool. In this paper, based on servo system characteristic, the cause of following error has been studied. It discussed the effect on machining precision of following error on part contour when machining circular contour. Then some calculation equations have been worked out. In order to reduce the following error, the method of compound control has been advanced in the last, and it has been proved to be a feasible way to reduce the influence of follow error on machining contour of NC machine tool.
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Scholle, Michael D., Doug McLaughlin, and Zachary A. Gurard-Levin. "High-Throughput Affinity Selection Mass Spectrometry Using SAMDI-MS to Identify Small-Molecule Binders of the Human Rhinovirus 3C Protease." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 8 (June 19, 2021): 974–83. http://dx.doi.org/10.1177/24725552211023211.
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Affinity selection mass spectrometry (ASMS) has emerged as a powerful high-throughput screening tool used in drug discovery to identify novel ligands against therapeutic targets. This report describes the first high-throughput screen using a novel self-assembled monolayer desorption ionization (SAMDI)–ASMS methodology to reveal ligands for the human rhinovirus 3C (HRV3C) protease. The approach combines self-assembled monolayers of alkanethiolates on gold with matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry (MS), a technique termed SAMDI-ASMS. The primary screen of more than 100,000 compounds in pools of 8 compounds per well was completed in less than 8 h, and informs on the binding potential and selectivity of each compound. Initial hits were confirmed in follow-up SAMDI-ASMS experiments in single-concentration and dose–response curves. The ligands identified by SAMDI-ASMS were further validated using differential scanning fluorimetry (DSF) and in functional protease assays against HRV3C and the related SARS-CoV-2 3CLpro enzyme. SAMDI-ASMS offers key benefits for drug discovery over traditional ASMS approaches, including the high-throughput workflow and readout, minimizing compound misbehavior by using smaller compound pools, and up to a 50-fold reduction in reagent consumption. The flexibility of this novel technology opens avenues for high-throughput ASMS assays of any target, thereby accelerating drug discovery for diverse diseases.
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Wazir, Sarah, Mirko M. Maksimainen, Heli I. Alanen, Albert Galera-Prat, and Lari Lehtiö. "Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 1 (June 12, 2020): 67–76. http://dx.doi.org/10.1177/2472555220928911.
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ADP-ribosylation is a post-translational modification involved in the regulation of many vital cellular processes. This posttranslational modification is carried out by ADP-ribosyltransferases converting β-NAD+ into nicotinamide and a protein-linked ADP-ribosyl group or a chain of PAR. The reverse reaction, release of ADP-ribose from the acceptor molecule, is catalyzed by ADP-ribosylhydrolases. Several hydrolases contain a macrodomain fold, and activities of human macrodomain protein modules vary from reading or erasing mono- and poly-ADP-ribosylation. Macrodomains have been linked to diseases such as cancer, making them potential drug targets. Discovery of inhibitors requires robust biochemical tools mostly lacking for hydrolases, and here we describe an inhibitor screening assay against mono-ADP-ribosylhydrolyzing enzymes. The activity-based assay uses an α-NAD+, anomer of β-NAD+, which is accepted as a substrate by MacroD1, MacroD2, and ARH3 due to its resemblance to the protein-linked ADP-ribose. The amount of α-NAD+ present after hydrolysis is measured by chemically converting it on a microtiter plate to a fluorescent compound. We optimized the assay for MacroD2 and performed a proof-of-concept compound screening. Three compounds were identified as screening hits with micromolar potency. However, further characterization of the compounds identified them as protein destabilizers, excluding further follow-up studies. Validation and screening demonstrated the usability of the in vitro assay for MacroD2, and we also demonstrate the applicability of the assay as a tool for other human ADP-ribosylhydrolases.
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Pa, Pai Shan. "Design of Surface Finish Using Compound Processes of Grinding and Electrochemical Finishing Following Turning." Key Engineering Materials 373-374 (March 2008): 782–85. http://dx.doi.org/10.4028/www.scientific.net/kem.373-374.782.
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A new finish method uses an effective electrode connecting with a nonconductive grinding tool to execute the design of compound processes of electrochemical finishing and grinding following turning is investigated. The submitted processes can be used for various turning operations. Through simple equipment attachment, electrochemical finishing and grinding can follow to execute the finishing process on the same machine. Among the factors affecting electrochemical finishing the performance of grinding combined with electrochemical finishing is primarily discussed. In the experiment, the electrode is used with continuous and pulsed direct current. The grinding tool moves following the electrode and grinds the workpiece surface. The experimental parameters are electrical current rating, feed rate of electrode and grinding tool, rotational speed of workpiecel, pulsed period, and geometry of finish-tool. The results show that pulsed direct current with longer off-time can slightly improve the finish effect for its dregs discharge mobility. Using an adequate rotational speed of workpiece with high rotational speed is advantageous to the finish effect. A thinner plate-form electrode with a smaller end radius is associated with larger discharge space and produces higher current density and provides faster feed rate and a better finish effect. The grinding can effectively increase the finish effect. An effective and a low-cost finish process through the design electrode and using the grinding assistance in the electrochemical finishing after turning process make the surface of workpiece smooth and bright.
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Iqbal, Zarina, and Saima Sadaf. "Sitagliptin (Januvia) patent litigation: Another link in the judicial train of ‘Proactive Infringement’ of patented rights in developing countries." Journal of Generic Medicines: The Business Journal for the Generic Medicines Sector 16, no. 2 (March 29, 2020): 64–71. http://dx.doi.org/10.1177/1741134320912776.
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Driven by increasing instances of successful ‘at-risk’ launch of patented drugs in America and Europe, the strategy of using ‘proactive infringement’ as a legal tool is now getting-in, in developing countries. The rationale behind launch-at-risk is to counterbalance the innovator companies’ strategies of getting the patented product life extended through protecting improvement innovations and maintain market exclusivity even after the expiration of the compound patent. The battle for market and drive for higher profits between generics and innovator drug companies has extended the application of at-risk launch of the generic drugs even when compound patent is still running. Sitagliptin (Januvia) may be ranked at top of the drugs that have been fiercely litigated in the developing countries during their patent term. This article reviews the outcome of sitagliptin patent litigation and impact on the market exclusivity in some developing countries. This takes the position that the existing conflict between the innovators and generics can be resolved by diluting the misconception that patents on improvement innovations are misuse of patent system or inappropriate extension of patented product life on the part of innovator companies. Whether trivial, simplified or complex, if novel and non-obvious, further improvements in the precursor drugs are patentable within the legal framework of the patent system. The real issue is the scope of monopoly granted to the secondary or follow-on patents. Once the compound patent has expired, follow-on patents on improvements relating to the same compound should not be allowed to use as legal-barrier for the generic medicines entry to the market.
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Metz, Alexander, Jan Wollenhaupt, Steffen Glöckner, Niki Messini, Simon Huber, Tatjana Barthel, Ahmed Merabet, et al. "Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking." Acta Crystallographica Section D Structural Biology 77, no. 9 (August 23, 2021): 1168–82. http://dx.doi.org/10.1107/s2059798321008196.
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In recent years, crystallographic fragment screening has matured into an almost routine experiment at several modern synchrotron sites. The hits of the screening experiment, i.e. small molecules or fragments binding to the target protein, are revealed along with their 3D structural information. Therefore, they can serve as useful starting points for further structure-based hit-to-lead development. However, the progression of fragment hits to tool compounds or even leads is often hampered by a lack of chemical feasibility. As an attractive alternative, compound analogs that embed the fragment hit structurally may be obtained from commercial catalogs. Here, a workflow is reported based on filtering and assessing such potential follow-up compounds by template docking. This means that the crystallographic binding pose was integrated into the docking calculations as a central starting parameter. Subsequently, the candidates are scored on their interactions within the binding pocket. In an initial proof-of-concept study using five starting fragments known to bind to the aspartic protease endothiapepsin, 28 follow-up compounds were selected using the designed workflow and their binding was assessed by crystallography. Ten of these compounds bound to the active site and five of them showed significantly increased affinity in isothermal titration calorimetry of up to single-digit micromolar affinity. Taken together, this strategy is capable of efficiently evolving the initial fragment hits without major synthesis efforts and with full control by X-ray crystallography.
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Rietz, Anne, Kevin J. Hodgetts, Hrvoje Lusic, Kevin M. Quist, Erkan Y. Osman, Christian L. Lorson, and Elliot J. Androphy. "Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy." Life Science Alliance 4, no. 1 (November 24, 2020): e202000889. http://dx.doi.org/10.26508/lsa.202000889.
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Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.
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Cohen, Y. C., S. Hassin-Baer, L. Olmer, R. Barishev, Y. Goldhammer, L. Freedman, and B. Mozes. "MS-CANE: a computer-aided instrument for neurological evaluation of patients with multiple sclerosis: enhanced reliability of expanded disability status scale (EDSS) assessment." Multiple Sclerosis Journal 6, no. 5 (October 2000): 355–61. http://dx.doi.org/10.1177/135245850000600511.
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Kurtzke's EDSS remains the most widely-used measure for clinical evaluation of MS patients. However, several studies have demonstrated the limited reliability of this tool. We introduce a computerized instrument, MS-CANE (Multiple Sclerosis Computer-Aided Neurological Examination), for clinical evaluation and follow up of patients with multiple sclerosis (MS) and to compare its reliability to that of conventional Expanded Disability Status Scale (EDSS) assessment. We developed a computerized interactive instrument, based on the following principles: structured gathering of neurological findings, reduction of compound notions to their basic components, use of precise definitions, priority setting and automated calculations of EDSS and functional systems scores. An expert panel examined the consistency of MS-CANE with Kurtzke's specifications. To determine the effect of MS-CANE on the reliability of EDSS assessment, 56 MS patients underwent paired conventional EDSS and MS-CANE-based evaluations. The inter-observer agreement in both methods was determined and compared using the kappa statistic. The expert panel judged the tool to be compatible with the basic concepts of Kurtzke's EDSS. The use of MS-CANE increased the reliability of EDSS assessment: Kappa statistic was found to be 0.42 (i.e. moderate agreement) for conventional EDSS assessment versus 0.69 (i.e. substantial agreement) for MS-CANE (P=0.002). We conclude that the use of this tool may contribute towards a standardized and reliable assessment of EDSS. Within clinical trials, this could increase the power to detect effects, thus reducing trial duration and the cohort size required.
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Kashyap, Surender, and Anjali Solanki. "Challenges in Endobronchial Tuberculosis: From Diagnosis to Management." Pulmonary Medicine 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/594806.
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Despite the rapid advancement in diagnostic and therapeutic modalities, endobronchial tuberculosis (EBTB), defined as tuberculous infection of the tracheobronchial tree, continues to remain challenging for clinicians. Nonspecific respiratory symptoms along with normal chest radiograph in 10–20% of cases may be alleged for the diagnostic delay. Variable diagnostic yield with sputum microscopy might further compound the problem. In such cases, high resolution computed tomography (HRCT) works as a more sensitive tool and demonstrates involvement of tracheobronchial tree described classically as “tree-in-bud” appearance. Bronchoscopic biopsy is considered the most reliable method for confirmation of the diagnosis with 30% to 84% positivity in different series. Evolution of the disease is also unpredictable with frequent progression to bronchostenosis, therefore requiring regular follow-up and early intervention to halt the natural course. This review article elaborates various aspects of the disease with specific focus on diagnostic dilemma and recent advances in interventional bronchoscopy. In addition, this discussion evokes optimism for further research and introduction of innovative therapeutic modalities.
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Peters, Kristian, Gerd Balcke, Niklas Kleinenkuhnen, Hendrik Treutler, and Steffen Neumann. "Untargeted In Silico Compound Classification—A Novel Metabolomics Method to Assess the Chemodiversity in Bryophytes." International Journal of Molecular Sciences 22, no. 6 (March 23, 2021): 3251. http://dx.doi.org/10.3390/ijms22063251.
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In plant ecology, biochemical analyses of bryophytes and vascular plants are often conducted on dried herbarium specimen as species typically grow in distant and inaccessible locations. Here, we present an automated in silico compound classification framework to annotate metabolites using an untargeted data independent acquisition (DIA)–LC/MS–QToF-sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH) ecometabolomics analytical method. We perform a comparative investigation of the chemical diversity at the global level and the composition of metabolite families in ten different species of bryophytes using fresh samples collected on-site and dried specimen stored in a herbarium for half a year. Shannon and Pielou’s diversity indices, hierarchical clustering analysis (HCA), sparse partial least squares discriminant analysis (sPLS-DA), distance-based redundancy analysis (dbRDA), ANOVA with post-hoc Tukey honestly significant difference (HSD) test, and the Fisher’s exact test were used to determine differences in the richness and composition of metabolite families, with regard to herbarium conditions, ecological characteristics, and species. We functionally annotated metabolite families to biochemical processes related to the structural integrity of membranes and cell walls (proto-lignin, glycerophospholipids, carbohydrates), chemical defense (polyphenols, steroids), reactive oxygen species (ROS) protection (alkaloids, amino acids, flavonoids), nutrition (nitrogen- and phosphate-containing glycerophospholipids), and photosynthesis. Changes in the composition of metabolite families also explained variance related to ecological functioning like physiological adaptations of bryophytes to dry environments (proteins, peptides, flavonoids, terpenes), light availability (flavonoids, terpenes, carbohydrates), temperature (flavonoids), and biotic interactions (steroids, terpenes). The results from this study allow to construct chemical traits that can be attributed to biogeochemistry, habitat conditions, environmental changes and biotic interactions. Our classification framework accelerates the complex annotation process in metabolomics and can be used to simplify biochemical patterns. We show that compound classification is a powerful tool that allows to explore relationships in both molecular biology by “zooming in” and in ecology by “zooming out”. The insights revealed by our framework allow to construct new research hypotheses and to enable detailed follow-up studies.
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Lv, Meng, Jingwen Deng, Nan Tang, Yuejin Zeng, and Chuanjian Lu. "Efficacy and Safety of Tripterygium Wilfordii Hook F on Psoriasis Vulgaris: A Systematic Review and Meta-Analysis of Randomized Controlled Trials." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/2623085.
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Background. Psoriasis is a chronic autoimmune-mediated skin disease that is characterized by persistent localized erythematous scaly plaque. Tripterygium wilfordii Hook F (TwHF), a well-known Chinese medicine that has been used for centuries in China to treat immune diseases, inflammation, and tumor, is accompanied by a degree of toxic effects. Its clinical efficacy and safety on psoriasis are incompletely understood. Aim. To summarize evidence concerning the efficacy and safety of TwHF in treating psoriasis. Methods. EMBASE, Ovid MEDLINE, PubMed, Web of Science, Springer, Cochrane Library, CNKI, CBM, Wanfang, and VIP database were searched up to October 2017. The included literature was assessed and extracted by two independent reviewers. To enhance the available evidence, a systematic review was performed to examine all relevant published literature relating to randomized controlled trials (RCTs) of TwHF. Relative ratios (RRs) and 95% confidence intervals (CIs) were calculated, and a meta-analysis was conducted with RevMan 5.3 software. Results. Twenty eligible RCTs with 1872 participants were included for systematic review and meta-analysis. Studies were assessed using the Cochrane risk of bias tool. The meta-analysis of add-on effect of TwHF conferred benefit for psoriasis: combination treatment with compound glycyrrhizin (four studies, OR = 0.34, 95% CI 0.22–0.52, P<0.00001, I2=0%), combination treatment with acitretin (three studies, OR = 0.25, 95% CI 0.10–0.63, P=0.003, I2=50%), and combination treatment with compound amino-polypeptide tablet (three studies, OR = 0.37, 95% CI 0.22–0.63, P=0.0002, I2=0%). Conclusions. Despite several mild side effects of TwHF, there is evidence that TwHF is an effective therapy for psoriasis. However, the conclusions are limited by the small number of included trials. More well-designed RCTs with extensive follow-up periods are warranted to clarify the effects and safety of TwHF in treating psoriasis. Trial Registration. This review was registered in the International Prospective Register of Systematic Reviews (CRD42016041363).
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Wróbel, Konrad, and Stanisław Wołowiec. "Low generation polyamidoamine dendrimers (PAMAM) and biotin-PAMAM conjugate – the detailed structural studies by 1H and 13C nuclear magnetic resonance spectroscopy." European Journal of Clinical and Experimental Medicine 18, no. 4 (2021): 281–85. http://dx.doi.org/10.15584/ejcem.2020.4.4.
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Introduction. The concept of targeted drug delivery is nowadays based on nanoparticle transporters. Such drug delivery systems for cancer cells should follow the requirements like: efficient drug release, selective binding and internalization to cancer cells. The anticancer drug selectivity can be achieved by attachment of cancer cell-recognizing molecules, like biotin. Among nanosized carriers the PAMAM dendrimers are tested intensely, especially they can be modified by covalent attachment of prodrug molecules and biotin as targeting molecule. Aim. We aimed at construction and characterization of a conjugate formed between PAMAM and biotin (Biot). The nuclear magnetic resonances is powerful tool to determine both the structure and stoichiometry of the conjugate. Material and methods. PAMAM G0 has been synthesized and functionalized with biotin by reaction with N-hydroxysuccinimide ester of biotin to obtain G0 double-substituted with biotin. All the compound were thoroughly characterized by the NMR spectroscopy. Results. The conjugate of PAMAM G0 dendrimer with two amide-bonded biotin molecules was obtained and fully characterized by NMR spectroscopy. Conclusion. N-hydroxysuccinimide ester of biotin spontaneously reacts with PAMAM G0 to obtain the conjugate of 2:1 biotin: G0 stoichiometry. The latter was designed as a targeting molecule in formation of megameric multidrug delivery system.
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N., Ezhilvathani, Suruthi P., and Jeiganesh M. "Profile of refractive errors and amblyopia in 5-15 yrs of school going children at a Union territory tertiary health centre." International Journal of Research in Medical Sciences 7, no. 5 (April 26, 2019): 1929. http://dx.doi.org/10.18203/2320-6012.ijrms20191703.
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Background: Poor vision in childhood affects performance in school and has a significant impact on future life of child in terms of education and development. Current study aims at detecting the magnitude and patterns of refractive errors with amblyopia screening so that effective measures can be planned at the right time to minimize the burden.Methods: Hospital based cross sectional study conducted on 200 children between 5-15 years attending the ophthalmology OPD of a tertiary health care centre, Puducherry. Interpretation and data analysis were done by SPSS software version 13.0.Results: Mean age of presentation was 9 years. Female to male ratio in the present study was 1.3:1. Positive family history was noted among 48 children suggesting strong impact of genetic factor in refractive errors. Among 20 children who were already on spectacle correction, the most common refractive error was compound myopic astigmatism. Among 30 children who were diagnosed with amblyopia, 8 children below 8 years of age had improved vision on 1 month follow up of post treatment with spectacles and occlusion therapy and 22 children did not show improvement suggesting amblyopia can be corrected if intervention was instituted before the age of 8 years.Conclusions:Refractive errors with or without amblyopia is a significant cause of childhood visual impairment. Though it is a hospital-based study, the results were in consistent with previously published hospital and population based study. This study also expected to serve as a tool for primary health care physicians to have an overview of magnitude and patterns of refractive errors in children presenting to hospital since refractive error is a significant public health problem worldwide.Background: Poor vision in childhood affects performance in school and has a significant impact on future life of child in terms of education and development. Current study aims at detecting the magnitude and patterns of refractive errors with amblyopia screening so that effective measures can be planned at the right time to minimize the burden.Methods: Hospital based cross sectional study conducted on 200 children between 5-15 years attending the ophthalmology OPD of a tertiary health care centre, Puducherry. Interpretation and data analysis were done by SPSS software version 13.0.Results: Mean age of presentation was 9 years. Female to male ratio in the present study was 1.3:1. Positive family history was noted among 48 children suggesting strong impact of genetic factor in refractive errors. Among 20 children who were already on spectacle correction, the most common refractive error was compound myopic astigmatism. Among 30 children who were diagnosed with amblyopia, 8 children below 8 years of age had improved vision on 1 month follow up of post treatment with spectacles and occlusion therapy and 22 children did not show improvement suggesting amblyopia can be corrected if intervention was instituted before the age of 8 years.Conclusions: Refractive errors with or without amblyopia is a significant cause of childhood visual impairment. Though it is a hospital-based study, the results were in consistent with previously published hospital and population based study. This study also expected to serve as a tool for primary health care physicians to have an overview of magnitude and patterns of refractive errors in children presenting to hospital since refractive error is a significant public health problem worldwide.
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von Barnekow, Ariel, Núria Bonet-Codina, and Dani Tost. "Can 3D Gamified Simulations Be Valid Vocational Training Tools for Persons with Intellectual Disability?" Methods of Information in Medicine 56, no. 02 (2017): 162–70. http://dx.doi.org/10.3414/me16-02-0014.
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SummaryObjective: To investigate if 3D gamified simulations can be valid vocational training tools for persons with intellectual disability.Methods: A 3D gamified simulation composed by a set of training tasks for cleaning in hostelry was developed in collaboration with professionals of a real hostel and pedagogues of a special needs school. The learning objectives focus on the acquisition of vocabulary skills, work procedures, social abilities and risk prevention. Several accessibility features were developed to make the tasks easy to do from a technological point-of-view. A pilot experiment was conducted to test the pedagogical efficacy of this tool on intellectually disabled workers and students.Results: User scores in the gamified simulation follow a curve of increasing progression. When confronted with reality, they recognized the scenario and tried to reproduce what they had learned in the simulation. Finally, they were interested in the tool, they showed a strong feeling of immersion and engagement, and they reported having fun.Conclusions: On the basis of this experiment we believe that 3D gamified simulations can be efficient tools to train social and professional skills of persons with intellectual disabilities contributing thus to foster their social inclusion through work.
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Panchal, Ishan I., Sandip N. Badeliya, Rakesh Patel, Ashish Patel, and Animesh Devaligar. "In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3- (Isoquinolin-4-yl)-1H-Pyrazolo[3,4-d]Pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors." Current Drug Discovery Technologies 16, no. 3 (October 14, 2019): 297–306. http://dx.doi.org/10.2174/1568009618666181102144934.
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Background: mTORC1/ PI3K control multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, are all important for cell and tissue growth. Sapanisertib and Dactolisib inhibit PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Methods: Dactolisib contains quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin scaffold and Sapanisertib contains benzo[d]oxazol-5-yl-1-ethyl-1H-pyrazolo[3,4-d]pyrimidinnucleous. From the reference to both of drug novel series of 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin was developed by molecular docking. In sillico analysis was done with SWISSADME online tools. Results: Among all the designed derivatives, compounds 6(-10.6 kcal/mol) , 12( -10.7 kcal/mol), 14( -10.2 kcal/mol), and 16(-10.2 kcal/mol) have a good binding affinity than others. Biological activity was predicted by Molinspirationonline software tool showing that all compounds are active on G- protein coupled receptor. In silico toxicity profile of designed compounds was performed using the SWISSADME program, indicating that all the compounds follow the Lipinski rule of five and do not penetrate Blood brain barrier. Conclusion: Series of pyrazolo[3,4-d]pyrimidin derivatives gives good binding affinity with pan- PI3-Kinese/Mtor inhibitors. The present study provided a better understanding of the molecular modeling requisite for maintaining and/or improving PI3K/mTOR inhibitors.
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Bebbere, D., S. Pirino, L. Bogliolo, F. Ariu, E. Pintus, S. Nieddu, S. Pau, and S. Ledda. "124 EXPRESSION OF PLURIPOTENCY MARKERS IN GENITAL RIDGES OF OVINE FOETUSES." Reproduction, Fertility and Development 22, no. 1 (2010): 221. http://dx.doi.org/10.1071/rdv22n1ab124.
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Fundamental problems of primordial germ cell (PGC) allocation, characterization, lineage restriction, and differentiation have been extensively studied in the mouse. Historically, these cells can be identified using criteria as alkaline phosphatase, but also by the expression of other pluripotency markers suchas OCT4, Nanog, cKIT, SSEA1, SSEA4. Much less is known about PGC inother mammals. The objective ofthis study wasto describe, for the first time, the expression of multiple pluripotency markers in the genital ridges of ovine fetuses evaluating the binding of antibodies for stem cell surface markers (SSEA-1 and EMA-1) and the expression of Oct4, Nanog, and Sox2 genes. Ovine fetuses (24 and 27 days) were collected from slaughtered ewes and transported in a PBS solution at 4°C, to be processed as follows: Immunohistochemistry: 4 foetuses for each age were frozen in OCT TissueTek freezing compound and stored at -80°C. Tissue blocks were cut in 6-μm sections, placed on slides, and immediately prepared for indirect immunofluorescent staining. Section were fixed in 4% paraformaldehyde (10 min) and incubated overnight with SSEA-1 (1:100) and EMA-1 (1:50) antibodies (Hybridoma bank). Antibodies were detected with fluorescently-labelled goat anti-mouse secondary antibodies (1:100 dilution; Sigma) in 15% goat serum in DPBS for 1 h at room temperature. After washing, slides were mounted using ProLong antifade mounting medium (Molecular Probes). Gene expression: total RNA was extracted from fetal genital ridge samples with Trizol™ (Invitrogen). Any contaminating DNA was removed with RNase-free DNase I (Invitrogen). First strand cDNA synthesis was performed with SuperScript™ III RNase H-Reverse Transcriptase (Invitrogen) in the presence of RNase inhibitor (Promega). Real Time PCR amplification was performed in a BioRad iCycler™, with Platinum SYBR Green qPCR Super Mix UDG (Invitrogen). The relative quantification of the target genes was calculated with the 2-ddCt method (Livak and Schmittgen 2001 Methods 25, 402-408), after normalization against β-actin expression levels. Fragment identity was confirmed by sequencing. Our results indicate that the cortical region of the genital ridges is positive to stem cell surface markers. A larger number of positive cells was recorded in Day 24 fetuses with respect to Day 27 ones. The SSEA-1 and EMA-1 showed identical expression patterns. Similar levels of Oct4 and Nanog mRNA were detected in the genital ridges at both stages, whereas Sox2 displayed a lower abundance at Day 27. In conclusion, ovine PGC can be recognized by stem cell surface antigens and by the expression of Oct4, Nanog, and Sox2 pluripotency markers, as in mouse. The combined biomolecular and immunohistochemical approach provides a useful tool to follow the ovine PGC during in vitro culture to derive pluripotent stem cells in this species.
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da Silva, Rosivaldo Xavier, Carlos William de Araujo Paschoal, Clenilton Costa dos Santos, Alberto García-Fernández, Jorge Salgado-Beceiro, María Antonia Señarís-Rodríguez, Manuel Sanchez-Andujar, and Ariel Nonato Almeida de Abreu Silva. "Raman Spectroscopy Studies on the Barocaloric Hybrid Perovskite [(CH3)4N][Cd(N3)3]." Molecules 25, no. 20 (October 16, 2020): 4754. http://dx.doi.org/10.3390/molecules25204754.
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Temperature-dependent Raman scattering and differential scanning calorimetry were applied to the study of the hybrid organic-inorganic azide-perovskite [(CH3)4N][Cd(N3)3], a compound with multiple structural phase transitions as a function of temperature. A significant entropy variation was observed associated to such phase transitions, |∆S| ~ 62.09 J·kg−1 K−1, together with both a positive high barocaloric (BC) coefficient |δTt/δP| ~ 12.39 K kbar−1 and an inverse barocaloric (BC) coefficient |δTt/δP| ~ −6.52 kbar−1, features that render this compound interesting for barocaloric applications. As for the obtained Raman spectra, they revealed that molecular vibrations associated to the NC4, N3– and CH3 molecular groups exhibit clear anomalies during the phase transitions, which include splits and discontinuity in the phonon wavenumber and lifetime. Furthermore, variation of the TMA+ and N3– modes with temperature revealed that while some modes follow the conventional red shift upon heating, others exhibit an unconventional blue shift, a result which was related to the weakening of the intermolecular interactions between the TMA (tetramethylammonium) cations and the azide ligands and the concomitant strengthening of the intramolecular bondings. Therefore, these studies show that Raman spectroscopy is a powerful tool to gain information about phase transitions, structures and intermolecular interactions between the A-cation and the framework, even in complex hybrid organic-inorganic perovskites with highly disordered phases.
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COMI, Antonio, Berta BUTTARAZZI, Massimiliano SCHIRALDI, Rosy INNARELLA, Martina VARISCO, and Paolo TRAINI. "An advanced planner for urban freight delivering." Archives of Transport 4, no. 48 (December 31, 2018): 27–40. http://dx.doi.org/10.5604/01.3001.0012.8363.
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The paper aims at introducing an advanced delivery tour planner to support operators in urban delivery operations through a combined approach which chooses delivery bays and delivery time windows while optimizing the delivery routes. After a literature review on tools for the management and the control of the delivery system implemented for optimizing the usage of on-street delivery bays, a prototypical tour delivery planner is described. The tool allows transport and logistics operators to book the delivery bays and to have real-time suggestions on the delivery tour to follow, through the minimization of the total delivery time. Currently, at development phase, the tool has been tested in a target zone, considering the road network and time/city delivering constraints and real-time data about vehicles location, traffic and delivery bay availability. The tool identifies the possible tours based on the delivery preferences, ranks the possible solutions according to the total route time based on information on the road network (i.e. travel time forecasts), performs a further optimization to reduce the total travel times and presents the user the best alternative along with the indications of which delivery bay to use in each delivery stop. The developed prototype is composed by two main parts: a web application that manages communication between the database and the road network simulation, and, an Android mobile App that supports transport and logistic operators in managing their delivering, pre trip and en route, showing and updating routing based on real-time information.
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Finšgar, Matjaž, Klodian Xhanari, and Helena O. Ćurković. "Cyclic Voltammetry as an Electroanalytical Tool for Analysing the Reaction Mechanisms of Copper in Chloride Solution Containing Different Azole Compounds." Current Analytical Chemistry 16, no. 4 (June 1, 2020): 465–74. http://dx.doi.org/10.2174/1573411014666180704114202.
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Background: Cyclic voltammetry is widely employed in electroanalytical studies because it provides fast information about the redox potentials of the electroactive species and the influence of the medium on the redox processes. Azole compounds have been found to be effective corrosion inhibitors for copper in chloride-containing solutions. The aim of this work was to investigate in detail the influence of the addition of various azole compounds on the oxidation mechanism of copper in chloride-containing solutions, using cyclic voltammetry. Methods: The influence of thirteen azole compounds, at three different concentrations on the electrochemical/ chemical reactions of pure copper immersed in 3 wt.% NaCl solution was studied using cyclic voltammetry at different scan rates. The change of the peak current and potential with the scan rate were investigated. The possible linearity was compared with the theoretically derived mechanism. The possible reaction mechanisms were discussed based on the linearity of these parameters (peak current and potential) with the scan rate compared to theoretically derived models. Results: Both the peak current and peak potential of the copper samples immersed in chloridecontaining solutions with additions of the majority of azole compounds showed linearity with the square root of the scan rate, suggesting that copper follows the Müller-Calandra passivation model. The same behavior was also found for copper in chloride-containing solutions without additions of azole compounds. A linear variation of the peak potential with the natural logarithm of the scan rate and linear variation of the peak potential with the square root of the scan rate was observed for the copper samples immersed in chloride-containing solutions with the addition of 10 mM of 2-mercapto-1- methylimidazole, imidazole, or 2-aminobenzimidazole. This suggests that copper follows irreversible redox reactions under a diffusion controlled process. No other linear relations of the peak current and peak potential with the scan rate were found. Conclusion: Copper oxidation in chloride-containing solutions is controlled by passivation (following the Müller-Calandra passivation model) upon the addition of the majority of the selected azoles. In the minority of cases, irreversible redox reactions that follow a diffusion-controlled process were identified. None of the systems followed an adsorption-controlled process. Moreover, none of the tested systems underwent reversible redox reactions that followed a diffusion controlled process.
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Mohamed, Magda F., Hamdi M. Hassaneen, Emad M. Elzayat, Salwa M. El-Hallouty, May El-Manawaty, Fatma M. Saleh, Yasmin Mohamed, et al. "Biological Activity, Apoptotic Induction and Cell Cycle Arrest of New Hydrazonoyl Halides Derivatives." Anti-Cancer Agents in Medicinal Chemistry 19, no. 9 (October 23, 2019): 1141–49. http://dx.doi.org/10.2174/1871520619666190306123658.
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Background:The hydrazonoyl halides are presently an important target in the field of medicinal chemistry. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to a myriad of both heterocyclic and acyclic compounds. In addition, they have diverse biological activities such as antiviral, anthelmintic, antiarthropodal, fungicidal, herbicidal, insecticidal, pesticidal, acaricidal and miticidal Activity correlated to the presence of hydrazonoyl halides. Moreover, many applications in both industrial and pharmaceutical fields have been found to be associated with these halides. Depending on the above facts and continuation to our work, we herein report on the evaluation of the anticancer activity of these two halides prepared according to the published work and trying to know their molecular mechanism that they proceed to stop proliferation and metastasis of tumor cells by molecular tools such as real time PCR using different apoptotic genes, and cell cycle assay.Objective:The goal of this present study is to bring attention to the biological activities of hydrazonoyl halides and the molecular pathway they follow to exert their role in apoptotic death of cancer cell.Methods:Synthesis of hydrazonoyl halides 2c and 2f. The cytotoxic effect against different human cancer cell lines PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines as MCF-10 and MCF-12 in a monolayer culture model was evaluated. Their mechanism of action inside cancer cell was evaluated using different molecular tools.Conclusion:Strong and promising chemotherapeutic hydrazonoyl halides (2a-2f) were evaluated for their different biological activities. As antimicrobial agents, results indicated that three compounds 2a, 2e and 2f exhibited high activity against two tested gram positive bacteria Staphylococcus aureus, Bacillus subtilis, and gram negative ones Escherichia coli, and Pseudomonas aeruginosa, the rest of the compounds were found to be moderately active against the tested microorganisms. Regarding their antifungal effect, compound 2c exhibited potent and promising effect against Candida albicans, while 2b was the most potent toward Aspergillus flavus Link. The compound 2f has repellent effect. With respect to the in vitro antitumor screening, this was done on different human cancer cell lines; namely PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines; as MCF-10 and MCF-12 (normal breast epithelial cell and non-tumorigenic breast epithelial cell line) in a monolayer culture model where screening has been conducted at 100μg/ml (single dose test). Single dose test (100μg/ml) showed that, in case of PC3, all compounds have cytotoxic activity over 90% inhibition, 4 compounds have cytotoxic activity with 100% inhibition with Human colon cancer cell line, 4 compounds showed over 90% inhibition with MCF7 cell line and 4 compounds showed cytotoxic activity over 90% inhibition with HepG-2. Results of IC50 values for most promising compounds showed compounds with values lower than 20μM for all tested human cancer cell line. The promising hydrazonoyl halide 2c and 2f were selected for molecular study to know how they could act inside cancer cell causing death. Two biochemical tests were performed using the two halides 2c and 2f to predict their mechanism of action against breast carcinoma. Real time PCR analysis indicates that the two compounds induced the apoptosis of MCF7 cells through the up regulation of caspase-3, BAX mediated P53 mechanism but unfortunately, they promote the expression of anti-apoptotic protein BCL2. Also, cell cycle assay was performed using two different cell lines MCF7 and HCT116 and data revealed that the two compounds 2c and 2f induced apoptotic cells death of both lines via cell growth arrest at G2/M phase. In addition, it was noted that 2c induced arrest in the two lines more efficiently than 2f at G2/M phase.
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Cole, Peter D., Richard A. Drachtman, Angela K. Smith, Margaret Masterson, John Glod, and Barton A. Kamen. "Phase IIB Trial of Aminopterin in Multiagent Therapy for Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) at High Risk of Relapse." Blood 108, no. 11 (November 16, 2006): 1860. http://dx.doi.org/10.1182/blood.v108.11.1860.1860.
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Abstract The antifolate aminopterin (AMT) may offer clinical advantages over the related compound methotrexate (MTX), due to its pharmacodynamic and pharmacokinetic properties (Cancer Chemother Pharmacol2006;57:826). These properties may lead to greater ease of administration and less pharmacodynamic variability than is seen with oral MTX. In our phase II trial, we demonstrated that AMT at its MTD (4 mg/m2/week in two doses, 12 h apart) had significant activity among children with relapsed/refractory ALL (Clin Cancer Res2005; 11: 8089). The phase IIB trial was conducted to test whether AMT can be safely incorporated at its MTD in multiagent therapy in place of oral MTX for children with newly diagnosed ALL at high risk (HR) of relapse by NCI criteria. The backbone of intensive antimetabolite-based therapy has been previously published (JCO1996;14:2803, Cancer Chemother Pharmacol2006;57:826). Thirty-three HR patients have been treated with AMT. With median follow up of 2.5 years, 2-yr EFS is 85% ± 7%. Seventeen have completed all planned therapy, and all have completed the Consolidation phase of weekly AMT at its MTD (along with mercaptopurine twice daily and intrathecal therapy every other week), allowing a description of the toxicity possibly attributable to AMT in the setting of multiagent ALL therapy. Oral AMT had complete bioavailability (compared to IV AMT kinetics on the Phase I and II trials). Bone marrow penetration by AMT, as indicated by steady state RBC AMT concentrations, is identical to that of MTX when MTX is given at 25-fold higher doses (100 mg/m2/week). During maintenance therapy, RBC AMT is proportional to the average weekly AMT dose, but was not predictive of hematologic toxicity. Hematologic toxicity among HR patients is similar to that observed among concurrent standard risk patients who receive identical therapy except for MTX in place of AMT and no delayed intensification. HR patients who are homozygous wild-type for both polymorphisms in the gene for methyl-tetrahydrofolate reductase (MTHFR C677T and A1298C) had higher mean neutrophil counts during weekly AMT therapy than those with one or more polymorphic allele (2687 ± 333, N=7 vs. 1613 ± 83, N=22; P<0.001). Patients homozygous for a polymorphism in methionine synthase reductase (MTRR G66A) had lower average neutrophil counts (P<0.01). Grade 3–4 mucositis has occurred in only 15% of HR patients during AMT therapy. HR patients were less likely to have grade 3–4 hepatotoxicity (SGPT elevation) than concurrent SR patients (28% vs 60%; P<0.05). Two of the first five HR patients experienced reversible grade 3–4 neurotoxicity during Consolidation. However, no grade 3–4 neurotoxicity attributable to AMT has occurred among the subsequent 28 patients, treated after a protocol amendment added leucovorin rescue after oral AMT (analogous to rescue given to patients receiving oral MTX; JNCI, 1992;84:252). In summary, AMT can be safely given to children with ALL in place of systemic MTX, with neither excessive toxicity nor risk of relapse. RBC AMT content is indicative of recent AMT exposure, and may be a useful tool for monitoring compliance. Functional polymorphisms in genes relevant to folate metabolism are predictive of AMT-induced toxicity, as is seen for MTX. The proper role for AMT in therapy for patients with ALL deserves further study. This well-tolerated therapy, centered on outpatient oral antimetabolite therapy may be especially suitable for adolescents and young adults with ALL.
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Brog, Jean-Pierre, Claire-Lise Chanez, Aurelien Crochet, and Katharina Fromm. "Polymorphism, what it is and how to identify it." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1386. http://dx.doi.org/10.1107/s2053273314086136.
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Polymorphism is a very important phenomenon not only in basic research, but certainly in pharmaceutical industry and materials science. Polymorphs possess different properties, for instance the solubility or the mechanical resistance can differ dramatically from one polymorph to the other – properties which can be crucial for their application. Hence, it is important to be able to control the formation of polymorphs and to understand their formation. We here gave some insights into the basic knowledge of polymorph formation and their identification and characterization in order to give an overview on the current state of the art. In order to give interested peoples a tool in hand to test their compounds for polymorphism, we established a series of flow sheets to follow, depending on the class of compounds, hoping that they are useful for many scientists who are not so well acquainted with polymorphism. The presented schemes resume thus the identification steps for polymorphs. It should also help to use the term polymorph correctly in order to reduce the number of publications in which this term is not used in a correct way.
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Pini, Jonathan, Gabriele Siciliano, Pauline Lahaut, Serge Braun, Sandrine Segovia-Kueny, Anna Kole, Ines Hérnando, et al. "E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 743–54. http://dx.doi.org/10.3233/jnd-210655.
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By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients’ social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients’ and physicians’ unmet needs. It is vital to improve several aspects of patients’ quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients’ data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment. Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients’ states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients’ follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound. In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.
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Konstanty, Janusz Stefan. "The mechanics of sawing granite with diamond wire." International Journal of Advanced Manufacturing Technology 116, no. 7-8 (July 10, 2021): 2591–97. http://dx.doi.org/10.1007/s00170-021-07577-3.
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AbstractToday, wire sawing of natural stone is undergoing widespread commercialization. In addition to rock extraction and processing with single wires, composed of a multitude of diamond-impregnated beads mounted onto a steel rope, this technology is increasingly used for slabbing of granite blocks on multi-wire machines. Evolving sophistication of stone sawing equipment dictates novel tool designs and formulations. For technologists specifying bead compositions, it is a common habit to instinctively follow the circular saw segment design guidelines. A poor tool performance is often an undesirable consequence of such an approach. To meet that challenge, theoretical models of sawing granite by means of a diamond wire saw and a diamond circular saw have been presented and contrasted with respect to diamond loading conditions. The analytical treatments are supported by scarcely available industrial quantitative assessments and qualitative observations. The evaluation of cutting forces and the identification of system characteristics affecting wire vibration and wire rotation are instrumental in both machine design and tool formulation. For practitioners working with granite, the provided knowledge is also essential to diagnose and prevent problems inherent in wire sawing, such as the high incidence of wire breakage, unsatisfactory tool life and cutting capability and eccentric bead wear. Graphical abstract
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Carbonari, Artur Wilson, José Mestnik-Filho, and Rajendra Narain Saxena. "Impurities in Magnetic Materials Studied by PAC Spectroscopy." Defect and Diffusion Forum 311 (March 2011): 39–61. http://dx.doi.org/10.4028/www.scientific.net/ddf.311.39.
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Perturbed gamma-gamma angular correlation (PAC) spectroscopy is a precise and highly efficient tool to follow the temperature dependence of local magnetic fields in any material. Its resolution and efficiency does not depend on temperature and therefore can measure local fields at low as well as high temperature with the same accuracy. Due its versatility in using different probe nuclei it can sense the local magnetic fields at different sites in the crystalline structure of materials. In this review, important results obtained with PAC spectroscopy are shown in two classes of materials: transition metal and transition-metal based compounds and rare earth elements and rare-earth-element based compounds using mainly three different probe nuclei:111Cd,181Ta and140Ce. PAC spectroscopy has contributed to the systematic study of the magnetic hyperfine field in impurities in matrices of Fe, Co and Ni as well as in transition-metal based Heusler alloys. It has also provided important contribution to the investigation of magnetism in rare-earth elements and intermetallic compounds. An still open issue concerning the local fields in metallic magnetic compounds and elements is the exchange interaction between the magnetic ions of the host and a dilute magnetic impurity, which acts as a defect in the magnetic lattice. PAC spectroscopy has been contributing to study this problem with success. Also shown in this review is the crucial role of ab-initio first principle calculations in the interpretation of PAC results.
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Romasko, Edward J., Sawona Biswas, Batsal Devkota, Jayaraman Vijayakumar, Sowmyra Jairam, Christopher S. Thom, Matthew C. Dulik, et al. "Utility of Whole Exome Sequencing in Diagnosis of Pediatric Platelet Disorders: A Subanalysis of the Pediseq Study." Blood 128, no. 22 (December 2, 2016): 3726. http://dx.doi.org/10.1182/blood.v128.22.3726.3726.
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Abstract Background: Inherited Platelet Disorders (IPD) are individually rare disorders that have many different molecular causes. Diagnosis of IPD is often complicated by the need for complex testing that is not readily available at many centers and the lack of available testing to define the molecular cause of some disorders. While some platelet disorders are sufficiently defined by functional characterization, recent data suggests that some platelet disorders may predispose to significant other complications including cancer predisposition, myelofibrosis or hearing loss. Therefore, it may be important to establish a molecular diagnosis to better counsel families about necessary follow up and possible risks. The goal of this study was to determine the diagnostic yield of whole exome sequencing in a cohort of 22 pediatric patients with clinical presentation suggesting an underlying genetic cause (or positive family history of platelet disorder with no prior genetic diagnosis). Methods: Peripheral blood was collected from patients identified as likely to have an inherited platelet disorder after informed consent. Samples were also obtained from parents and siblings for co-segregation and variant calling. Genomic DNA was extracted manually using the Gentra Puregene Blood Kit. Exome capture was performed using the Agilent SureSelect v4 and 100 base paired end sequencing was done on an IlluminaHiSeq 2000 with 100X average coverage. Sequencing reads were generated in FASTQ format and mapped to human genome GRCh37 (hg19) and Novoalign v2.08 was used for optimal alignment. Disease-related variants were extracted from HGMD to identify variants that might be missed. Variant filtering and pathogenicity classification was performed using a customized pipeline and manual curation. We identified 53 genes of interest and on average across all exomes with an indication for a platelet disorder, bases were sequenced at a minimum depth of 15X to be considered covered within an exon. 80.4% of exons were 100% covered with this technology completely, while 10.4% of exons were partially covered (>40 to <100% bases) and 9.2% of exons were not covered (<40% of bases covered at a minimum of 15X depth). Results: 22 patients were enrolled over a 12-month period. Overall, 82% of patients had variants identified in platelet related genes on whole exome sequencing with 64% of patients returning at least one variant of uncertain significance (14) and 23% (5) patients returning definite positive results. One patient referred for further work up carried the initial diagnosis of ITP, but had macrothrombocytopenia since early childhood and bleeding out of proportion to the platelet count. Flow cytometry and functional studies performed on referral suggested possible Bernard Soulier Syndrome and sequencing confirmed homozygous pathogenic mutation in GP9. One patient with congenital thrombocytopenia and history of intracranial hemorrhage with a similarly affected sibling had confirmed pathogenic MYH9 mutation, allowing clinicians to offer prenatal diagnosis during a third pregnancy. One patient with a significant bleeding phenotype was a compound heterozygote for two novel RASGRP2 variants, but the functional significance of those variants is uncertain and further studies are underway to determine whether these variants are causative. 18% of patients (4) had negative sequencing results (no reportable variants in platelet related genes identified). Conclusions: Whole exome sequencing can be a powerful diagnostic tool in identifying the molecular cause of disease in a cohort of patients with suspected inherited platelet disorders. The majority of patients, however, will receive results of uncertain significance and centers that undertake this testing will require an infrastructure to allow for further functional evaluation, which will help in reclassification of these variants, and ensure that results are correctly interpreted. Clinicians who undertake ES to diagnose IPD need to understand limitations of the test as well as the full significance of results that may be returned. Disclosures Lambert: Novartis: Consultancy.
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List, Markus, Marlene Pedersen Elnegaard, Steffen Schmidt, Helle Christiansen, Qihua Tan, Jan Mollenhauer, and Jan Baumbach. "Efficient Management of High-Throughput Screening Libraries with SAVANAH." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 2 (October 13, 2016): 196–202. http://dx.doi.org/10.1177/1087057116673607.
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High-throughput screening (HTS) has become an indispensable tool for the pharmaceutical industry and for biomedical research. A high degree of automation allows for experiments in the range of a few hundred up to several hundred thousand to be performed in close succession. The basis for such screens are molecular libraries, that is, microtiter plates with solubilized reagents such as siRNAs, shRNAs, miRNA inhibitors or mimics, and sgRNAs, or small compounds, that is, drugs. These reagents are typically condensed to provide enough material for covering several screens. Library plates thus need to be serially diluted before they can be used as assay plates. This process, however, leads to an explosion in the number of plates and samples to be tracked. Here, we present SAVANAH, the first tool to effectively manage molecular screening libraries across dilution series. It conveniently links (connects) sample information from the library to experimental results from the assay plates. All results can be exported to the R statistical environment or piped into HiTSeekR ( http://hitseekr.compbio.sdu.dk ) for comprehensive follow-up analyses. In summary, SAVANAH supports the HTS community in managing and analyzing HTS experiments with an emphasis on serially diluted molecular libraries.
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Cheng, Du, Melissa Yuan, Imali Perera, Ashley O’Connor, Alexander I. Evins, Thomas Imahiyerobo, Mark Souweidane, and Caitlin Hoffman. "Developing a 3D composite training model for cranial remodeling." Journal of Neurosurgery: Pediatrics 24, no. 6 (December 2019): 632–41. http://dx.doi.org/10.3171/2019.6.peds18773.
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OBJECTIVECraniosynostosis correction, including cranial vault remodeling, fronto-orbital advancement (FOA), and endoscopic suturectomy, requires practical experience with complex anatomy and tools. The infrequent exposure to complex neurosurgical procedures such as these during residency limits extraoperative training. Lack of cadaveric teaching tools given the pediatric nature of synostosis compounds this challenge. The authors sought to create lifelike 3D printed models based on actual cases of craniosynostosis in infants and incorporate them into a practical course for endoscopic and open correction. The authors hypothesized that this training tool would increase extraoperative facility and familiarity with cranial vault reconstruction to better prepare surgeons for in vivo procedures.METHODSThe authors utilized representative craniosynostosis patient scans to create 3D printed models of the calvaria, soft tissues, and cranial contents. Two annual courses implementing these models were held, and surveys were completed by participants (n = 18, 5 attending physicians, 4 fellows, 9 residents) on the day of the course. These participants were surveyed during the course and 1 year later to assess the impact of this training tool. A comparable cohort of trainees who did not participate in the course (n = 11) was also surveyed at the time of the 1-year follow-up to assess their preparation and confidence with performing craniosynostosis surgeries.RESULTSAn iterative process using multiple materials and the various printing parameters was used to create representative models. Participants performed all major surgical steps, and we quantified the fidelity and utility of the model through surveys. All attendees reported that the model was a valuable training tool for open reconstruction (n = 18/18 [100%]) and endoscopic suturectomy (n = 17/18 [94%]). In the first year, 83% of course participants (n = 14/17) agreed or strongly agreed that the skin and bone materials were realistic and appropriately detailed; the second year, 100% (n = 16/16) agreed or strongly agreed that the skin material was realistic and appropriately detailed, and 88% (n = 14/16) agreed or strongly agreed that the bone material was realistic and appropriately detailed. All participants responded that they would use the models for their own personal training and the training of residents and fellows in their programs.CONCLUSIONSThe authors have developed realistic 3D printed models of craniosynostosis including soft tissues that allow for surgical practice simulation. The use of these models in surgical simulation provides a level of preparedness that exceeds what currently exists through traditional resident training experience. Employing practical modules using such models as part of a standardized resident curriculum is a logical evolution in neurosurgical education and training.
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Berti, Beatrice, Lavinia Fanelli, Roberto de Sanctis, Roberta Onesimo, Concetta Palermo, Daniela Leone, Sara Carnicella, et al. "Oral and Swallowing Abilities Tool (OrSAT) for Type 1 SMA Patients: Development of a New Module." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 589–601. http://dx.doi.org/10.3233/jnd-200614.
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We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life. The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child’s ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria. In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3–24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format. When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (p < 0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties.
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Brinkman, Paul, Waqar M. Ahmed, Cristina Gómez, Hugo H. Knobel, Hans Weda, Teunis J. Vink, Tamara M. Nijsen, et al. "Exhaled volatile organic compounds as markers for medication use in asthma." European Respiratory Journal 55, no. 2 (September 12, 2019): 1900544. http://dx.doi.org/10.1183/13993003.00544-2019.
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IntroductionAsthma is a heterogeneous condition, characterised by chronic inflammation of the airways, typically managed with inhaled bronchodilators and corticosteroids. In the case of uncontrolled asthma, oral corticosteroids (OCSs) are often prescribed. Good adherence and inhalation technique are associated with improved outcomes; however, it is difficult to monitor appropriate drug intake and effectiveness in individual patients. Exhaled breath contains thousands of volatile organic compounds (VOCs) that reflect changes in the body's chemistry and may be useful for monitoring drug pharmacokinetics/pharmacodynamics. We aimed to investigate the association of exhaled VOCs in severe asthma patients from the U-BIOPRED cohort (by gas chromatography coupled with time-of-flight mass spectrometry) with urinary levels of salbutamol and OCSs (by liquid chromatography coupled with high-resolution mass spectrometry).MethodsSamples were collected at baseline and after 12–18 months of follow-up. Statistical analysis was based on univariate and multivariate modelling, followed by area under the receiver operating characteristic curve (AUC) calculation. Results were verified through longitudinal replication and independent validation.ResultsData were available for 78 patients (baseline n=48, replication n=30 and validation n=30). Baseline AUC values were 82.1% (95% CI 70.4–93.9%) for salbutamol and 78.8% (95% CI 65.8–91.8%) for OCS. These outcomes could be adequately replicated and validated. Additional regression analysis between qualified exhaled VOCs and urinary concentrations of salbutamol and prednisone showed statistically significant correlations (p<0.01).ConclusionWe have linked exhaled VOCs to urinary detection of salbutamol and OCSs. This merits further development of breathomics into a point-of-care tool for therapeutic drug monitoring.
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Lorin–Latxague, Chrystelle, and Anne–Marie Melin. "Radical induced damage ofMicrococcus luteusbacteria monitored using FT‒IR spectroscopy." Spectroscopy 19, no. 1 (2005): 17–26. http://dx.doi.org/10.1155/2005/386404.
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Oxidative damage induced by ascorbic acid (AA) and hydrogen peroxide (H2O2) was monitored by Fourier transform infrared spectroscopy (FT‒IR); it appeared as a rapid and convenient means to follow the biochemical changes generated in the culture media of the yellow-pigmentedMicrococcus luteus. Beyond a threshold of 20 mM for AA and of 40 mM for H2O2(final concentration), antioxidant systems were overwhelmed and significant changes were observed in the bacterial spectra, particularly in the 1430–900 cm−1region; this spectral window provided large information about carboxylate groups, phosphate-carrying compounds and polysaccharides implicated in the radical process. The spectroscopic results indicated that for the same final concentration, the toxicity of H2O2was less important than that of AA towardM. luteuscells, although H2O2had a more damaging effect on proteins. Thus, FT-IR spectroscopy was an appropriate physico-chemical tool suitable in biochemical and clinical research for early characterization of any type of radical aggression, and for rapid detection of the damage intensity.
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Ahmad, Ijaz, Mohammad Rehan, Mansour A. Balkhyour, and Iqbal M. Ismail. "Assessment of Occupational Health and Safety in Motor Vehicle Repair Workshops in Jeddah." Biosciences, Biotechnology Research Asia 14, no. 3 (September 25, 2017): 901–13. http://dx.doi.org/10.13005/bbra/2524.
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ABSTRACT: This study aims to examine the occupational health and safety (OHS) status in motor vehicle repair workshops (MVRW) industry in the city of Jeddah, Kingdom of Saudi Arabia (KSA). An inspection tool composed of 10 OHS components and 69 items was employed through observations, interviews, walk through survey and focused group discussions. The data was collected from local workshops (LWs, N=62) and multinational companies’ workshops (CWs, N=11). The mean positive response for OHS components among surveyed LWs and CWs was as follow; personal protective equipment’s (PPEs) (28% and 61%), fire protection and emergency management (52% and 91%), provision of facilities (69% and 94%), electric safety (44% and 82%), general workshop safety (43% and 82%), housekeeping (18% and 84%), chemical exposure (16% and 69%), maintenance and services (54% and 86%), manual handling (84% and 100%) and tool safety (58% and 91%), respectively. The overall OHS mean positive response, complying best practices and regulations, of all OHS elements in LWs was 47% which was much lower than 84% positive response for CWs. The impact of OHS on workers’ health was also discussed together with recommendations given for further improvement.
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Elliott, Stephen N., Ryan J. Kettler, Peter A. Beddow, Alexander Kurz, Elizabeth Compton, Dawn McGrath, Charles Bruen, et al. "Effects of Using Modified Items to Test Students with Persistent Academic Difficulties." Exceptional Children 76, no. 4 (July 2010): 475–95. http://dx.doi.org/10.1177/001440291007600406.
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This study investigated the effects of using modified items in achievement tests to enhance accessibility. An experiment determined whether tests composed of modified items would reduce the performance gap between students eligible for an alternate assessment based on modified achievement standards (AA-MAS) and students not eligible, and the impact on student proficiency levels. Three groups of eighth-grade students ( N = 755) from four states took original and modified versions of reading and mathematics tests. Findings indicate modified item conditions were significantly easier for all students and modifications would result in more AA-MAS eligible students meeting proficiency status. Study limitations and follow-up research on item modifications and the performance of students with disabilities are discussed.
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Tondelier, Christophe, David Benanou, Thomas Thouvenot, and Arnaud Genin. "Novel on-tap passive sampling for odorous compounds in drinking water." Water Supply 8, no. 2 (July 1, 2008): 197–205. http://dx.doi.org/10.2166/ws.2008.067.
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Because taste and odour events in drinking water are often fleeting and unpredictable phenomena, an innovating passive sampler has been developed to trap off-flavour compounds, directly at the tap of the consumer: ARISTOT (Advanced Relevant Investigation Sampler for Taste & Odour at Tap). Each tool is equipped with seven SBSE stir bars, magnetic stirring roads coated with a polydimethylsiloxane (PDMS) phase, allowing the sorption of water organic compounds into PDMS at each tap opening. To study the efficiency of these passives samplers, a private network pilot unit has been created in our laboratory, equipped with four faucets in series, solenoids valves for automation of the system and a mixing chamber, developed to spike drinking water with odourous compounds in order to have homogenous smelling water at each tap. After enrichment, the bars are taken out and are then in-line thermo-desorbed and analysed by gas chromatography coupled with a mass spectrometer. Results showed a high sensitivity of the system, which was able to quickly analyse odourous compounds at the sub ng/L level. A “multishot” method was developed to analyse every molecule trapped on the seven stir bars in only one chromatographic run increasing sensitivity. To follow enrichment of stir bars, loading and unloading were studied and showed a very slight unloading of the stir bar under a clean water flow rate which allowed us to previously spike every stir bar with an internal standard to see analytical variations. The influence of heated water was also investigated and seems to lead to a higher unloading of the stir bar, but according to a qualitative aspect this loss is balanced by the high sensitivity.
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Santos, Albano Joel Moreira, Cláudia Sofia Gomes Cardoso, Albertina Alice Ribeiro Mota, Patrícia Raquel Heleno Belmonte, Manuel António Campo Grande Oliveira, and Joaquim Carlos Gomes Esteves da Silva. "Fate and behaviour of acetaminophen, 17α-ethynylestradiol and carbamazepine in aqueous solution." Water Science and Technology 81, no. 2 (January 15, 2020): 395–409. http://dx.doi.org/10.2166/wst.2020.121.
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Abstract Pharmaceuticals are invaluable tools for the prevention and treatment of human and animal diseases. Human evolution led to the increase of life expectancy, which promoted the increase of consumption of pharmaceuticals. These compounds are consistently detected in superficial waters, and whilst degradation processes are expected to mitigate their levels, they also induce the formation of potentially harmful by-products. The compounds studied in this work were acetaminophen, 17α-ethynylestradiol and carbamazepine. High-performance liquid chromatography coupled with ultraviolet diode-array detection was used to follow the degradation reactions, whilst liquid chromatography associated with ultraviolet diode-array detection and mass spectrometry was applied in the determination of by-products. Ethynylestradiol proved to be the most reactive (t1/2 = 38.6 ± 1.9 seconds) and carbamazepine the least reactive (t1/2 = 481.4 ± 16.7 minutes) when exposed to active chlorine. In relation to disinfection by-products, two monochlorinated analogues were detected for acetaminophen, one monochlorinated for carbamazepine, and one mono- and one trichlorinated for ethynylestradiol. Chlorine levels and water pH proved to be the most influential variables on the degradation of the compounds, with and without dissolved organic matter in solution. All pharmaceuticals displayed significant photostability towards artificial solar radiation, with acetaminophen being slightly more stable.
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Toplak, Marko, Stuart T. Read, Christophe Sandt, and Ferenc Borondics. "Quasar: Easy Machine Learning for Biospectroscopy." Cells 10, no. 9 (September 3, 2021): 2300. http://dx.doi.org/10.3390/cells10092300.
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Data volumes collected in many scientific fields have long exceeded the capacity of human comprehension. This is especially true in biomedical research where multiple replicates and techniques are required to conduct reliable studies. Ever-increasing data rates from new instruments compound our dependence on statistics to make sense of the numbers. The currently available data analysis tools lack user-friendliness, various capabilities or ease of access. Problem-specific software or scripts freely available in supplementary materials or research lab websites are often highly specialized, no longer functional, or simply too hard to use. Commercial software limits access and reproducibility, and is often unable to follow quickly changing, cutting-edge research demands. Finally, as machine learning techniques penetrate data analysis pipelines of the natural sciences, we see the growing demand for user-friendly and flexible tools to fuse machine learning with spectroscopy datasets. In our opinion, open-source software with strong community engagement is the way forward. To counter these problems, we develop Quasar, an open-source and user-friendly software, as a solution to these challenges. Here, we present case studies to highlight some Quasar features analyzing infrared spectroscopy data using various machine learning techniques.
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Damasso, M., M. Pinamonti, G. Scandariato, and A. Sozzetti. "Biases in retrieving planetary signals in the presence of quasi-periodic stellar activity." Monthly Notices of the Royal Astronomical Society 489, no. 2 (August 12, 2019): 2555–71. http://dx.doi.org/10.1093/mnras/stz2216.
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Abstract Gaussian process regression is a widespread tool used to mitigate stellar correlated noise in radial velocity (RV) time series. It is particularly useful to search for and determine the properties of signals induced by small-sized low-mass planets (Rp < 4 R⊕, mp < 10 M⊕). By using extensive simulations based on a quasi-periodic representation of the stellar activity component, we investigate the ability in retrieving the planetary parameters in 16 different realistic scenarios. We analyse systems composed by one planet and host stars having different levels of activity, focusing on the challenging case represented by low-mass planets, with Doppler semi-amplitudes in the range 1–3 $\rm{\,m\,s^{-1}}$. We consider many different configurations for the quasi-periodic stellar activity component, as well as different combinations of the observing epochs. We use commonly employed analysis tools to search for and characterize the planetary signals in the data sets. The goal of our injection-recovery statistical analysis is twofold. First, we focus on the problem of planet mass determination. Then, we analyse in a statistical way periodograms obtained with three different algorithms, in order to explore some of their general properties, as the completeness and reliability in retrieving the injected planetary and stellar activity signals with low false alarm probabilities. This work is intended to provide some understanding of the biases introduced in the planet parameters inferred from the analysis of RV time series that contain correlated signals due to stellar activity. It also aims to motivate the use and encourage the improvement of extensive simulations for planning spectroscopic follow-up observations.
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Jantzen, Rodolphe, Yves Payette, Thibault de Malliard, Catherine Labbé, Nolwenn Noisel, and Philippe Broët. "Validation of breast cancer risk assessment tools on a French-Canadian population-based cohort." BMJ Open 11, no. 4 (April 2021): e045078. http://dx.doi.org/10.1136/bmjopen-2020-045078.
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ObjectivesEvaluate the accuracy of the Breast Cancer Risk Assessment Tool (BCRAT), International Breast Cancer Intervention Study risk evaluation tool (IBIS), Polygenic Risk Scores (PRS) and combined scores (BCRAT+PRS and IBIS +PRS) to predict the occurrence of invasive breast cancers at 5 years in a French-Canadian population.DesignPopulation-based cohort study.SettingWe used the population-based cohort CARTaGENE, composed of 43 037 Quebec residents aged between 40 and 69 years and broadly representative of the population recorded on the Quebec administrative health insurance registries.Participants10 200 women recruited in 2009–2010 were included for validating BCRAT and IBIS and 4555 with genetic information for validating the PRS and combined scores.Outcome measuresWe computed the absolute risks of breast cancer at 5 years using BCRAT, IBIS, four published PRS and combined models. We reported the overall calibration performance, goodness-of-fit test and discriminatory accuracy.Results131 (1.28%) women developed a breast cancer at 5 years for validating BCRAT and IBIS and 58 (1.27%) for validating PRS and combined scores. Median follow-up was 5 years. BCRAT and IBIS had an overall expected-to-observed ratio of 1.01 (0.85–1.19) and 1.02 (0.86–1.21) but with significant differences when partitioning by risk groups (p<0.05). IBIS’ c-index was significantly higher than BCRAT (63.42 (59.35–67.49) vs 58.63 (54.05–63.21), p=0.013). PRS scores had a global calibration around 0.82, with a CI including one, and non-significant goodness-of-fit tests. PRS’ c-indexes were non-significantly higher than BCRAT and IBIS, the highest being 64.43 (58.23–70.63). Combined models did not improve the results.ConclusionsIn this French-Canadian population-based cohort, BCRAT and IBIS have good mean calibration that could be improved for risk subgroups, and modest discriminatory accuracy. Despite this modest discriminatory power, these tools can be of interest for primary care physicians for delivering a personalised message to their high-risk patients, regarding screening and lifestyle counselling.
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Hoverman, J. Russell, Tae W. Jang, and Jim R. Schwartz. "Eleven-year experience with a web-based medication occurrence (MO) reporting tool in a community oncology practice." Journal of Clinical Oncology 34, no. 7_suppl (March 1, 2016): 53. http://dx.doi.org/10.1200/jco.2016.34.7_suppl.53.
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53 Background: At ASCO 2007, we presented 2 year experience with a web-based Medication Occurrence (MO) reporting tool. We now report the 11 year experience in a single outpatient oncology practice. Methods: Since December 2003, Texas Oncology (TxO) sites have entered information on Medication Occurrence (MO) reports in an electronic Variance Reporting tool. The pharmacy management team generates reports monthly for the Texas Oncology Quality Oversight Committee and each site Quality Committee for analysis and follow-up action. The data are analyzed according to a pre-set group of parameters (retail vs. clinic, near miss vs. actual occurrence, severity level 1-8, categories of occurrence). Recently these data were analyzed for the years 2004-2014 to assess trends in MOs. Results: Over 11 years there were 2,163,249 transactions for a chemotherapy infusion or injection. There were 10845 MOs of which 5,143 were adverse drug reactions (ADRs). Near misses accounted for 16.7% of unadjusted MO rate and 31.8% when ADRs were excluded. MO rate with ADR was 0.46%, without ADR 0.24%. Retail MO rate was 0.02% on 1,771,148 transactions. Rituximab was 20.9% and paclitaxel 16.4% of ADRs. Tying reporting to clinic performance increased reporting by site and number of sites. EHR related MOs and Near Misses were each reported as MOs and artificially inflate numbers due to double counting. There were 10 deaths over 11 years. With these data, we were able to 1) Promote an epinephrine protocol for severe drug reactions, 2) Obviate the need for AEDs at every site, 3) Find no difference in rituximab reactions by geographic region, 4) Make assessments regarding cost and toxicity of iron compounds, 5) Target specific drugs for ADR risk. 6) Assess prophylactic corticosteroid regimens in taxane administration. Conclusions: Web-based reporting in the outpatient community setting is feasible and identified many topics for quality improvement initiatives. The importance of double-checking and a culture of safety is reinforced by the number of avoided MOs indicated by the near miss percentage.
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Zhang, Xuan, Jordan E. Krechmer, Michael Groessl, Wen Xu, Stephan Graf, Michael Cubison, John T. Jayne, Jose L. Jimenez, Douglas R. Worsnop, and Manjula R. Canagaratna. "A novel framework for molecular characterization of atmospherically relevant organic compounds based on collision cross section and mass-to-charge ratio." Atmospheric Chemistry and Physics 16, no. 20 (October 19, 2016): 12945–59. http://dx.doi.org/10.5194/acp-16-12945-2016.
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Abstract. A new metric is introduced for representing the molecular signature of atmospherically relevant organic compounds, the collision cross section (Ω), a quantity that is related to the structure and geometry of molecules and is derived from ion mobility measurements. By combination with the mass-to-charge ratio (m∕z), a two-dimensional Ω − m∕z space is developed to facilitate the comprehensive investigation of the complex organic mixtures. A unique distribution pattern of chemical classes, characterized by functional groups including amine, alcohol, carbonyl, carboxylic acid, ester, and organic sulfate, is developed on the 2-D Ω − m∕z space. Species of the same chemical class, despite variations in the molecular structures, tend to situate as a narrow band on the space and follow a trend line. Reactions involving changes in functionalization and fragmentation can be represented by the directionalities along or across these trend lines, thus allowing for the interpretation of atmospheric transformation mechanisms of organic species. The characteristics of trend lines for a variety of functionalities that are commonly present in the atmosphere can be predicted by the core model simulations, which provide a useful tool to identify the chemical class to which an unknown species belongs on the Ω − m∕z space. Within the band produced by each chemical class on the space, molecular structural assignment can be achieved by utilizing collision-induced dissociation as well as by comparing the measured collision cross sections in the context of those obtained via molecular dynamics simulations.
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Rubio-Pérez, Gabriel, Natalia Muñoz-Rujas, Fernando Aguilar, Rebecca Ravotti, Lukas Müller, and Eduardo Montero. "Evolution of the Study of Phase Diagram of Binary and Ternary Mixtures Involving Fatty Acid Esters." Materials 14, no. 2 (January 13, 2021): 369. http://dx.doi.org/10.3390/ma14020369.
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Interest in phase change materials keeps on rising as thermal energy storage grows in popularity in the scientific community as a promising complement for renewable energies in the future. Extending the possibilities beyond pure compounds, the use of mixtures (especially eutectics) widens the range of suitable phase change materials (PCM) available in the market. However, a precise knowledge of the mixtures’ phase behavior is required, making phase diagrams the most appropriate tools to follow. The aim of this work is to collect and analyze published literature concerning the phase diagrams of fatty acid esters mixtures, which constitute promising candidates as PCM due to their attractive properties, such as high latent heat, chemical stability and the possibility of extracting them from vegetable and animal oils. The topic appears as a still open scientific field, where further studies need to be performed to complete, complement and perfect the currently available information.
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Lakshmi Sarvani, M., B. V. Kranthi, and S. Mounica Reddy. "FUNDUS FLUORESCEIN ANGIOGRAPHY AS A DIAGNOSTIC TOOL IN AGERELATED MACULAR DEGENERATION." International Journal of Advanced Research 8, no. 12 (December 31, 2020): 1035–49. http://dx.doi.org/10.21474/ijar01/12249.
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Background:Age related macular degeneration (ARMD) is a leading cause of severe irreversible vision impairment in developed countries. It is a hereditary degenerative condition involving the choriocapillaries, Bruchs retinal pigment epithelium and photoreceptors. Early stage disease is characterized by deposition of drusen under the RPE cells into Bruchs membrane. In late stages disease may progress to either geographic atrophy also known as Dry AMD or neovascular also known as Wet AMD. Loss of vision in dry AMD is due to photoreceptors and atrophy of RPE with loss of choriocapillaries whereas choroidal neovascularization (CNV) is associated with breakthrough of choroidal neovascular vessels through Bruchs membrane and RPE causing hemorrhagic , exudative , or disciform AMD. Although the clinical diagnosis of AMD can be established based on patients history and fundus examination, Fluorescein Angiography (FA) is the most important ancilliary test for classifying the disease in its different subtypes, especially in its wet form. Nowdays, optical coherence tomography (OCT) is being more used than FFA for monitoring the response to treatment, although FA is still very useful in some cases. FA is a powerful imaging modality to identify the presence, location and size of the neovascular complex which is composed of choroidal neovascular lesion and its components. FA is a useful diagnostic method and also an important clinicaresearch tool, displaying lesion morphology data. Many clinical trials of AMD rely on FA characterization for both eligibility and treatment endpoints. Objectives: To assess the role of fundus fluorescein angiography in age related macular disorders. To know the varies types of ARMD and its pattern. To know the progression and response to treatment in ARMD To find neovascularisation and occult lesions Study design: Cross sectional study Methods: This study included 100 patients with macular pathology, who were detected to have AMD in either eye, who presented themselves to outpatient Department of ophthalmology in SanthiRam medical college and general Hoapital,nandyal. A careful detailed history was taken regarding the duration and symptoms of the disease followed by eye examination which included visual acuity, slit lamp examination and macular function test. Detailed fundus examination with 90D indirect and direct ophthalmoscope. Thorough systemic examination was done followed by blood investigations and ECG. Under aseptic precaution blood samples were collected from anterior cubital vein and the following tests were carried out. 1. Complete hemogram 2. Random blood sugar 3. Fasting lipid profile 4. Serum creatinine And urine routine was done. Medical fitness for the procedure was obtained. Patient was explained the procedure and proper informed consent was taken after which fundus fluorescein angiography was performed. Results: Totally 100 patients fulfilling the inclusion criteria were included in the study, with an age range of 50 years and above of both gender. Dry AMD was present in 90 patients (90%) patients and 10 patients (10%) showed wet or exudative AMD. Interpretation and conclusion: The fluorescein angiography helped in diagnosis, type of ARMD and its further classification. It also helped in planning treatment and its response at follow up.
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Blin, Kai, Hyun Uk Kim, Marnix H. Medema, and Tilmann Weber. "Recent development of antiSMASH and other computational approaches to mine secondary metabolite biosynthetic gene clusters." Briefings in Bioinformatics 20, no. 4 (November 3, 2017): 1103–13. http://dx.doi.org/10.1093/bib/bbx146.
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Abstract Many drugs are derived from small molecules produced by microorganisms and plants, so-called natural products. Natural products have diverse chemical structures, but the biosynthetic pathways producing those compounds are often organized as biosynthetic gene clusters (BGCs) and follow a highly conserved biosynthetic logic. This allows for the identification of core biosynthetic enzymes using genome mining strategies that are based on the sequence similarity of the involved enzymes/genes. However, mining for a variety of BGCs quickly approaches a complexity level where manual analyses are no longer possible and require the use of automated genome mining pipelines, such as the antiSMASH software. In this review, we discuss the principles underlying the predictions of antiSMASH and other tools and provide practical advice for their application. Furthermore, we discuss important caveats such as rule-based BGC detection, sequence and annotation quality and cluster boundary prediction, which all have to be considered while planning for, performing and analyzing the results of genome mining studies.
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Goodman, Lindsey Martin, Machelle Moeller, Amy E. Guthrie, Marc A. Earl, Nathan A. Pennell, Timothy D. Gilligan, and James Stevenson. "The Morbidity and Mortality Conference (MMC) in Oncology: A patient safety and root cause analysis (RCA)-driven approach at the Cleveland Clinic Taussig Cancer Institute (TCI)." Journal of Clinical Oncology 32, no. 30_suppl (October 20, 2014): 191. http://dx.doi.org/10.1200/jco.2014.32.30_suppl.191.
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191 Background: MMC has been traditionally viewed as an educational tool. However, negative associations with MMC include emphasis on individual error and assigning blame, with little attention to improving patient safety and quality of care. MMC at the TCI has been designed to provide an opportunity to discuss MMC cases in an open, non-judgmental setting. Methods: Since September 2013, a monthly MMC, open to all caregivers, not just physicians, has been held as part of CME certified oncology grand rounds. Two cases are discussed per session and are obtained from nursing, pharmacy, and physician recommendation through the hospital Safety Event Reporting System or direct communication. Fellows investigate and present cases with patient and provider information de-identified to assure the discussion occurs in a blame-free setting. RCA is performed to determine action items. Process and safety improvements are recommended where applicable. Ongoing follow-up and improvement tracking is reported at future MMCs. The MMC governance committee, composed of the TCI quality officer, quality director, fellow representative, and a multi-disciplinary group of providers, meets quarterly to review cases and follow up action items under the guidance of the TCI MMC charter. The MMC governance committee reports to the TCI Quality Steering Committee. Results: Cases reviewed to date include chemotherapy dosing/administration errors (23%), hospital acquired medical complications (31%), communication breakdown between caregivers (15%), and end of life care (31%). An average of 3.5 action items has resulted from each case with 75% addressed within 90 days. Physician attendance is 59% higher and 23% more physicians report that they are very likely to change their practice behaviors from MMC than other grand rounds presentations. Conclusions: A patient safety driven MMC, delivered in an open setting, can be an effective tool to improve quality of care and caregiver communication in a large academic cancer center. High provider attendance and survey feedback reflects engagement in the process and will be essential to sustaining a meaningful and productive MMC.
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Elliott, Robert E., Stephen A. Sands, Russell G. Strom, and Jeffrey H. Wisoff. "Craniopharyngioma Clinical Status Scale: a standardized metric of preoperative function and posttreatment outcome." Neurosurgical Focus 28, no. 4 (April 2010): E2. http://dx.doi.org/10.3171/2010.2.focus09304.
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Object Controversy persists concerning the optimal treatment of craniopharyngiomas in children, and no standard outcome metric exists for comparison across treatment modalities, nor is there one that adequately reflects the multisystem dysfunction that may arise. Methods The authors retrospectively analyzed the records of 86 consecutive children who underwent a uniform treatment paradigm of attempted radical resection performed by a single surgeon. Excluding 3 perioperative deaths and 3 patients with inadequate follow-up, 80 children (34 girls and 46 boys; mean age 9.56 years; mean follow-up 9.6 years) composed the study group (53 primary and 27 previously treated/recurrent tumors). Building on existing classification schemes proposed by De Vile for hypothalamic dysfunction and Wen for overall functional outcome, the authors devised a more nuanced classification system (Craniopharyngioma Clinical Status Scale [CCSS]) that assesses outcome across 5 axes, including neurological examination, visual status, pituitary function, hypothalamic dysfunction, and educational/occupational status at last follow-up (there is a 4-tiered grading scale in each domain, with increasing values reflecting greater dysfunction). Results There was a significant increase in pituitary dysfunction following treatment—consistent with the high rates of diabetes insipidus and hypopituitarism common to the surgical management of craniopharyngiomas—and less dramatic deterioration in hypothalamic function or cognitive domains. Significant improvement in vision was also demonstrated, with no significant overall change in neurological status. Preoperative CCSS scores predicted postoperative outcome better than clinical characteristics like patient age, sex, tumor size, and the location or presence of hydrocephalus. Conclusions Preoperative CCSS scores predicted outcome with higher accuracy than clinical or imaging characteristics. In lieu of randomized trials, the CCSS may provide a useful outcome assessment tool for comparison across treatment paradigms and surgical approaches. Long-term follow-up is critical to the analysis of outcomes of craniopharyngioma treatment, given the often-delayed sequelae of all therapies and the high recurrence rates of these tumors.
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Ibarguengoitia, O., I. Calvo, D. Montero, L. Vega, C. García, O. Fernandez, I. Torre, et al. "AB0151 FOLLOW-UP IN A MULTIDISCIPLINARY UNIT IMPROVES PREGNANCY OUTCOME IN INFLAMMATORY ARTHROPATIES ON BIOLOGICAL THERAPY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1103.2–1103. http://dx.doi.org/10.1136/annrheumdis-2021-eular.715.
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Background:Women with inflammatory arthropaties have fertility problems and complications during pregnancy and frequently biological therapy (BT) is required for the disease control.Objectives:To evaluate pregnancy in women with inflammatory arthropaties in a multidisciplinary unit composed of Rheumatologists and Obstetricians: describe disease evolution, complications and treatment used (including BT).Methods:Retrospective and descriptive study of the evolution of pregnancy in patients withinflammatory diseases (Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) and Juvenile Idiopathic Arthritis (JIA)) and follow-up in a multidisciplinary unit for more than 15 years (until December 2020). Demographics, maternal disease, time until conception, previous abortions and presence of antibodies were collected. In addition, during follow-up, treatment, abortions, Caesarean sections (C-section), preterm births, disease activity and maternal/fetal complications were collected.Results:We registered 41 pregnancies (32 women): 20 RA (62.5%), 9 SpA (28.1%) and 3 JIA (9.4%). Maternal average age at diagnosis was 27.1±6.6 years and average age at childbirth/abortion was 34.9±5.1 years.It took an average time of 9.6±8.5 months to conceive. 9.8% received fertility treatment with in vitro fertilization techniques.AntiRo antibodies were registered in 7.3% of patients and 34.1% had at least 1 antiphospholipid antibody.At the time of gestational desire/gestation 17 women (12 RA, 4 SpA, 2 JIA) were receiving BT: 7 certolizumab (CZP), 7 adalimumab (ADA), 3 etanercept (ETN). 1 patient was being treated with baricitinib. Due to pregnancy, ADA was changed to CZP in 3 women and BT was stopped in 6 cases (3 ETN, 2 ADA, 1 CZP) as well as baricitinib. In 2 cases, ADA was stopped at week 17 of pregnancy (medical indication). Pregnancy was completed with BT (CZP) in 9 cases.9 abortions were registered prior to follow-up in the unit (0.28 abortions/mother) and 3 during follow-up (0.09 abortions/mother): 2 of them in women with CZP.C-section was performed in 26.8% of cases.Preterm birth (<37 weeks) happened in 9.7% (n: 4) of the pregnancies: 1 case in a woman with CZP.A total of 17 different fetal/maternal complications were registered during follow-up: 6 in the BT group (35.3%) compared to 11 (64.7%) in the group without BT, being Intrauterine Growth Restriction (IUGR) more frequent among women with BT. Infections were not more common in patients with BT. Complications are listed in Table 1.Table 1.COMPLICATIONSWITH BT (n, %) n: 11WITHOUT BT (n, %) n: 30IUGR3 (27.3%)1 (3.3%)LOW BIRTH WEIGHT2 (18.2%)2 (6.6%)INFECTION1 (9.1%)4 (13.3%)CHOLESTASIS0 (0%)2 (6.6%)PREECLAMPSIA0 (0%)1 (3.3%)DIABETES MELLITUS0 (0%)1 (3.3%)HIGH BLOOD PRESSURE0 (0%)0 (0%)NEPHROPATY0 (0%)0 (0%)NEONATAL LUPUS0 (0%)0 (0%)HEART BLOCK (0%)0 (0%)MALFORMATION0 (0%)0 (0%)HELLP SYNDROME0/0%)0 (0%)TOTAL6 (54.6%)11 (36.4%)Regarding concomitant treatment, low dose prednisone was used in 48.8% of pregnancies, hydroxychloroquine in 51.2%, sulfasalazine in 9.8% and acetylsalicylic acid in 51.2%. We didn´t find differences in the use of these treatments between the two groups.Median DAS28 among RA patients and available data was under 2.6 throughout pregnancy as well as previously and posteriorly. No differences in median DAS28 were found between women with BT and without BT. SpA patients had BASDAI lower than 4 in both groups during pregnancy and previously.Conclusion:In our series, as described in the literature, women with inflammatory arthropaties are older and are more likely to have preterm births compared to general population. Fewer abortions were registered during follow-up in the multidisciplinary unit. Appropriate disease control was maintained during pregnancy, also previously and afterwards. We registered more IUGR and low birth weight among women with BT but given the low number of patients with BT no statistically significant conclusions about complications can be drawn. Therefore, more studies among pregnant women with BT are necessary.Disclosure of Interests:None declared
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Hu, Li Ming, Heng Zhen Lee, Jian Wang, and Jian Ting Du. "Centrifuge Modeling and Numerical Simulation of Air Sparging Process." Advanced Materials Research 378-379 (October 2011): 445–48. http://dx.doi.org/10.4028/www.scientific.net/amr.378-379.445.
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Air sparging (AS) is one of the in-situ groundwater remediation techniques for remediating volatile organic compounds (VOCs) contaminated soil, and the knowledge of air flow features is essential in designing air sparging system for soil remediation. The centrifuge modeling technique was employed to simulate the in-situ conditions and to investigate air follow characteristics during air sparging by using glass beads as soils. Several centrifugal modeling tests were performed under various g-levels. According to the test results, the zone of influence (ZOI) during air sparging is in a truncated-cone shape under various g-levels, which can be expressed by the lateral expansion around the air injection point and the cone angle between the vertical axis and the boundary of ZOI. A 2D numerical model is used to model the air movement during air sparging process. The ZOI and the water saturation distribution were obtained. The results agree well with the centrifuge test data, which indicates the two phase flow model is reasonable to simulate the air sparging process. It was also shown that air compressibility and buoyant force have a significant influence on the extent of ZOI and should be adequately considered. Hence centrifuge modeling and numerical simulation can be used as a design tool for in-situ air sparging system
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Salama, Zienab M., Neamatallah G. Ahmed, and Asmaa M. Mahmoud. "Tertiary Trauma Survey: Nurses Performance and Polytrauma Patients’ Outcomes." Evidence-Based Nursing Research 1, no. 1 (April 11, 2019): 13. http://dx.doi.org/10.47104/ebnrojs3.v1i1.30.
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Context: Tertiary Trauma Survey is an important tool for the detection of missed injury, and some trauma units have created their protocol for tertiary trauma surveys to decrease the incidence of missed injuries in trauma patients. Aim: This study aims to assess nurses' performance regarding tertiary Survey and Poly-trauma patients’ outcome. Methods: Descriptive exploratory design utilized to achieve the aim of the study. A convenient sample of all available nurs- es (50 nurses) who are working in the intensive care unit at the emergency hospital affiliated to Ain Shams University Hos- pitals. A purposeful sample composed of (50) adult patients diagnosed as poly-trauma patients recruited from the same units. Data obtained through three main tools; Self-administered questionnaire for nurses, nurses practice observational checklist and clinical outcome record for patients.
Results: Nurses under study had an unsatisfactory level of knowledge and practice regarding tertiary trauma survey (44%&32%) respectively. There was a highly statistically significant positive correlation between the total level of knowledge and practice. There was the difference between injury severity score and laboratory, hemodynamic status, physi- cal assessment and radiological findings of polytrauma patients on admission and after 24 hours.
Conclusion: Less than half and less than one-third of the nurses under study had an unsatisfactory level of knowledge and practice respectively, regarding tertiary trauma survey. There was highly statistically significant positive correlation between the total level of knowledge and total level practice. Polytrauma patients' outcome, revealed a statistically significant differ- ence between injury severity score, hemodynamic status, physical assessment and radiological findings in polytrauma pa- tients on admission and after 24 hours. Recommendations: Further research is needed to follow the patients' outcome and missed injury. Replication of the current study on larger probability sample is recommended to achieve generalization of the result. Tailored Training courses are needed for nurses to improve unsatisfactory knowledge and practices regarding tertiary trauma survey- integrated studies with the emergency medical team to communicate patients' outcome research findings.
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Cholet, Orianne, Alain Hénaut, Serge Casaregola, and Pascal Bonnarme. "Gene Expression and Biochemical Analysis of Cheese-Ripening Yeasts: Focus on Catabolism of l-Methionine, Lactate, and Lactose." Applied and Environmental Microbiology 73, no. 8 (February 16, 2007): 2561–70. http://dx.doi.org/10.1128/aem.02720-06.
Full textAbstract:
ABSTRACT DNA microarrays of 86 genes from the yeasts Debaryomyces hansenii, Kluyveromyces marxianus, and Yarrowia lipolytica were developed to determine which genes were expressed in a medium mimicking a cheese-ripening environment. These genes were selected for potential involvement in lactose/lactate catabolism and the biosynthesis of sulfur-flavored compounds. Hybridization conditions to follow specifically the expression of homologous genes belonging to different species were set up. The microarray was first validated on pure cultures of each yeast; no interspecies cross-hybridization was observed. Expression patterns of targeted genes were studied in pure cultures of each yeast, as well as in coculture, and compared to biochemical data. As expected, a high expression of the LAC genes of K. marxianus was observed. This is a yeast that efficiently degrades lactose. Several lactate dehydrogenase-encoding genes were also expressed essentially in D. hansenii and K. marxianus, which are two efficient deacidifying yeasts in cheese ripening. A set of genes possibly involved in l-methionine catabolism was also used on the array. Y. lipolytica, which efficiently assimilates l-methionine, also exhibited a high expression of the Saccharomyces cerevisiae orthologs BAT2 and ARO8, which are involved in the l-methionine degradation pathway. Our data provide the first evidence that the use of a multispecies microarray could be a powerful tool to investigate targeted metabolism and possible metabolic interactions between species within microbial cocultures.