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Chaudhary, Hammad Tufail, and Shahida Hasnain. "IN-SILICO ANALYSIS." Professional Medical Journal 23, no. 02 (October 10, 2016): 217–22. http://dx.doi.org/10.29309/tpmj/2016.23.02.1074.
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ntroduction: Different pathogen reducing technologies are being implementedwhich includes S-303. CD-61 is important receptor for clotting. Pathogen reducing agents arebeing studied extensively to probe its effects. Objective: We conducted this study to reviewthe docking of S-303 at CD-61, to look into the effect of S-303 on function of platelets. StudyDesign: This was an observational study. Setting: In-silico study. Period: March 2015 toAugust 2015. Method: The study was carried out in-silico. PDB (Protein data bank) code ofTirofiban bound to CD-61 was 2vdm. CD-61 was docked with Tirofiban using online dockingtools i.e. Patchdock and Firedock. Then, S-303 and CD-61 were also docked. Best dockingposes to active sites of 2vdm were found. Interactions of ligands and CD-61 were obtained.Then comparison of Hydrogen Bonds, Hydrogen Bond Lengths, Hydrophobic bonds of 2vdmmolecule and best poses of docking results were done. Patchdock and Firdock results of bestposes were also analyzed using SPSS-16. Results: The Hydrogen bonds and Hydrogen bondlength and hydrophobic bonds of docking results were compared to 2vdm. 2 best poses wereobtained for docking of tirofiban to CD-61. No docking to active site was observed in Patchdockand firedock for S-303to CD-61. Conclusion: S-303 did not bind to the active site of CD-61. Wecan assume that S-303 doe
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Prajapat, Rajneesh, Suman Jain, Manish K. Vaishnav, and Sonal Sogani. "In Silico Characterization of Surface Glycoprotein [QHD43416] of Severe Acute Respiratory Syndrome-Coronavirus 2." Chinese Journal of Medical Research 3, no. 2 (June 25, 2020): 32–36. http://dx.doi.org/10.37515/cjmr.091x.3201.
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The novel coronavirus (SARS-CoV-2) reported from Wuhan, China, that spread rapidly and cause severe acute respiratory syndrome. The disease associated with infection of SARS-CoV-2 that is referred as COVID-19 (Coronavirus Disease 2019). In the present study, the surface glycoprotein [QHD43416] of SARS-CoV-2 was characterized for structure analysis and validation to provide information about its three-dimensional structure by using in silico tools and techniques. The surface glycoprotein [QHD43416] sequence of SARS-CoV-2 was retrieved from NCBI and its PDB file was designed by using phyre2 server. The RAMPAGE and UCLA-DOE (Verify 3D) was used for analysis and validation of structure model of protein. The model quality estimation based on the ProSA. Alignment of surface glycoprotein [QHD43416], revealed homology (72% identity) with spike protein of bat coronavirus [BM48-31/BGR/2008]. The model corresponding to probability conformation with 90.5% residue of core section, 9.1 % of allowed section and 0.4 % residue of outer section in φ-ψ plot, that specifies accuracy of prediction model. The Verify 3D results shows that 59.53% residues have average 3D-1D score >= 0.2 this determines compatibility of 3D model with its amino acid sequence (1D). ProSA Z-score -11.19 represents the good quality of the model. The structure and function of coronavirus surface glycoprotein could be predicted by in silico modeling studies. The protein model will be further used for designing of vaccine / drug development against coronavirus infection.
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Bayer, Benjamin, Roger Dalmau Diaz, Michael Melcher, Gerald Striedner, and Mark Duerkop. "Digital Twin Application for Model-Based DoE to Rapidly Identify Ideal Process Conditions for Space-Time Yield Optimization." Processes 9, no. 7 (June 25, 2021): 1109. http://dx.doi.org/10.3390/pr9071109.
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The fast exploration of a design space and identification of the best process conditions facilitating the highest space-time yield are of great interest for manufacturers. To obtain this information, depending on the design space, a large number of practical experiments must be performed, analyzed, and evaluated. To reduce this experimental effort and increase the process understanding, we evaluated a model-based design of experiments to rapidly identify the optimum process conditions in a design space maximizing space-time yield. From a small initial dataset, hybrid models were implemented and used as digital bioprocess twins, thus obtaining the recommended optimal experiment. In cases where these optimum conditions were not covered by existing data, the experiment was carried out and added to the initial data set, re-training the hybrid model. The procedure was repeated until the model gained certainty about the best process conditions, i.e., no new recommendations. To evaluate this workflow, we utilized different initial data sets and assessed their respective performances. The fastest approach for optimizing the space-time yield in a three-dimensional design space was found with five initial experiments. The digital twin gained certainty after four recommendations, leading to a significantly reduced experimental effort compared to other state-of-the-art approaches. This highlights the benefits of in silico design space exploration for accelerating knowledge-based bioprocess development, and reducing the number of hands-on experiments, time, energy, and raw materials.
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Oberleitner, Thomas, Thomas Zahel, Barbara Pretzner, and Christoph Herwig. "Holistic Design of Experiments Using an Integrated Process Model." Bioengineering 9, no. 11 (November 3, 2022): 643. http://dx.doi.org/10.3390/bioengineering9110643.
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Statistical experimental designs such as factorial, optimal, or definitive screening designs represent the state of the art in biopharmaceutical process characterization. However, such methods alone do not leverage the fact that processes operate as a mutual interplay of multiple steps. Instead, they aim to investigate only one process step at a time. Here, we want to develop a new experimental design method that seeks to gain information about final product quality, placing the right type of run at the right unit operation. This is done by minimizing the simulated out-of-specification rate of an integrated process model comprised of a chain of regression models that map process parameters to critical quality attributes for each unit operation. Unit operation models are connected by passing their response to the next unit operation model as a load parameter, as is done in real-world manufacturing processes. The proposed holistic DoE (hDoE) method is benchmarked against standard process characterization approaches in a set of in silico simulation studies where data are generated by different ground truth processes to illustrate the validity over a range of scenarios. Results show that the hDoE approach leads to a >50% decrease in experiments, even for simple cases, and, at the same time, achieves the main goal of process development, validation, and manufacturing to consistently deliver product quality.
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Florczuk, Patrycja, and Joanna Gruszczyńska. "GENETIC BACKGROUND OF CHONDRODYSPLASIA IN DOMESTIC DOG (CANIS LUPUS FAMILIARIS) – IN SILICO ANALYSIS." Acta Scientiarum Polonorum Zootechnica 15, no. 4 (January 10, 2017): 5–14. http://dx.doi.org/10.21005/asp.2016.15.4.01.
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Dmitriev, Alexander V., Alexey A. Lagunin, Dmitry А. Karasev, Anastasia V. Rudik, Pavel V. Pogodin, Dmitry A. Filimonov, and Vladimir V. Poroikov. "Prediction of Drug-Drug Interactions Related to Inhibition or Induction of Drug-Metabolizing Enzymes." Current Topics in Medicinal Chemistry 19, no. 5 (April 18, 2019): 319–36. http://dx.doi.org/10.2174/1568026619666190123160406.
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Drug-drug interaction (DDI) is the phenomenon of alteration of the pharmacological activity of a drug(s) when another drug(s) is co-administered in cases of so-called polypharmacy. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent type of DDI, which often appears as a result of the inhibition or induction of drug-metabolising enzymes (DME). In this review, we summarise in silico methods that may be applied for the prediction of the inhibition or induction of DMEs and describe appropriate computational methods for DDI prediction, showing the current situation and perspectives of these approaches in medicinal and pharmaceutical chemistry. We review sources of information on DDI, which can be used in pharmaceutical investigations and medicinal practice and/or for the creation of computational models. The problem of the inaccuracy and redundancy of these data are discussed. We provide information on the state-of-the-art physiologically- based pharmacokinetic modelling (PBPK) approaches and DME-based in silico methods. In the section on ligand-based methods, we describe pharmacophore models, molecular field analysis, quantitative structure-activity relationships (QSAR), and similarity analysis applied to the prediction of DDI related to the inhibition or induction of DME. In conclusion, we discuss the problems of DDI severity assessment, mention factors that influence severity, and highlight the issues, perspectives and practical using of in silico methods.
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Jager, Sven, and Oliver Buß. "Neue in silico-Methoden für die Etablierung einer Grünen Chemie." BIOspektrum 24, no. 1 (February 2018): 96–98. http://dx.doi.org/10.1007/s12268-018-0892-y.
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Gubin, Alexander N., J. Muthoni Njoroge, Urszula Wojda, Svetlana D. Pack, Maria Rios, Marion E. Reid, and Jeffery L. Miller. "Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family." Blood 96, no. 7 (October 1, 2000): 2621–27. http://dx.doi.org/10.1182/blood.v96.7.2621.
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Abstract Identification of the 25 known human blood group molecules is of fundamental importance for the fields of erythroid cell biology and transfusion medicine. Here we provide the first molecular description of the “Dombrock” blood group system. A candidate gene was identified by in silico analyses of approximately 5000 expressed sequence tags (ESTs) from terminally differentiating human erythroid cells. Transfection experiments demonstrated specific binding of anti-Dombrock and confirmed glycosylphosphatidylinositol membrane attachment. Dombrock expression is developmentally regulated during erythroid differentiation and occurs at highest levels in the fetal liver. Homology studies suggest that the Dombrock molecule is a member of the adenosine 5′-diphosphate (ADP)–ribosyltransferase ectoenzyme gene family. Genotypic comparisons suggest Doa versus Dob antigenicity results from a single amino acid substitution within an encoded arginine-glycine-aspartic acid (RGD) motif of the molecule.
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Gubin, Alexander N., J. Muthoni Njoroge, Urszula Wojda, Svetlana D. Pack, Maria Rios, Marion E. Reid, and Jeffery L. Miller. "Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family." Blood 96, no. 7 (October 1, 2000): 2621–27. http://dx.doi.org/10.1182/blood.v96.7.2621.h8002621_2621_2627.
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Identification of the 25 known human blood group molecules is of fundamental importance for the fields of erythroid cell biology and transfusion medicine. Here we provide the first molecular description of the “Dombrock” blood group system. A candidate gene was identified by in silico analyses of approximately 5000 expressed sequence tags (ESTs) from terminally differentiating human erythroid cells. Transfection experiments demonstrated specific binding of anti-Dombrock and confirmed glycosylphosphatidylinositol membrane attachment. Dombrock expression is developmentally regulated during erythroid differentiation and occurs at highest levels in the fetal liver. Homology studies suggest that the Dombrock molecule is a member of the adenosine 5′-diphosphate (ADP)–ribosyltransferase ectoenzyme gene family. Genotypic comparisons suggest Doa versus Dob antigenicity results from a single amino acid substitution within an encoded arginine-glycine-aspartic acid (RGD) motif of the molecule.
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Hann, M. M., S. Peace, S. Skerratt, D. Hirst, and S. Butterworth. "Experimental and in silico approaches to target selection and tractability for drug discovery. Highlights from the Society for Medicines Research Conference. London - March 21, 2022." Drugs of the Future 47, no. 9 (2022): 693. http://dx.doi.org/10.1358/dof.2022.47.9.3453460.
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Lachmann, Nils, Diana Stauch, and Axel Pruß. "Common and well-documented Allele List: unverzichtbares Hilfsmittel für die moderne HLA-Typisierung." Transfusionsmedizin - Immunhämatologie, Hämotherapie, Immungenetik, Zelltherapie 9, no. 04 (November 2019): 241–45. http://dx.doi.org/10.1055/a-0898-1122.
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ZusammenfassungDie Typisierung der humanen Leukozytenantigene (HLA) vor Organ- und hämatopoetischer Stammzelltransplantation zur Beurteilung der Kompatibilität von Spender und Empfänger wird heutzutage in der Regel molekulargenetisch mittels Amplifikation, Hybridisierung oder Sequenzierung durchgeführt. Durch die exponentiell steigende Anzahl an neu entdeckten HLA-Allelen treten vermehrt Mehrdeutigkeiten, sogenannte Ambiguitäten, in der HLA-Typisierung auf, die aufgelöst werden müssen, um zu einem eindeutigen Ergebnis zu gelangen. Mithilfe kategorisierter Allelfrequenzen (häufig, gut dokumentiert und selten) in Form von CWD-Allellisten (CWD: common and well-documented) ist die In-silico-Auflösung von Ambiguitäten durch den Ausschluss seltener Allele als mögliches Ergebnis realisierbar. Ausgehend von einer amerikanischen CWD-Liste existieren derzeit auch eine europäische, deutsche und chinesische CWD-Liste, die jeweils regionale Unterschiede in den Allelfrequenzen erkennbar werden lassen. Durch die Anwendung von CWD-Allelfiltern in der klinischen HLA-Typisierung können Zeit, Kosten und Arbeitskraft eingespart werden.
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Agase, D. M., K. K. Gupta, A. Wasnik, M. S. Markam, S. B. Zade, P. M. Mohurle, and T. S. Kothe. "Differential gene expression and co-regulated expression of genes in leukemia: an in-silico approach to identify potent biomarker." Journal of Applied and Natural Science 13, no. 2 (June 2, 2021): 585–92. http://dx.doi.org/10.31018/jans.v13i2.2650.
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A biomarker can be measured, used to diagnose or classify disease, and measure progress as well as the therapeutic response of the disease. Early diagnosis and selection of appropriate treatment can be critical for the successful treatment of diseases. Identification and characterization of potent diagnostic biomarkers, and therapeutic targets rely heavily on traditional in vitro screens which require extensive resources and time. Integration of in silico screens prior to experimental validation can improve the efficiency and potency of biomarkers as well as reduce the cost and time of biomarker discovery. Considering the need, present work was undertaken to identify biomarkers for different classes of leukemia. Differential Gene Expression (DGE) analysis and co-regulated expression analysis were used for in silico identification and characterise a potent biomarker for leukemia. On the basis of in silico screening, the present study proposed seven protein-coding (CD38, TSC22D3, TNFRSF25, AGL, LARGE1, ARHGAP32, and PARM1) genes for the diagnosis of leukemia. The study also proposed a novel three-step lineage-specific model for the diagnosis of leukemia. In the three-step diagnosis model, the first group of biomarkers with an association of clinical and hematological parameters diagnose leukemia. The second group of biomarkers diagnoses acute and chronic form of leukemia. The third group of biomarkers identifies whether it belongs to myeloid lineage or lymphoid lineage.
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Osterwalder, Uli, and Christian Surber. "Charakterisierung von Sonnenschutzleistung: Quo vadis?" Der Hautarzt 73, no. 4 (March 25, 2022): 276–82. http://dx.doi.org/10.1007/s00105-022-04958-x.
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ZusammenfassungDie Aufgabe der ersten Sonnenschutzmittel war es, die Entstehung von Sonnenbrand zu verhindern und, dem Zeitgeist der 1950/60er-Jahre folgend, die Bräunung der Haut nicht zu beeinträchtigen. Schnell entstand die Notwendigkeit, die Schutzleistung zu quantifizieren. Ursprünglich unter Zuhilfenahme des natürlichen – heute eines künstlichen – Sonnenlichts wurde eine Methode zur Bestimmung eines Sonnenschutzfaktor (SPF) entwickelt. Dieser ist heute formal als das Verhältnis zwischen minimaler erythemwirksamer UV-Dosis auf mit Sonnenschutzmittel geschützter und minimaler erythemwirksamer UV-Dosis auf ungeschützter Haut definiert (ISO 24444:2019). Drei Beobachtungen stellen die Eignung der Methode infrage: 1) Zwischen-Labor-Variabilität: Trotz strenger Normierung sind Resultate von SPF-Bestimmungen aus verschiedenen Labors und Regionen sehr großen Schwankungen unterworfen. 2) Natürliches vs. künstliches Sonnenlicht: Das Strahlungsspektrum des künstlichen Sonnenlichts unterscheidet sich von dem des natürlichen Sonnenlichts. Die mit künstlichem Sonnenlicht bestimmten SPFs (wie auf allen derzeit im Handel befindlichen Sonnenschutzmitteln abgebildet) sind im Vergleich zur SPF-Bestimmung mit natürlichem Sonnenlicht deutlich zu hoch. 3) Erythembelastung: Bei der Bestimmung des SPF werden die Probanden potenziell schädlicher Strahlung ausgesetzt. Vor diesem Hintergrund werden alternative Methoden – In-vitro-SPF, hybride diffuse Reflexionsspektroskopie (HDRS) und In-silico-Berechnungen – vorgestellt. Diese haben das Potenzial, die heutige mit erheblichen Einschränkungen verbundene Methode abzulösen. Als Sofortmaßnahme wird die Rückbesinnung auf die für alle verständliche Beschreibung niedriger, mittlerer, hoher und sehr hoher Schutz empfohlen, in Zukunft unter Berücksichtigung des Spektrums des natürlichen Sonnenlichtes.
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Wu, Chengyue, David A. Hormuth, Ty Easley, Victor Eijkhout, Federico Pineda, Gregory S. Karczmar, and Thomas E. Yankeelov. "An in silico validation framework for quantitative DCE-MRI techniques based on a dynamic digital phantom." Medical Image Analysis 73 (October 2021): 102186. http://dx.doi.org/10.1016/j.media.2021.102186.
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Akbar, Shehla, Saiqa Ishtiaq, Muhammad Jahangir, Sameh S. Elhady, Hanin A. Bogari, Abdelrahman M. Alahdal, Mohamed L. Ashour, and Fadia S. Youssef. "Evaluation of The Antioxidant, Antimicrobial, and Anticancer Activities of Dicliptera bupleuroides Isolated Compounds Using In Vitro and In Silico Studies." Molecules 26, no. 23 (November 27, 2021): 7196. http://dx.doi.org/10.3390/molecules26237196.
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Phytochemical investigation of chloroform fraction (DBC) and ethyl acetate fraction (DBE) of D. bupleuroides (Acanthaceae) resulted in the isolation of β-sitosterol (1) from DBC and vanillic acid (2) from DBE, which were first to be isolated from D. bupleuroides. β-Sitosterol (1) exhibited substantial antioxidant activity (IC50 = 198.87 µg/mL), whereas vanillic acid (2) showed significant antioxidant power (IC50 = 92.68 µg/mL) employing 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical scavenging capacity assay. Both compounds showed pronounced antimicrobial activity using the agar disc diffusion method, particularly against fungi showing MIC values of 0.182 and 0.02 concerning Candida albicans, respectively, and 0.001 mg/mL regarding Penicillium notatum. They revealed considerable antibacterial activity with MIC values ranging between 0.467 and 0.809 mg/mL. Vanillic acid (2) exhibited substantial anticancer potential displaying 48.67% cell viability at a concentration of 100 μg/mL using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyl-2H-Tetrazolium Bromide) assay concerning HepG2 cell lines. These results were further consolidated by in silico studies on different enzymes, where vanillic acid displayed a high fitting score in the active pockets of DNA-gyrase, dihydrofolate reductase, aminoglycoside nucleotidyltransferase, and β-lactamase. It also inhibited human cyclin-dependent kinase 2 (CDK-2) and DNA topoisomerase II, as revealed by the in silico studies. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) prediction showed that vanillic acid exhibited reasonable pharmacodynamic, pharmacokinetic, and toxicity properties and, thus, could perfectly together with D. bupleuroides crude extract be incorporated in pharmaceutical preparations to counteract cancer and microbial invasion, as well as oxidative stress. Thus, it is concluded that D. bupleroides could be a potential source of therapeutically active compounds, which would be helpful for the discovery of clinically effective and safe drugs.
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Parisi, Giacomo, Ida Freda, Cécile Exertier, Cristina Cecchetti, Elena Gugole, Gabriele Cerutti, Lucia D’Auria, et al. "Dissecting the Cytochrome P450 OleP Substrate Specificity: Evidence for a Preferential Substrate." Biomolecules 10, no. 10 (October 6, 2020): 1411. http://dx.doi.org/10.3390/biom10101411.
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The cytochrome P450 OleP catalyzes the epoxidation of aliphatic carbons on both the aglycone 8.8a-deoxyoleandolide (DEO) and the monoglycosylated L-olivosyl-8.8a-deoxyoleandolide (L-O-DEO) intermediates of oleandomycin biosynthesis. We investigated the substrate versatility of the enzyme. X-ray and equilibrium binding data show that the aglycone DEO loosely fits the OleP active site, triggering the closure that prepares it for catalysis only on a minor population of enzyme. The open-to-closed state transition allows solvent molecules to accumulate in a cavity that forms upon closure, mediating protein–substrate interactions. In silico docking of the monoglycosylated L-O-DEO in the closed OleP–DEO structure shows that the L-olivosyl moiety can be hosted in the same cavity, replacing solvent molecules and directly contacting structural elements involved in the transition. X-ray structures of aglycone-bound OleP in the presence of L-rhamnose confirm the cavity as a potential site for sugar binding. All considered, we propose L-O-DEO as the optimal substrate of OleP, the L-olivosyl moiety possibly representing the molecular wedge that triggers a more efficient structural response upon substrate binding, favoring and stabilizing the enzyme closure before catalysis. OleP substrate versatility is supported by structural solvent molecules that compensate for the absence of a glycosyl unit when the aglycone is bound.
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Würfel, Franziska M., Ralph M. Wirtz, Christoph Winterhalter, Mario Taffurelli, Donatella Santini, Anna Mandrioli, Elke Veltrup, et al. "Das Nicht-Pseudogen HLA‑J ist ein neuer prognostischer Marker für das Ansprechen auf Therapie und das Überleben bei Brustkrebs." Senologie - Zeitschrift für Mammadiagnostik und -therapie 18, no. 04 (December 2021): 353–64. http://dx.doi.org/10.1055/a-1678-0867.
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ZusammenfassungHumane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA‑G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA‑J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA‑J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA‑J, und der HLA‑J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt.
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Gassner, Christoph. "Molekulare Blutgruppenbestimmung." Transfusionsmedizin - Immunhämatologie, Hämotherapie, Immungenetik, Zelltherapie 7, no. 02 (May 2017): 87–94. http://dx.doi.org/10.1055/s-0043-104615.
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ZusammenfassungDie erste molekulare Analyse einer menschlichen Blutgruppe erfolgte 1983 mittels eines Restriktions-Fragment-Längen-Polymorphismus (RFLP) am System Xg. Seither wurden in unzähligen Studien die molekularen Ursachen für Blutgruppen und deren Antigene erforscht,und das resultierende Wissen für eine ständige Verbesserung der entsprechenden Analysemethoden verwendet. Die Untersuchung kausaler Punktmutationen (Single Nucleotide Polymorphism, SNP) aller 36 von der International Society for Blood Transfusion (ISBT) anerkannten Blutgruppensysteme erlaubt heute eine der Serologie ebenbürtige, exakte Vorhersage der Blutgruppenantigene. In Patienten wird die molekulare Blutgruppenbestimmung bevorzugt in Form von Einzelprobenanalytik für die Diagnose von RhD-Varianten eingesetzt, um damit transfusionsrelevante Entscheidungen bezüglich RhD zu treffen und um die Rh-Prophylaxe noch zielsicherer zu steuern. An Spenderproben und im Hochdurchsatz ermöglicht die Blutgruppen-Genotypisierung die Schaffung einer ausreichenden Anzahl von Spender-Datensätzen, um immunisierte Patienten bestverträglich zu transfundieren oder deren Immunisierung bereits im Ansatz zu vermeiden. Gleichzeitig werden heutzutage an den gleichen Proben zusätzlich eine Vielzahl weiterer SNPs zur Identifikation von Spendern mit seltener Negativität für hochfrequente Antigene getestet. Derartig umfassende Spender-Datensätze werden bereits ideal genutzt für „In-silico-Kreuzproben“ eingesetzt. Next Generation Sequencing (NGS) ist auch in der Transfusionsmedizin der „neue Stern am Horizont“ und wird vermutlich innert weniger Jahre eine wichtige Rolle in der Analyse kompletter Blutgruppengenome (chronischer) Empfänger spielen. Blutgruppenbestimmung als frühestes Beispiel echter personalisierter Medizin wird in ihrer molekularen Version mit dazu beitragen, den gebührenden Platz der Transfusionsmedizin in der modernen Medizin zu behaupten.
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Ianevski, Aleksandr, Rouan Yao, Eva Zusinaite, Hilde Lysvand, Valentyn Oksenych, Tanel Tenson, Magnar Bjørås, and Denis Kainov. "Active Components of Commonly Prescribed Medicines Affect Influenza A Virus–Host Cell Interaction: A Pilot Study." Viruses 13, no. 8 (August 3, 2021): 1537. http://dx.doi.org/10.3390/v13081537.
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Background: Every year, millions of people are hospitalized and thousands die from influenza A virus (FLUAV) infection. Most cases of hospitalizations and death occur among the elderly. Many of these elderly patients are reliant on medical treatment of underlying chronic diseases, such as arthritis, diabetes, and hypertension. We hypothesized that the commonly prescribed medicines for treatment of underlying chronic diseases can affect host responses to FLUAV infection and thus contribute to the morbidity and mortality associated with influenza. Therefore, the aim of this study was to examine whether commonly prescribed medicines could affect host responses to virus infection in vitro. Methods: We first identified 45 active compounds from a list of commonly prescribed medicines. Then, we constructed a drug–target interaction network and identified the potential implication of these interactions for FLUAV–host cell interplay. Finally, we tested the effect of 45 drugs on the viability, transcription, and metabolism of mock- and FLUAV-infected human retinal pigment epithelial (RPE) cells. Results: In silico drug–target interaction analysis revealed that drugs such as atorvastatin, candesartan, and hydroxocobalamin could target and modulate FLUAV–host cell interaction. In vitro experiments showed that at non-cytotoxic concentrations, these compounds affected the transcription and metabolism of FLUAV- and mock-infected cells. Conclusion: Many commonly prescribed drugs were found to modulate FLUAV–host cell interactions in silico and in vitro and could therefore affect their interplay in vivo, thus contributing to the morbidity and mortality of patients with influenza virus infections.
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Baral, Adesh, Ritesh Gorkhali, Amit Basnet, Shubham Koirala, and Hitesh Kumar Bhattarai. "Selection of the Optimal L-asparaginase II Against Acute Lymphoblastic Leukemia: An In Silico Approach." JMIRx Med 2, no. 3 (September 8, 2021): e29844. http://dx.doi.org/10.2196/29844.
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Background L-asparaginase II (asnB), a periplasmic protein commercially extracted from E coli and Erwinia, is often used to treat acute lymphoblastic leukemia. L-asparaginase is an enzyme that converts L-asparagine to aspartic acid and ammonia. Cancer cells are dependent on asparagine from other sources for growth, and when these cells are deprived of asparagine by the action of the enzyme, the cancer cells selectively die. Objective Questions remain as to whether asnB from E coli and Erwinia is the best asparaginase as they have many side effects. asnBs with the lowest Michaelis constant (Km; most potent) and lowest immunogenicity are considered the most optimal enzymes. In this paper, we have attempted the development of a method to screen for optimal enzymes that are better than commercially available enzymes. Methods In this paper, the asnB sequence of E coli was used to search for homologous proteins in different bacterial and archaeal phyla, and a maximum likelihood phylogenetic tree was constructed. The sequences that are most distant from E coli and Erwinia were considered the best candidates in terms of immunogenicity and were chosen for further processing. The structures of these proteins were built by homology modeling, and asparagine was docked with these proteins to calculate the binding energy. Results asnBs from Streptomyces griseus, Streptomyces venezuelae, and Streptomyces collinus were found to have the highest binding energy (–5.3 kcal/mol, –5.2 kcal/mol, and –5.3 kcal/mol, respectively; higher than the E coli and Erwinia asnBs) and were predicted to have the lowest Kms, as we found that there is an inverse relationship between binding energy and Km. Besides predicting the most optimal asparaginase, this technique can also be used to predict the most optimal enzymes where the substrate is known and the structure of one of the homologs is solved. Conclusions We have devised an in silico method to predict the enzyme kinetics from a sequence of an enzyme along with being able to screen for optimal alternative asnBs against acute lymphoblastic leukemia.
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Wang, Zhenyu, and Christos Georgakis. "On the Performance of DoDE in a class of in silico Fermentation Processes and the Impact of the Input Domain." IFAC Proceedings Volumes 46, no. 31 (2013): 163–68. http://dx.doi.org/10.3182/20131216-3-in-2044.00015.
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Gurung, Rajya L., Liesel M. FitzGerald, Ebony Liu, Bennet J. McComish, Georgia Kaidonis, Bronwyn Ridge, Alex W. Hewitt, et al. "Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema." International Journal of Molecular Sciences 23, no. 7 (April 6, 2022): 4042. http://dx.doi.org/10.3390/ijms23074042.
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Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
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Caltabiano, Rosario, Rocco De Pasquale, Eliana Piombino, Giorgia Campo, Ferdinando Nicoletti, Eugenio Cavalli, Katia Mangano, and Paolo Fagone. "Macrophage Migration Inhibitory Factor (MIF) and Its Homologue D-Dopachrome Tautomerase (DDT) Inversely Correlate with Inflammation in Discoid Lupus Erythematosus." Molecules 26, no. 1 (January 1, 2021): 184. http://dx.doi.org/10.3390/molecules26010184.
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Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.
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Cárdenas-García, Maura, and Pedro Pablo González-Pérez. "Applying the Tuple Space-Based Approach to the Simulation of the Caspases, an Essential Signalling Pathway." Journal of Integrative Bioinformatics 10, no. 1 (March 1, 2013): 19–28. http://dx.doi.org/10.1515/jib-2013-225.
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Summary Apoptotic cell death plays a crucial role in development and homeostasis. This process is driven by mitochondrial permeabilization and activation of caspases. In this paper we adopt a tuple spaces-based modelling and simulation approach, and show how it can be applied to the simulation of this intracellular signalling pathway. Specifically, we are working to explore and to understand the complex interaction patterns of the caspases apoptotic and the mitochondrial role. As a first approximation, using the tuple spacesbased in silico approach, we model and simulate both the extrinsic and intrinsic apoptotic signalling pathways and the interactions between them. During apoptosis, mitochondrial proteins, released from mitochondria to cytosol are decisively involved in the process. If the decision is to die, from this point there is normally no return, cancer cells offer resistance to the mitochondrial induction.
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Pérez-Ramos, Adrián, Rabia Ladjouzi, Abdellah Benachour, and Djamel Drider. "Evidence for the Involvement of Pleckstrin Homology Domain-Containing Proteins in the Transport of Enterocin DD14 (EntDD14); a Leaderless Two-Peptide Bacteriocin." International Journal of Molecular Sciences 22, no. 23 (November 28, 2021): 12877. http://dx.doi.org/10.3390/ijms222312877.
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Bacteriocins synthesis is initiated from an inactive precursor, which is composed of an N-terminal leader peptide attached to a C-terminal pro-peptide. However, leaderless bacteriocins (LLB) do not possess this N-terminal leader peptide nor undergo post-translational modifications. These atypical bacteriocins are observed to be immediately active after their translation in the cytoplasm. However, although considered to be simple, the biosynthetic pathway of LLB remains to be fully understood. Enterocin DD14 (EntDD14) is a two-peptide LLB produced by Enterococcus faecalis 14, which is a strain isolated from meconium. In silico analysis of DNA encoding EntDD14 located a cluster of 10 genes ddABCDEFGHIJ, where ddE and ddF encode the peculiar DdE and DdF proteins, carrying pleckstrin homology (PH) domains. These modules are quite common in Eucarya proteins and are known to be involved in intracellular signaling or cytoskeleton organization. To elucidate their role within the EntDD14 genetic determinants, we constructed deletion mutants of the ddE and ddF genes. As a result, the mutants were unable to export EntDD14 outside of the cytoplasm even though there was a clear expression of structural genes ddAB encoding EntDD14, and genes ddHIJ encoding an ABC transporter. Importantly, in these mutant strains (ΔddE and ΔddF), EntDD14 was detected by mass spectrometry in the intracellular soluble fraction exerting, upon its accumulation, a toxic effect on the producing strain as revealed by cell-counting and confocal microscopy analysis. Taken together, these results clearly indicate that PH domain-containing proteins, such as DdE and DdF, are involved in the transport of the leaderless two-peptide EntDD14.
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Easley, Ty O., Zhen Ren, Byol Kim, Gregory S. Karczmar, Rina F. Barber, and Federico D. Pineda. "Enhancement-constrained acceleration: A robust reconstruction framework in breast DCE-MRI." PLOS ONE 16, no. 10 (October 28, 2021): e0258621. http://dx.doi.org/10.1371/journal.pone.0258621.
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In patients with dense breasts or at high risk of breast cancer, dynamic contrast enhanced MRI (DCE-MRI) is a highly sensitive diagnostic tool. However, its specificity is highly variable and sometimes low; quantitative measurements of contrast uptake parameters may improve specificity and mitigate this issue. To improve diagnostic accuracy, data need to be captured at high spatial and temporal resolution. While many methods exist to accelerate MRI temporal resolution, not all are optimized to capture breast DCE-MRI dynamics. We propose a novel, flexible, and powerful framework for the reconstruction of highly-undersampled DCE-MRI data: enhancement-constrained acceleration (ECA). Enhancement-constrained acceleration uses an assumption of smooth enhancement at small time-scale to estimate points of smooth enhancement curves in small time intervals at each voxel. This method is tested in silico with physiologically realistic virtual phantoms, simulating state-of-the-art ultrafast acquisitions at 3.5s temporal resolution reconstructed at 0.25s temporal resolution (demo code available here). Virtual phantoms were developed from real patient data and parametrized in continuous time with arterial input function (AIF) models and lesion enhancement functions. Enhancement-constrained acceleration was compared to standard ultrafast reconstruction in estimating the bolus arrival time and initial slope of enhancement from reconstructed images. We found that the ECA method reconstructed images at 0.25s temporal resolution with no significant loss in image fidelity, a 4x reduction in the error of bolus arrival time estimation in lesions (p < 0.01) and 11x error reduction in blood vessels (p < 0.01). Our results suggest that ECA is a powerful and versatile tool for breast DCE-MRI.
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Ravindran, Anindita, Danthasinghe Waduge Badrajee Piyarathna, Jie Gohlke, Vasanta Putluri, Tanu Soni, Stacy Lloyd, Patricia Castro, et al. "Lipid Alterations in African American Men with Prostate Cancer." Metabolites 12, no. 1 (December 22, 2021): 8. http://dx.doi.org/10.3390/metabo12010008.
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African-American (AA) men are more than twice as likely to die of prostate cancer (PCa) than European American (EA) men. Previous in silico analysis revealed enrichment of altered lipid metabolic pathways in pan-cancer AA tumors. Here, we performed global unbiased lipidomics profiling on 48 matched localized PCa and benign adjacent tissues (30 AA, 24 ancestry-verified, and 18 EA, 8 ancestry verified) and quantified 429 lipids belonging to 14 lipid classes. Significant alterations in long chain polyunsaturated lipids were observed between PCa and benign adjacent tissues, low and high Gleason tumors, as well as associated with early biochemical recurrence, both in the entire cohort, and within AA patients. Alterations in cholesteryl esters, and phosphatidyl inositol classes of lipids delineated AA and EA PCa, while the levels of lipids belonging to triglycerides, phosphatidyl glycerol, phosphatidyl choline, phosphatidic acid, and cholesteryl esters distinguished AA and EA PCa patients with biochemical recurrence. These first-in-field results implicate lipid alterations as biological factors for prostate cancer disparities.
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Ahmed, Atallah F., Zhi-Hong Wen, Ahmed H. Bakheit, Omer A. Basudan, Hazem A. Ghabbour, Abdullah Al-Ahmari, and Chien-Wei Feng. "A Major Diplotaxis harra-Derived Bioflavonoid Glycoside as a Protective Agent against Chemically Induced Neurotoxicity and Parkinson’s Models; In Silico Target Prediction; and Biphasic HPTLC-Based Quantification." Plants 11, no. 5 (February 27, 2022): 648. http://dx.doi.org/10.3390/plants11050648.
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Oxidative stress and chronic inflammation have a role in developing neurodegenerative diseases such as Parkinson’s disease (PD) and inflammatory movement disorders such as rheumatoid arthritis that affect millions of populations. In searching for antioxidant and anti-inflammatory molecules from natural sources that can counteract neurodegenerative diseases and arthritis, the flavonoid-rich extract of Diplotaxis harra (DHE) was selected based on its in vitro antioxidant and anti-inflammatory activities. DHE could inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages from 100% to the level of 28.51 ± 18.67 and 30.19 ± 5.00% at 20 μg/mL, respectively. A TLC bioautography of DHE fractions using 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) led to the isolation of a major antioxidant compound which was identified by X-ray diffraction analysis as isorhamnetin-3-O-β-D-glucoside (IR3G). IR3G also exhibited a potent anti-inflammatory activity, particularly by suppressing the upregulation of iNOS expression, similar to that of dexamethasone (DEX) at 10 μM to the level of 35.96 ± 7.80 and 29.34 ± 6.34%, respectively. Moreover, IR3G displayed a strong neuroprotectivity (>60% at 1.0−4–1.0−3 μM) against 6-hydroxydopamine (6-OHDA)-challenged SHSY5Y neuroblastoma, an in vitro model of dopaminergic neurons for Parkinson’s disease (PD) research. Accordingly, the in vivo anti-Parkinson potentiality was evaluated, where it was found that IR3G successfully reversed the 6-OHDA-induced locomotor deficit in a zebrafish model. A study of molecular docking and molecular dynamic (MD) simulation of IR3G and its aglycone isorhamnetin (IR) against human acetylcholine esterase (AChE), monoamine oxidase B (MAO-B), and Polo-like kinase-2 (PLK2) was performed and further outlined a putative mechanism in modulating neurodegenerative diseases such as PD. The free radical scavenging, anti-inflammatory through anti-iNOS and anti-COX-2 expression, and neuroprotective activities assessed in this study would present partial evidence for the potentiality of D. harra-derived IR3G as a promising natural therapeutic agent against neurodegenerative diseases and inflammatory arthritis. Finally, a biphasic HPTLC method was developed to estimate the biomarker IR3G in D. harra quantitatively.
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Vona, Barbara, Marcus Müller, Saskia Dofek, Martin Holderried, Hubert Löwenheim, and Anke Tropitzsch. "Big data in der Diagnostik genetischer Schwerhörigkeit." Laryngo-Rhino-Otologie 98, S 01 (March 2019): S32—S81. http://dx.doi.org/10.1055/a-0803-6149.
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ZusammenfassungDie vollständige Sequenzierung des menschlichen Genoms demonstriert als ein grundlegendes Beispiel eindrucksvoll die Entstehung einer großen Datenmenge (engl.: big data) in Wissenschaft und Medizin. Die Entschlüsselung des menschlichen Genoms stellt das bemerkenswerte Ergebnis multidisziplinärer Zusammenarbeit dar und gilt als eines der größten und erfolgreichsten Vorhaben der Menschheitsgeschichte. Die Bedeutung dieser Entdeckung lag nicht nur darin, die Sequenz von 3,2 Milliarden Nukleotiden des humanen Genoms zu identifizieren, sondern in Zukunft auch krankheitsassoziierte Variationen zu verstehen und dieses Wissen auf individualisierte Behandlungsansätze der personalisierten Medizin anzuwenden. Die Genomik hat sich seitdem mit bemerkenswerter Geschwindigkeit weiterentwickelt. Hierzu haben im Wesentlichen digitale, technologische Fortschritte in der Sequenzierung, Computer- und Bioinformatik wesentlich beigetragen. Die dadurch entstandenen großen genomischen Datenmengen haben den Begriff „big data“ hervorgebracht. Die heutige bioinformatisch geleitete Einzelfallanalyse genetischer Befunde im Krankheitskontext erfordert in der Regel die Verwendung mehrerer großer Datenmengen. Diese Datenmengen liegen in Form von strukturierten genetischen Datenbanken vor und werden bspw. im Rahmen von in silico Analyseprogramme und Allel-Häufigkeitsanalysen verwendet. Die aktuellen Technologien der Hochdurchsatzsequenzierung sind in der Lage kostengünstige und qualitativ hochwertige Daten zu erzeugen. Dies reicht von der Analyse mit gezielten krankheitsassoziierten Gen-Panels, über die Exom Analyse, bis hin zur Entschlüsselung des gesamten Genoms. Diese neuen Möglichkeiten haben die Diagnostik von Erbkrankheiten revolutioniert und wirken sich auf die Diagnostik der genetischen Schwerhörigkeit aus.Die Analyse der genetischen Grundlagen der vererbbaren Form des Hörverlusts ist aufgrund großer genetischer Heterogenität und klinischer Variabilität in 2-facher Hinsicht eine besondere Herausforderung. Es sind bereits über 150 Gene bekannt, die an nicht-syndromalen und syndromalen Formen des Hörverlusts beteiligt sind. Das Mutationsspektrum eines einzelnen Hörverlust-assoziierten Gens kann mehrere zehn bis hunderte von pathogenen Varianten aufweisen. Darüber hinaus kann die Interpretation neuer Varianten eine Herausforderung darstellen, insbesondere, wenn widersprüchliche Informationen in Datenbanken hinterlegt wurden. Detaillierte und strukturierte phänotypische Informationen haben sich in der Diagnostik einiger Formen des Hörverlusts als äußerst vielversprechend erwiesen, sind aber bisher nicht für alle genetischen Formen von Schwerhörigkeit nutzbar. Während mit enormer Geschwindigkeit ständig neues Wissen sowohl im diagnostischen als auch im wissenschaftlichen Kontext entsteht, stellt diese überwältigende Menge an Informationen eine zunehmende Herausforderung für Fachärzte dar. Die fachärztliche Versorgung übernimmt hier neue Aufgaben und fungiert als Schnittstelle zwischen dem humangenetisch-diagnostischen Labor und dem Patienten. Zu diesen Aufgaben gehört die fachbezogene genetische Beratung und die klinische Einordnung von genetischen Befunden.Diese Übersicht soll als Referenz für HNO-Ärzte dienen, die einen Einstieg in die Molekulargenetik der Schwerhörigkeit erhalten möchten. Es erfolgt die Darstellung von Schlüsselkonzepten der molekulargenetischen Diagnostik. Gerade die komplexen Prozesse, die der Identifizierung und Interpretation von genetischen Varianten zugrunde liegen, wären ohne die die enormen zur Verfügung stehenden Datenmengen nicht denkbar. Insofern sind „big data“ unabdingbare Voraussetzung, um genetische Daten im konkreten Einzelfall zu filtern und gerade für den klinisch tätigen Arzt im Kontakt mit dem Patienten überschaubar und nutzbar zu machen.
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Marschik, Christian, Wolfgang Roland, and Jürgen Miethlinger. "A Network-Theory-Based Comparative Study of Melt-Conveying Models in Single-Screw Extrusion: A. Isothermal Flow." Polymers 10, no. 8 (August 19, 2018): 929. http://dx.doi.org/10.3390/polym10080929.
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In many extrusion processes, the metering section is the rate-controlling part of the screw. In this functional zone, the polymer melt is pressurized and readied to be pumped through the die. We have recently proposed a set of heuristic models for predicting the flow behavior of power-law fluids in two- and three-dimensional metering channels. These novel theories remove the need for numerical simulations and can be implemented easily in practice. Here we present a comparative study designed to validate these new methods against experimental data. Extensive experiments were performed on a well-instrumented laboratory single-screw extruder, using various materials, screw designs, and processing conditions. A network-theory-based simulation routine was written in MATLAB to replicate the flow in the metering zones in silico. The predictions of the three-dimensional heuristic melt-conveying model for the axial pressure profile along the screw are in excellent agreement with the experimental extrusion data. To demonstrate the usefulness of the novel melt-flow theories, we additionally compared the models to a modified Newtonian pumping model known from the literature.
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N. Alhashem, Yousef, Arshad Farid, Mohammed Al Mohaini, Muhammad Muzammal, Muhammad Hashim Khan, Arezoo Dadrasnia, Abdulkhaliq J. Alsalman, et al. "Protein Isolation and Separation Techniques of Pasteurella multocidavia One- and Two-Dimen-Sional Gel Electrophoresis." International Journal of Current Research and Review 14, no. 12 (2022): 01–08. http://dx.doi.org/10.31782/ijcrr.2022.141208.
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Introduction: Bacteria in the genus Pasteurella live as commensal parasites on the mucous membranes of vertebrates, particularly mammals and birds. Pasteurella species like Pasteurella multocida and Pasteurella haemolytica cause significant economic losses as a result of diseases caused by these two microorganisms. Objective: This study compares protein isolation and analysis methods for effective one and two-dimensional gel electrophoresis of Pasteurella multocidaproteins and a preliminary protein mapping and analysis of P. multocida serotype B. Methodology: Protein samples were obtained by two isolation methods: homogenisation/sonication and detergent lysis. 1D SDS-PAGE methodology was optimized for protein loading, separating gel percentages and gel size. Detergent lysis was the preferred isolation method of total proteins. Results: The optimum running condition for SDS-PAGE was determined to be 15 µg of protein loading run on a 12.5% separating gel with a gel size of 10cm x 10cm. Preliminary 1D SDS-PAGE analysis revealed 3 distinct protein bands (33 kDa, 39 kDa and >200 kDa), which could only be found specifically in serotype B samples. The samples were then separated by 2-DGE after optimization. The optimum running condition was 500µg of protein sample loaded using rehydration loading with immobilized pH gradient (IPG) strips pH 3–10 for the first-dimension isoelectric focusing (IEF) and 12.5% single percentage gel for the seconddimension SDS-PAGE. The protein map, which produced the most, spots were compared to in silico 2-DGE protein patterns of Pm70 in GELBANK database. Conclusion: A total of 23 proteins were identified and protein of 33 kDA was identified in both 1D SDS-PAGE and 2-DGE. This is the first protein analysis and the first protein map of P. multocida serotype B ever produced.
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Giancotti, Gilda, Giulio Nannetti, Gilda Padalino, Martina Landini, Nanci Santos-Ferreira, Jana Van Dycke, Valentina Naccarato, et al. "Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase." Viruses 15, no. 1 (December 27, 2022): 74. http://dx.doi.org/10.3390/v15010074.
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Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure–activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization.
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Bourbiaux, B. "Low salinity effects on oil recovery performance: underlying physical mechanisms and practical assessment." Oil & Gas Science and Technology – Revue d’IFP Energies nouvelles 75 (2020): 37. http://dx.doi.org/10.2516/ogst/2020030.
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This paper is a tentative synthesis of the main knowledge and experience gained from recent studies and application of Low Salinity Water Injection (LSWI) in carbonate and clayey silico-clastic rocks. A physical model based on ionic force is presented to explain the so-called Dual Layer Expansion (DLE) mechanism often invoked to account for the Low Salinity Effects (LSE) on rock wettability and oil recovery. The role played by the Multi Ion Exchange (MIE) mechanism is clarified, at least for clayey rocks. Eventually, the proposed physical analysis shows the complementary roles that injected brine concentration and composition can play on waterflood recovery efficiency depending on the Crude Oil Brine Rock (COBR) system under consideration. To account for the diversity of COBR systems, a straightforward modelling methodology is then proposed to simulate laboratory LSWI tests on a case-by-case basis and infer the actual evolution of residual oil saturation with brine concentration and/or composition. The simulation involves a wettability driver that may be either the global salinity or the square root of ionic force. The analysis of published results actually shows that the latter predicts low salinity effects on residual oil saturation better than the former. Hopefully, this paper contributes to the understanding of the DLE and MIE mechanisms induced by a smart water injection and provides a simple and robust methodology to simulate the reference coreflood experiments that remain necessary to assess and optimize LSWI.
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Lee, Chanjae, Min K. Bae, Nakjun Choi, Su Jeong Lee, and Sung-Jae Lee. "Genome Plasticity by Insertion Sequences Learned From a Case of Radiation-Resistant Bacterium Deinococcus geothermalis." Bioinformatics and Biology Insights 15 (January 2021): 117793222110374. http://dx.doi.org/10.1177/11779322211037437.
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The genome of the radiation-resistant bacterium Deinococcus geothermalis contains 19 types of insertion sequences (ISs), including 93 total transposases (Tpases) in 73 full-length ISs from the main chromosome and 2 mega plasmids. In this study, 68 ISs from the D. geothermalis genome were extracted to implicate the earlier genome before its mutation by transposition of ISs. The total size of eliminated ISs from genome was 78.85 kb. From these in silico corrections of mutation by the ISs, we have become aware of some bioinformatics factualness as follows: (1) can reassemble the disrupted genes if the exact IS region was eliminated, (2) can configure the schematic clustering of major DDE type Tpases, (3) can determine IS integration order across multiple hot spots, and (4) can compare genetic relativeness by the partial synteny analysis between D. geothermalis and Deinococcus strain S9. Recently, we found that several IS elements actively transferred to other genomic sites under hydrogen peroxide-induced oxidative stress conditions, resulting in the inactivation of functional genes. Therefore, the single species genome’s mobilome study provides significant support to define bacterial genome plasticity and molecular evolution from past and present progressive transposition events.
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Pérez-Ramos, Adrián, Rabia Ladjouzi, Marius Mihasan, Radja Teiar, Abdellah Benachour, and Djamel Drider. "Advances in Characterizing the Transport Systems of and Resistance to EntDD14, A Leaderless Two-Peptide Bacteriocin with Potent Inhibitory Activity." International Journal of Molecular Sciences 24, no. 2 (January 12, 2023): 1517. http://dx.doi.org/10.3390/ijms24021517.
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Enterocin DD14 (EntDD14) is a two-peptide leaderless bacteriocin produced by the Enterococcus faecalis 14 strain previously isolated from meconium. This bacteriocin is mainly active against Gram-positive bacteria. Leaderless bacteriocins do not undergo post-translational modifications and are therefore immediately active after their synthesis. As a result, the cells that produce such bacteriocins have developed means of protection against them which often involve transport systems. In this and our previous work, we constructed different mutants deleted in the genes involved in the transport functions, thus covering all the supposed components of this transport system, using Listeria innocua ATCC 33090 as the indicator strain to assess the activity of externalized EntDD14. We also assessed the self-resistance of the WT and all its engineered derivative mutants against EntDD14, provided extracellularly, in order to evaluate their self-resistance. The results obtained highlight that the ABC transporter constituted by the DdG, H, I, and J proteins contributes to EntDD14 export as well as resistance to an external supply of EntDD14. Our results also have established the essential role of the DdE and DdF proteins as primary transporters dedicated to the externalization of EntDD14. Moreover, the in silico data showed that DdE and DdF appear to assemble in a formation that forms an essential channel for the exit of EntDD14. This channel DdEF may interact with the ABC transporter DdGHIJ in order to control the flow of bacteriocin across the membrane, although the nature of this interaction remains to be elucidated.
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Arkorful, Mercy A., Nicole Noren Hooten, Yongqing Zhang, Amirah N. Hewitt, Lori Barrientos Sanchez, Michele K. Evans, and Douglas F. Dluzen. "MicroRNA-1253 Regulation of WASF2 (WAVE2) and its Relevance to Racial Health Disparities." Genes 11, no. 5 (May 20, 2020): 572. http://dx.doi.org/10.3390/genes11050572.
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The prevalence of hypertension among African Americans (AAs) in the US is among the highest of any demographic and affects over two-thirds of AA women. Previous data from our laboratory suggest substantial differential gene expression (DGE) of mRNAs and microRNAs (miRNAs) exists within peripheral blood mononuclear cells (PBMCs) isolated from AA and white women with or without hypertension. We hypothesized that DGE by race may contribute to racial differences in hypertension. In a reanalysis of our previous dataset, we found that the Wiskott–Aldrich syndrome protein Verprolin-homologous protein 2 (WASF2 (also known as WAVE2)) is differentially expressed in AA women with hypertension, along with several other members of the actin cytoskeleton signaling pathway that plays a role in cell shape and branching of actin filaments. We performed an in silico miRNA target prediction analysis that suggested miRNA miR-1253 regulates WASF2. Transfection of miR-1253 mimics into human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) significantly repressed WASF2 mRNA and protein levels (p < 0.05), and a luciferase reporter assay confirmed that miR-1253 regulates the WASF2 3′ UTR (p < 0.01). miR-1253 overexpression in HUVECs significantly increased HUVEC lamellipodia formation (p < 0.01), suggesting the miR-1253–WASF2 interaction may play a role in cell shape and actin cytoskeleton function. Together, we have identified novel roles for miR-1253 and WASF2 in a hypertension-related disparities context. This may ultimately lead to the discovery of additional actin-related genes which are important in the vascular-related complications of hypertension and influence the disproportionate susceptibility to hypertension among AAs in general and AA women in particular.
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Liang, Bo, Biao Zheng, Yan Zhou, Zheng-Quan Lai, Citing Zhang, Zilong Yan, Zhangfu Li, et al. "Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting." Evidence-Based Complementary and Alternative Medicine 2021 (June 17, 2021): 1–10. http://dx.doi.org/10.1155/2021/4812068.
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Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.
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Qi, Renli, Xiaoyu Qiu, Yong Zhang, Jing Wang, Qi Wang, Min Wu, Jinxiu Huang, and Feiyun Yang. "Comparison of LncRNA Expression Profiles during Myogenic Differentiation and Adipogenic Transdifferentiation of Myoblasts." International Journal of Molecular Sciences 20, no. 15 (July 30, 2019): 3725. http://dx.doi.org/10.3390/ijms20153725.
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Myoblasts could transdifferentiate into adipocytes or adipocyte-like cells, which have the capability of producing and storing intracellular lipids. Long-chain non-coding RNAs (lncRNAs) have many important physiological functions in eukaryotes, which include regulating gene expression, chromosome silencing, and nuclear transport. However, changes in the expression of lncRNAs in muscle cells during adipogenic transdifferentiation have not been investigated to date. Here, C2C12 myoblasts were seeded and then induced to undergo myogenic and adipogenic transdifferentiation. The expression profiles of lncRNAs in various differentiated cells were analyzed and then compared by digital gene expression (DGE) RNA sequencing. A total of 114 core lncRNAs from 836 differentially expressed lncRNAs in adipogenic cells were identified. Further investigation by in silico analysis revealed that the target genes of core lncRNAs significantly enriched various signaling pathways that were related to glucose and lipid metabolism and muscle growth. The lncRNA-GM43652 gene was a potential regulator of adipogenesis in muscle cells. It showed the highest levels of expression in adipogenic cells, and the knocking down lncRNA-GM43652 negatively influenced lipid deposition in transdifferentiated myoblasts. This study has identified the novel candidate regulators that may be assessed in future molecular studies on adipogenic conversion of muscle cells.
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Chatterjee, Krishnashis, Naciye Atay, Daniel Abler, Saloni Bhargava, Prativa Sahoo, Russell C. Rockne, and Jennifer M. Munson. "Utilizing Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to Analyze Interstitial Fluid Flow and Transport in Glioblastoma and the Surrounding Parenchyma in Human Patients." Pharmaceutics 13, no. 2 (February 4, 2021): 212. http://dx.doi.org/10.3390/pharmaceutics13020212.
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Background: Glioblastoma (GBM) is the deadliest and most common brain tumor in adults, with poor survival and response to aggressive therapy. Limited access of drugs to tumor cells is one reason for such grim clinical outcomes. A driving force for therapeutic delivery is interstitial fluid flow (IFF), both within the tumor and in the surrounding brain parenchyma. However, convective and diffusive transport mechanisms are understudied. In this study, we examined the application of a novel image analysis method to measure fluid flow and diffusion in GBM patients. Methods: Here, we applied an imaging methodology that had been previously tested and validated in vitro, in silico, and in preclinical models of disease to archival patient data from the Ivy Glioblastoma Atlas Project (GAP) dataset. The analysis required the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which is readily available in the database. The analysis results, which consisted of IFF flow velocity and diffusion coefficients, were then compared to patient outcomes such as survival. Results: We characterized IFF and diffusion patterns in patients. We found strong correlations between flow rates measured within tumors and in the surrounding parenchymal space, where we hypothesized that velocities would be higher. Analyzing overall magnitudes indicated a significant correlation with both age and survival in this patient cohort. Additionally, we found that neither tumor size nor resection significantly altered the velocity magnitude. Lastly, we mapped the flow pathways in patient tumors and found a variability in the degree of directionality that we hypothesize may lead to information concerning treatment, invasive spread, and progression in future studies. Conclusions: An analysis of standard DCE-MRI in patients with GBM offers more information regarding IFF and transport within and around the tumor, shows that IFF is still detected post-resection, and indicates that velocity magnitudes correlate with patient prognosis.
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Ahmad, Sheraz, Jieyu Zhang, Huaiqi Wang, Haowen Zhu, Qiaoqiao Dong, Suman Zong, Tingting Wang, Yu Chen, and Linquan Ge. "The Phosphoserine Phosphatase Alters the Free Amino Acid Compositions and Fecundity in Cyrtorhinus lividipennis Reuter." International Journal of Molecular Sciences 23, no. 23 (December 4, 2022): 15283. http://dx.doi.org/10.3390/ijms232315283.
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The mirid bug Cyrtorhinus lividipennis (Reuter) is an important predator that consumes eggs and young nymphs of the brown planthopper Nilaparvata lugens as a primary food source and thus becomes an important member of the rice ecosystem. We identified and characterized the ClPSP gene in C. lividipennis encoding the phosphoserine phosphatase enzyme. The ClPSP has an open reading frame (ORF) of 957 bp encoding a protein with a length of 294bp and it possesses a haloacid dehalogenase-like (HAD) hydrolase, phosphoserine phosphatase, eukaryotic-like (HAD_PSP_eu) conserved domain. Furthermore, the in silico analysis of the ClPSP gene unveiled its distinct characteristics and it serves as a key player in the modulation of amino acids. The ClPSP showed expression in all developmental stages, with higher expression observed in the ovary and fat body. Silencing the ClPSP by RNA interference (RNAi) significantly decreased PSP enzyme activity and expression compared to dsGFP at two days after emergence (2DAE). The dsPSP treatment altered free hemolymph amino acid compositions, resulting in a significant reduction of serine (Ser) and Arginine (Arg) proportions and a significant increase of Threonine (Thr), Cystine (Cys), and Tyrosine (Tyr) in the C. lividipennis female at 2 DAE. Additionally, a hindered total protein concentration in the ovary and fat body, and reduced vitellogenin (Vg) expression, body weight, and number of laid eggs, were also observed. The same treatment also prolonged the preoviposition period and hindered ovarian development. Our data, for the first time, demonstrated the influential role of the PSP gene in modulating the fecundity of C. lividipennis and provide a platform for future insect pest control programs using the PSP gene in modulating fecundity.
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Lu, Z., E. Altermann, F. Breidt, and S. Kozyavkin. "Sequence Analysis of Leuconostoc mesenteroides Bacteriophage Φ1-A4 Isolated from an Industrial Vegetable Fermentation." Applied and Environmental Microbiology 76, no. 6 (January 29, 2010): 1955–66. http://dx.doi.org/10.1128/aem.02126-09.
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ABSTRACT Vegetable fermentations rely on the proper succession of a variety of lactic acid bacteria (LAB). Leuconostoc mesenteroides initiates fermentation. As fermentation proceeds, L. mesenteroides dies off and other LAB complete the fermentation. Phages infecting L. mesenteroides may significantly influence the die-off of L. mesenteroides. However, no L. mesenteroides phages have been previously genetically characterized. Knowledge of more phage genome sequences may provide new insights into phage genomics, phage evolution, and phage-host interactions. We have determined the complete genome sequence of L. mesenteroides phage Φ1-A4, isolated from an industrial sauerkraut fermentation. The phage possesses a linear, double-stranded DNA genome consisting of 29,508 bp with a G+C content of 36%. Fifty open reading frames (ORFs) were predicted. Putative functions were assigned to 26 ORFs (52%), including 5 ORFs of structural proteins. The phage genome was modularly organized, containing DNA replication, DNA-packaging, head and tail morphogenesis, cell lysis, and DNA regulation/modification modules. In silico analyses showed that Φ1-A4 is a unique lytic phage with a large-scale genome inversion (∼30% of the genome). The genome inversion encompassed the lysis module, part of the structural protein module, and a cos site. The endolysin gene was flanked by two holin genes. The tail morphogenesis module was interspersed with cell lysis genes and other genes with unknown functions. The predicted amino acid sequences of the phage proteins showed little similarity to other phages, but functional analyses showed that Φ1-A4 clusters with several Lactococcus phages. To our knowledge, Φ1-A4 is the first genetically characterized L. mesenteroides phage.
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Wu, Yi-Ying, Sheng-Huei Wang, Chih-Hsien Wu, Li-Chen Yen, Hsing-Fan Lai, Ching-Liang Ho, and Yi-Lin Chiu. "In silico immune infiltration profiling combined with functional enrichment analysis reveals a potential role for naïve B cells as a trigger for severe immune responses in the lungs of COVID-19 patients." PLOS ONE 15, no. 12 (December 2, 2020): e0242900. http://dx.doi.org/10.1371/journal.pone.0242900.
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COVID-19, caused by SARS-CoV-2, has rapidly spread to more than 160 countries worldwide since 2020. Despite tremendous efforts and resources spent worldwide trying to explore antiviral drugs, there is still no effective clinical treatment for COVID-19 to date. Approximately 15% of COVID-19 cases progress to pneumonia, and patients with severe pneumonia may die from acute respiratory distress syndrome (ARDS). It is believed that pulmonary fibrosis from SARS-CoV-2 infection further leads to ARDS, often resulting in irreversible impairment of lung function. If the mechanisms by which SARS-CoV-2 infection primarily causes an immune response or immune cell infiltration can be identified, it may be possible to mitigate excessive immune responses by modulating the infiltration and activation of specific targets, thereby reducing or preventing severe lung damage. However, the extent to which immune cell subsets are significantly altered in the lung tissues of COVID-19 patients remains to be elucidated. This study applied the CIBERSORT-X method to comprehensively evaluate the transcriptional estimated immune infiltration landscape in the lung tissues of COVID-19 patients and further compare it with the lung tissues of patients with idiopathic pulmonary fibrosis (IPF). We found a variety of immune cell subtypes in the COVID-19 group, especially naïve B cells were highly infiltrated. Comparison of functional transcriptomic analyses revealed that non-differentiated naïve B cells may be the main cause of the over-active humoral immune response. Using several publicly available single-cell RNA sequencing data to validate the genetic differences in B-cell populations, it was found that the B-cells collected from COVID-19 patients were inclined towards naïve B-cells, whereas those collected from IPF patients were inclined towards memory B-cells. Further differentiation of B cells between COVID-19 mild and severe patients showed that B cells from severe patients tended to be antibody-secreting cells, and gene expression showed that B cells from severe patients were similar to DN2 B cells that trigger extrafollicular response. Moreover, a higher percentage of B-cell infiltration seems associated with poorer clinical outcome. Finally, a comparison of several specific COVID-19 cases treated with targeted B-cell therapy suggests that appropriate suppression of naïve B cells might potentially be a novel strategy to alleviate the severe symptoms of COVID-19.
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Gefen, Amit, and Graham Ross. "The subepidermal moisture scanner: the technology explained." Journal of Wound Care 29, Sup2c (February 1, 2020): S10—S16. http://dx.doi.org/10.12968/jowc.2020.29.sup2c.s10.
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The objective of this article is to explain the biophysical principles underlying the design of the subepidermal moisture (SEM) scanner, commercially known as the ‘SEM scanner’. We also describe the mode of operation of the SEM scanner in monitoring tissue health and detecting subtle abnormal changes in tissue physiology in patients and anatomical sites at a risk of a pressure ulcer (PU: also known as a pressure injury). The technology of the SEM scanner was approved last year for sales in the US by the Food and Drug Administration (FDA). The SEM scanner detects changes in fluid contents of human skin and subdermal tissues, to a tissue depth of several millimetres, by measuring ‘capacitance’, an electrical property of the locally examined tissue site to store electric charge. The capacitance of tissues, called ‘biocapacitance’, is strongly affected by the amount of fluid (water) in the tissue. When the first cells die in a forming PU, inflammatory signalling causes the permeability of blood vessel walls to increase and oedema to develop. Simply, the scanner detects the early appearance of oedema, which is called ‘micro-oedema.’ Calculation of a ‘SEM-delta’ value, which compares biocapacitance measurements, acquired across several tissue sites, some of which are healthy and others where the PU may evolve, eliminates potential effects of systemic changes in tissue fluid contents and provides a consistent quantitative measure of the tissue health conditions at the monitored anatomical site. Here, we describe SEM scanner technology, how it operates and has been laboratory tested (in computer simulations, in silico) before commercial launch. We explain why targeting the physical biomarker of oedema leads to the documented success of the SEM scanner in the multiple published clinical trials, proving its ability to early detect PUs that form under intact skin.
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Gefen, Amit, and Graham Ross. "The subepidermal moisture scanner: the technology explained." Journal of Wound Care 29, Sup9a (September 1, 2020): S4—S9. http://dx.doi.org/10.12968/jowc.2020.29.sup9a.s4.
Full textAbstract:
The objective of this article is to explain the biophysical principles underlying the design of the subepidermal moisture (SEM) scanner, commercially known as the ‘SEM scanner’. We also describe the mode of operation of the SEM scanner in monitoring tissue health and detecting subtle abnormal changes in tissue physiology in patients and anatomical sites at a risk of a pressure ulcer (PU: also known as a pressure injury). The technology of the SEM scanner was approved last year for sales in the US by the Food and Drug Administration (FDA). The SEM scanner detects changes in fluid contents of human skin and subdermal tissues, to a tissue depth of several millimetres, by measuring ‘capacitance’, an electrical property of the locally examined tissue site to store electric charge. The capacitance of tissues, called ‘biocapacitance’, is strongly affected by the amount of fluid (water) in the tissue. When the first cells die in a forming PU, inflammatory signalling causes the permeability of blood vessel walls to increase and oedema to develop. Simply, the scanner detects the early appearance of oedema, which is called ‘micro-oedema.’ Calculation of a ‘SEM-delta’ value, which compares biocapacitance measurements, acquired across several tissue sites, some of which are healthy and others where the PU may evolve, eliminates potential effects of systemic changes in tissue fluid contents and provides a consistent quantitative measure of the tissue health conditions at the monitored anatomical site. Here, we describe SEM scanner technology, how it operates and has been laboratory tested (in computer simulations, in silico) before commercial launch. We explain why targeting the physical biomarker of oedema leads to the documented success of the SEM scanner in the multiple published clinical trials, proving its ability to early detect PUs that form under intact skin.
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Norris, Gregory H., John Pfeiffer, Yuhan Zhang, Hope R. Esslinger, The SimBioSys Team, and Vinita Takiar. "Abstract 749: SimBioSys TumorScope accurately models and predicts response to neoadjuvant therapy in breast cancer - Validation study." Cancer Research 82, no. 12_Supplement (June 15, 2022): 749. http://dx.doi.org/10.1158/1538-7445.am2022-749.
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Abstract Neoadjuvant Therapy (NAT) for breast cancer results in higher rates of breast conservation surgery. Importantly, there is data supporting the use of multiple NAT regimens, with little guidance as to which one would be most effective for a given patient. Thus, tools that can accurately predict patient outcome before cancer treatment can provide guidance during treatment planning and increase the chances of therapy success. Here we present the first biophysical modelling platform, TumorScope (TS), capable of constructing a 3D model of the tumor microenvironment by integrating models for tumor morphology, metabolism, drug delivery and behavior, and vascularity. Thereby allowing visualization of response to multiple NATs for a given tumor. TS integrates patient data to create an in-silico tumor model capturing the tumor response trajectory, volume, dimensions, pathological complete response (pCR), residual cancer burden and tumor morphology, and risk of recurrence (ROR). To illustrate the clinical applicability and to validate TS we performed a single center validation study. Previously acquired pre-treatment standard of care (SOC) diagnostic data (demographics, drug regimen, imaging (DCE MRI), and pathology) was used as TS inputs. Using this baseline data only, TS predicted weekly volumetric response through the treatment time and used simulated residual volume to predict pCR and assessed the ROR. The validation was performed using ground truth from post treatment assessment of pCR, radiographic volumes extracted from MRIs and ROR information. A chart review was performed to identify consecutive patients who had received NAT and had a corresponding pre-treatment MRI at University of Cincinnati. A validation set was generated from this list and data processed through TS (n=81, after excluding 9 patients with poor quality DCE-MRIs). TS predicted pCR was predefined as a residual tumor volume < 0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. TS response (pCR vs. residual) prediction accuracy had an area under the curve (AUC) =0.912 with sensitivity and specificity of 88.9% and 92.5%, respectively. The performance was robust across all subtypes. Using SOC diagnostic data TS predicted the reduction in tumor volume with a median absolute volumetric error of 3.4% vs radiographic volume from pre-surgery DCE MRIs (n=59). TS prognostic ROR (High vs Low) had a hazard ratio [HR] 12.705, p=0.01 which was comparable as a prognostic indicator to actual pCR which had a [HR] 5.81, p=0.08. In summary, TS accurately predicts patient-specific response to NAT in early breast cancer using only baseline SOC pre-treatment data. This approach to a comprehensive view of the tumor represents a major step-forward in personalized clinical decision making. The results from this study will be used in a multi-center meta-analysis of TS performance characteristics. Citation Format: Gregory H. Norris, John Pfeiffer, Yuhan Zhang, Hope R. Esslinger, The SimBioSys Team, Vinita Takiar. SimBioSys TumorScope accurately models and predicts response to neoadjuvant therapy in breast cancer - Validation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 749.
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Yamoah, Kosj, Asmaa El-Kenawi, Shivanshu Awasthi, Amparo Serna, and Jasreman Dhillon. "RF05 | PSUN358 ANPEP: A potential regulator of tumor cell - macrophage metabolic interactions in prostate cancer of African American men." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A892—A893. http://dx.doi.org/10.1210/jendso/bvac150.1848.
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Abstract African American men (AA) are more than twice as likely to die of prostate cancer (PCa) compared to European American men (EA). Among many contributing factors, unraveling the metabolic derangements in PCa of AA holds a promise in reducing health disparity. We recently discovered that aminopeptidase N (ANPEP, CD13) represents one of the differentially expressed genes in PCa of AA compared with EA. While ANPEP plays regulatory and/or modulatory functions in many immune and metabolic pathological conditions, its role in PCa remains unknown. We sought to investigate the metabolic functions of ANPEP in PCa development and exploit its role as a therapeutic vulnerability, particularly in AA men. Accordingly, we prospectively examined the differential gene expression of PCa from clinically matched AA and EA in the VANDAAM clinical trial. The VANDAAM study is a validation study of DecipherTM genomic testing in 240 men with localized PCa. Our findings indicate that ANPEP is the top differentially expressed gene between AA and EA men. To explore the molecular mechanisms of ANPEP in PCa in unbiased fashion, we combined computational and experimental approaches. Our preliminary computational analyses revealed that ANPEP correlates with signatures of cholesterol transport, estrogen and androgen receptor (AR) signaling. Based on our recent study demonstrating dominance of these signatures in macrophage-rich PCa, we reasoned that ANPEP expression may be driven in part by high macrophage infiltration in AA. Thus, we compared immune cell repertoire in patients with high ANPEP and low ANPEP by deconvoluting immune cell content using the in silico approach, CIBERSORT. These analyses illustrated that only AA patients with high ANPEP expression significantly accumulated high content of M1 inflammatory macrophages. Immune phenotyping of prostate tumors demonstrated that ANPEP indeed represents a marker of M1 inflammatory macrophages and tumor-associated macrophages. In conclusion, these findings suggest that ANPEP is a macrophage related protein in PCa with a potential role in cholesterol transport and / or androgen signaling. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry (LC-HRMS) and explants derived from AA and EA prostate cancer patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
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Juszczynski, Przemyslaw, Jeffery L. Kutok, Ricardo C. T. Aguiar, Joydeep Mitra, and Margaret A. Shipp. "B-Aggressive Lymphoma Gene (BAL) Is a Risk-Related, γIFN-Inducible Gene That Is Expressed in Primary Diffuse Large B-Cell Lymphomas with a Brisk Host Inflammatory Response." Blood 104, no. 11 (November 16, 2004): 2035. http://dx.doi.org/10.1182/blood.v104.11.2035.2035.
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Abstract Although diffuse large B-cell lymphoma (DLBCL) is potentially curable with current therapy, a significant number of DLBCL patients still die of their disease. In a broad-based screen for genes and pathways associated with poor DLBCL outcome, we previously identified a novel risk-related gene, termed BAL (B-aggressive lymphoma). Thereafter, we cloned and characterized a major BAL partner protein, BBAP (B-aggressive lymphoma and BAL binding partner), described the nuclear trafficking patterns of both proteins and demonstrated that BAL functions as a modulator of transcription. In the current study, we characterized BAL expression in normal tonsil and primary DLBCLs and defined BAL regulation and potential functions in both cell types. Immunohistochemical staining of normal tonsil revealed that BAL was expressed by small numbers of germinal center (GC) cells and interfollicular cells with the morphologic features of centroblasts (with the GC) and immunoblasts (within the interfollicular areas). In primary DLBCLs, BAL was expressed by the malignant B cells. To gain insights regarding the regulation of BAL and BBAP expression in DLBCLs, we analyzed a series of 176 primary tumor biopsies transcriptionally profiled an U133A/B Affymetrix microarrays. BAL/BBAP high-expressing DLBCLs had evidence of a brisk host immune response, including increased expression of T/NK-cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cells markers and γIFN-induced transcripts, raising the possibility that BAL was induced by γIFN. Consistent with this hypothesis, γIFN treatment of DLBCL cell lines with low basal levels of BAL markedly increased BAL expression. In silico analysis revealed that the BAL and BBAP genes are located in 3q21 in head-to-head orientation and share the same CpG-related promoter. This shared promoter contains a conserved γIFN-responsive module composed of IRF and STAT binding elements. The BAL/BBAP bidirectional promoter was cloned into a pGL3 luciferase promoterless reporter vector and found to increase luciferase activity > 20-fold following γIFN stimulation. To gain further insights into regulation of BAL transcription, mutant versions of BAL promoter were generated and cloned. Luciferase assays demonstrated that the IRF binding site was necessary for γIFN-induced BAL transcription, whereas the STAT1 binding site had an accessory role. Taken together, these results demonstrate that BAL and BBAP genes are transcriptionally activated by γIFN in DLBCLs with features of a brisk host immune response including γIFN signaling. Preliminary studies suggest that BAL limits the efficacy of the observed host inflammatory response.
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Cole, John A., Joseph R. Peterson, Tyler M. Earnest, Michael J. Hallock, Daniel J. Cook, Eduardo Braun, Anu Antony, John R. Pfeiffer, and Tushar Pandey. "Abstract P1-08-31: Simbiosys tumorscope: Biophysical modeling of patient-specific response to chemotherapy." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–08–31—P1–08–31. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-08-31.
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Abstract Background: Breast Cancer (BC) patients exhibit a wide variety of responses to neoadjuvant chemotherapy (NACT). This is driven by factors both intrinsic (e.g., mutations, dysregulation, metabolic reprogramming) and extrinsic (e.g., nutrient/drug perfusion, interactions with surrounding healthy tissues and the tumor microenvironment (TME)) to the cells that make up each tumor. The SimBioSys TumorScope is a platform for making individualized predictions of the response of each patient's tumor to NACT. It employs 3D biophysical simulations that explicitly model the dynamics of cellular response to the ever-changing chemical milieu of drugs and nutrients that perfuse the TME during treatment, in order to predict when and where different regions of the tumor are growing, dying, and ultimately how a given patient will respond to treatment. Methods: The SimBioSys TumorScope constructs 3D in silico models of each patient's tumor directly from pretreatment DCE-MRIs. It combines this spatial model with personalized genome-scale models of tumor and tissue metabolism, pharmacokinetics, and pharmacodynamics, and vascular perfusion (based on DCE-MRI timeseries). The combined model is then simulated using a custom high-performance reaction-diffusion-material mechanics simulation engine which produces a spatio-temporal trajectory of tumor size, morphology, intra- and extracellular biochemistry. We evaluated the ability of the TumorScope software to predict volumetric response to NACT. A validation set comprising the pretreatment records (including MRIs) of 780 BC patients that underwent NACT was used. These patients spanned a wide range of tumor sizes, molecular subtypes, and NCCN-recommended treatment regimens. Simulations were initialized using each patient’s pretreatment MRI and pathology data and run from the start of therapy to the specified surgical date. Simulated tumor volumetric percent response (calculated as the ratio of change in tumor volume to initial volume) at the time of surgery was then compared with actual tumor volumetric percent response extracted from presurgical MRIs. Among patients for which event free survival data was available (n = 480), we performed a Cox proportional hazard analysis. Results: The SimBioSys TumorScope predicted pre-surgical tumor volumetric response with a median error of 0.03% and median absolute deviation of 8.2%. Among the patients for which EFS data was available, we found a hazard ratio of 1.8 associated with having a final simulated volume greater than 0.01 cc (p = 0.00048). Conclusions: The SimBioSys TumorScope produces accurate patient specific predictions of response to NACT using only standard-of-care pre-treatment data. Such predictions can aid in decision making, enabling physicians to select less-toxic regimens for patients in which a robust response is predicted, and more aggressive treatments and/or clinical trial enrollment when response is likely to be poor. Citation Format: John A Cole, Jr., Joseph R Peterson, Tyler M Earnest, Michael J Hallock, Daniel J Cook, Eduardo Braun, Anu Antony, John R Pfeiffer, Tushar Pandey. Simbiosys tumorscope: Biophysical modeling of patient-specific response to chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-31.
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Simons, Yael, Mohamed Hassan, George Chlipala, Oana Cristina Danciu, Vijayakrishna K. Gadi, Manmeet Singh, Gayatry Mohapatra, and Kent Hoskins. "Molecular characterization of luminal breast tumors in African American women." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 550. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.550.
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550 Background: Racial disparities in breast cancer (BC) mortality are attributed to later stage diagnoses and a higher incidence of triple-negative BC among African American (AA) women. In previous work, we showed that AA women with ER+ BC are more likely to develop biologically aggressive disease and are more likely to die from early stage, ER+ BC than non-Hispanic White women (Hoskins et al, JAMA Oncol, 2021). The underlying molecular drivers of this disparity are unknown. Here we report the molecular characterization of a series of luminal BC from AA women. Methods: Consecutive breast tumor specimens received in the Pathology Department underwent next generation sequencing (NGS). Unstained FFPE tissue sections were macro-dissected to isolate tumor cells, and nucleic acids were extracted using commercially available kits. DNA and RNA sequencing libraries were prepared with the Oncomine Comprehensive Assay v3 (OCAv3) (Thermo Fisher), which includes 161 driver genes and detects SNVs, CNVs, INDELs and gene fusions. Sequencing was performed on the Ion S5XL sequencer. Sequencing reads were mapped to the UCSC human genome build GRCh37/hg19 using Torrent Suite™ software (version 5.10; Thermo Fisher). Data analysis and variant calling was performed using the Ion Reporter analysis tool. Results: We identified 60 somatic driver gene alterations in luminal tumors from 35 AA patients (primary tumors, n = 26; metastatic tumors, n = 9). Recurrently altered genes identified in > 5% of tumors are listed in the Table. The most frequently altered gene was PIK3CA (42% of tumors). ESR1 gene fusions were seen in 25% of tumors. Interestingly, an equal frequency of ESR1 fusions were detected in primary (27%) and metastatic (22%) tumors, in contrast to activating mutations which are found in recurrent tumors following treatment with aromatase inhibitors. ARID1A alterations were identified in 17% of primary tumors. ARID1A encodes a subunit of the SWI/SNF chromatin remodeling complex. Alterations in ARID1A confer endocrine resistance, and are enriched in recurrent tumors in the literature. We also found a high number of CNVs in members of the FGF gene family (36% of tumors), which are also associated with resistance to endocrine therapy. An in silico analysis comparing our findings with publicly available datasets will be presented. Conclusions: This study of somatic driver gene alterations in a consecutive series of luminal breast tumors from AA patients found a higher than expected frequency of alterations in genes associated with endocrine resistance in untreated primary tumors, suggesting a partial explanation for racial disparities in survival.[Table: see text]
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Hassan, Daniel, Calvin A. Omolo, Victoria Oluwaseun Fasiku, Ahmed A. Elrashedy, Chunderika Mocktar, Bongani Nkambule, Mahmoud E. S. Soliman, and Thirumala Govender. "Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus." Pharmaceutics 12, no. 11 (November 14, 2020): 1093. http://dx.doi.org/10.3390/pharmaceutics12111093.
Full textAbstract:
Globally, human beings continue to be at high risk of infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA); and current treatments are being depleted due to antimicrobial resistance. Therefore, the synthesis and formulation of novel materials is essential for combating antimicrobial resistance. The study aimed to synthesize a quaternary bicephalic surfactant (StBAclm) and thereof to formulate pH-responsive vancomycin (VCM)-loaded quatsomes to enhance the activity of the antibiotic against MRSA. The surfactant structure was confirmed using 1H, 13C nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and high-resolution mass spectrometry (HRMS). The quatsomes were prepared using a sonication/dispersion method and were characterized using various in vitro, in vivo, and in silico techniques. The in vitro cell biocompatibility studies of the surfactant and pH-responsive vancomycin-loaded quatsomes (VCM-StBAclm-Qt1) revealed that they are biosafe. The prepared quatsomes had a mean hydrodynamic diameter (MHD), polydispersity index (PDI), and drug encapsulation efficiency (DEE) of 122.9 ± 3.78 nm, 0.169 ± 0.02 mV, and 52.22 ± 8.4%, respectively, with surface charge switching from negative to positive at pH 7.4 and pH 6.0, respectively. High-resolution transmission electron microscopy (HR-TEM) characterization of the quatsomes showed spherical vesicles with MHD similar to the one obtained from the zeta-sizer. The in vitro drug release of VCM from the quatsomes was faster at pH 6.0 compared to pH 7.4. The minimum inhibitory concentration (MIC) of the drug loaded quatsomes against MRSA was 32-fold and 8-fold lower at pH 6.0 and pH 7.4, respectively, compared to bare VCM, demonstrating the pH-responsiveness of the quatsomes and the enhanced activity of VCM at acidic pH. The drug-loaded quatsomes demonstrated higher electrical conductivity and a decrease in protein and deoxyribonucleic acid (DNA) concentrations as compared to the bare drug. This confirmed greater MRSA membrane damage, compared to treatment with bare VCM. The flow cytometry study showed that the drug-loaded quatsomes had a similar bactericidal killing effect on MRSA despite a lower (8-fold) VCM concentration when compared to the bare VCM. Fluorescence microscopy revealed the ability of the drug-loaded quatsomes to eradicate MRSA biofilms. The in vivo studies in a skin infection mice model showed that groups treated with VCM-loaded quatsomes had a 13-fold decrease in MRSA CFUs when compared to the bare VCM treated groups. This study confirmed the potential of pH-responsive VCM-StBAclm quatsomes as an effective delivery system for targeted delivery and for enhancing the activity of antibiotics.