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1
Apiwattanapong, Taweesup, and Mary Jean Harrold. "Selective path profiling." ACM SIGSOFT Software Engineering Notes 28, no. 1 (January 17, 2003): 35–42. http://dx.doi.org/10.1145/634636.586104.
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Eaton, Brian, Jeff Stewart, Jon Tedesco, and N. Cihan Tas. "Distributed Latency Profiling through Critical Path Tracing." Communications of the ACM 66, no. 1 (December 20, 2022): 44–51. http://dx.doi.org/10.1145/3570522.
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Wu, Zhichao, Zied Abdullaev, Drew Pratt, Hye-Jung Chung, Shannon Skarshaug, Valerie Zgonc, Candice Perry, et al. "PATH-46. DIAGNOSTIC IMPACT OF THE CNS TUMOR METHYLATION PROFILING IN A NEUROPATHOLOGY CONSULT PRACTICE." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi125—vi126. http://dx.doi.org/10.1093/neuonc/noab196.498.
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Abstract DNA methylation profiling coupled with the application of CNS tumor methylation classifier has contributed to precise and accurate diagnostics for a range of tumor types involving the central nervous system. The impact and characteristics of methylation profiling on tumor diagnosis has not been fully assessed in the setting of neuropathology consultation practice. A consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice were profiled over 2-year period and analyzed using the DKFZ/Heidelberg CNS tumor methylation classifier. Among the 1,045 cases received from outside institutions for consultation, the classifier was able to refine a histologically diagnosed entity (e.g. medulloblastoma) in 13.3% (n = 139) cases. A substantially new diagnosis was able to be rendered in an additional 17.9% (n = 187) cases, many of which could be confirmed using orthogonal methods. A “suggestive” (0.30-0.84) classifier score was found in 23% (242) cases and we found that complementary methods (UMAP, t-SNE and nearest-neighbors) were able to resolve this uncertainty in 118 cases. We found tumor purity significantly associated with varied classifier score (p = 1.53e-11). Computational tumor purity adjustment by deconvolution on a subset of gliomas provided a proof-of-concept to resolve diagnostics in the setting of low tumor purity. Overall, this work directly assesses the benefit of methylation classification in a set of diagnostically challenging CNS tumors, addresses tumor purity diminished methylation signal and provides complementary approaches to address diagnostics in cases of low-confidence classifier scores.
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Schepke, Elizabeth, Maja Löfgren, Torsten Pietsch, Thomas Olsson Bontell, Teresia Kling, Anna Wenger, Sandra Ferreyra Vega, et al. "PATH-08. DNA methylation profiling improves routine diagnostics of paediatric CNS tumours: a prospective population-based study." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i159—i160. http://dx.doi.org/10.1093/neuonc/noac079.592.
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Abstract AIMS: Paediatric brain tumours are rare and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort. Methods: All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared to the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist. Results: 240 tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed and for some of these also refined, 6% were incongruent and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory or could not be predicted. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients.Conclusions: Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and molecular information important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.
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Sahu, A. K., G. K. Sahu, D. K. Dash, S. P. Mishra, K. Mishra, P. Kashyap, and V. Jain. "ASSESSMENT OF IN VITRO NARINGENIN RELEASE FROM SOLID LIPID NANOPARTICLES AND KINETIC MODEL PROFILING: APPLIED ULTRAVIOLET-VISIBLE SPECTROPHOTOMETER." INDIAN DRUGS 54, no. 11 (November 28, 2017): 46–57. http://dx.doi.org/10.53879/id.54.11.11035.
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A new, simple, specific, rapid, precise, highly accurate, reproducible and cost effective Ultraviolet-Visible spectrophotometric method was developed and validated, according to the International Harmonization Guidelines, for the determination of naringenin from solid lipid nanoparticles. Absorption maximum of Naringenin was found to be at 287.49nm in methanol. The linearity range was found to be 5-25μg/mL with high correlation coefficient value of 0.999. The detection and quantification limits were found to be 0.1879μg/mL and 0.5694μg/mL, respectively. This method was shown to be specific, selective, precise at the intra-day (relative standard deviation less than 0.7046%) and inter-day (relative standard deviation less than 1.5424%) level and accurate with recoveries between 98.77-100.43% (relative standard deviation less than 0.3924%). Method robustness observation indicates that method was robust. The suitability of the method for naringenin quantifications was assessed by the determination of entrapment parameters and by studying the naringenin release profile from SLNs. High entrapment efficiency (91.922 ± 0.717%) and drug loading (3.506 ± 0.027%) were observed. Kinetic models (zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Baker-Lonsdale) were used to fit the obtained release profile and to predict the in vivo performance of naringenin-loaded SLNs. An anomalous non-Fickian transport was found, which indicate a controlled drug release system.
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Brusač, Jeličić, Amidžić Klarić, Nigović, Turk, Klarić, and Mornar. "Pharmacokinetic Profiling and Simultaneous Determination of Thiopurine Immunosuppressants and Folic Acid by Chromatographic Methods." Molecules 24, no. 19 (September 24, 2019): 3469. http://dx.doi.org/10.3390/molecules24193469.
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With the increase in the number of medicines patients have to take, there has been a rapid rise of fixed-dose combinations (FDCs) in the last two decades. Prior to FDC development, pharmacokinetic properties of active pharmaceutical ingredients (APIs) have to be evaluated, as well as methods for their determination developed. So as to increase patient compliance in inflammatory bowel disease, three novel FDCs of thiopurine immunosuppressants and folic acid are proposed; physico-chemical and pharmacokinetic properties such as hydrophobicity, lipophilicity and plasma protein binding of all APIs are evaluated. Moreover, experimental results of different properties are compared to those computed by various on-line prediction platforms so as to evaluate the viability of the in silico approach. A simultaneous method for their determination is developed, optimized, validated and applied to commercial tablet formulations. The method has shown to be fast, selective, accurate and precise, showing potential for reliable determination of API content in proposed FDCs during its development.
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Wuestefeld, Andreas, and Matt Wilks. "How to twist and turn a fiber: Performance modeling for optimal DAS acquisitions." Leading Edge 38, no. 3 (March 2019): 226–31. http://dx.doi.org/10.1190/tle38030226.1.
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The success of a distributed acoustic sensing (DAS) survey depends on strain energy impeding at favorable angles at most sections of the fiber. Although constrained to the path of the wellbore, there are various design parameters that can influence the recorded DAS amplitude. We present here a method to model the performance of DAS installations. We use precise raypath modeling in complex velocity models to determine ray incidence angles and show variations between different wrapping angles and detection thresholds. We then propose a way to evaluate the performance of the DAS acquisition design, and how to optimize processing, based on the percentage of DAS channels above a chosen amplitude threshold. For microseismic studies, the best wrapping angle of the fiber can be determined, which may be defined as covering the target area most homogeneously. For vertical seismic profiling projects, surface shot positions can be evaluated for their predicted recorded energy.
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Barboza, Mariana, David A. Sela, Claire Pirim, Riccardo G. LoCascio, Samara L. Freeman, J. Bruce German, David A. Mills, and Carlito B. Lebrilla. "Glycoprofiling Bifidobacterial Consumption of Galacto-Oligosaccharides by Mass Spectrometry Reveals Strain-Specific, Preferential Consumption of Glycans." Applied and Environmental Microbiology 75, no. 23 (October 2, 2009): 7319–25. http://dx.doi.org/10.1128/aem.00842-09.
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ABSTRACT Galacto-oligosaccharides (GOS) are versatile food ingredients that possess prebiotic properties. However, at present there is a lack of precise analytical methods to demonstrate specific GOS consumption by bifidobacteria. To better understand the role of GOS as prebiotics, purified GOS (pGOS) without disaccharides and monosaccharides was prepared and used in bacterial fermentation experiments. Growth curves showed that all bifidobacteria assayed utilized and grew on pGOS preparations. We used a novel mass spectrometry approach involving matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) to determine the composition of oligosaccharides in GOS syrup preparations. MALDI-FTICR analysis of spent fermentation media demonstrated that there was preferential consumption of selected pGOS species by different bifidobacteria. The approach described here demonstrates that MALDI-FTICR is a rapid-throughput tool for comprehensive profiling of oligosaccharides in GOS mixtures. In addition, the selective consumption of certain GOS species by different bifidobacteria suggests a means for targeting prebiotics to enrich select bifidobacterial species.
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Liu, Anthony P. Y., Chris T. L. Chan, Edmond S. K. Ma, Wilson W. S. Ho, Dennis T. L. Ku, Matthew M. K. Shing, Amanda N. C. Kan, Godfrey C. F. Chan, and Ho-Keung Ng. "PATH-10. Nanopore sequencing reveals novel ALK fusion with interposed element in a neonate with hemispheric glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i160. http://dx.doi.org/10.1093/neuonc/noac079.594.
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Abstract Here we describe the clinical course and unique molecular findings in a female neonate with infantile hemispheric glioma (IHG). The patient presented at the age of 17 days with macrocephaly and suboptimal weight gain. MRI brain revealed an 8.5cm mass over the right frontal region with significant mass effect and entrapment of ventricles. Urgent ventriculoperitoneal shunt insertion and biopsy of the highly vascular lesion was performed. Pathology was compatible with glioblastoma multiforme. Methylation profiling classified the sample as inflammatory tumor tissue (MNP v11b4), while panel RNA-sequencing revealed a fusion event between HMBOX1 and ALK which has not been described in primary CNS tumors. Long-read sequencing with the Nanopore system further revealed complex genomic rearrangement involving an interposed genomic fragment from a third chromosome with validation by Sanger sequencing. Based on an integrated diagnosis of IHG, the patient went on to receive neoadjuvant chemotherapy per the CNS-14 protocol (cyclophosphamide, carboplatin, etoposide) with significant tumor shrinkage. Near total removal of the lesion was achieved after 4 cycles of chemotherapy and adjuvant treatment with 4 additional cycles was given. The patient tolerated therapy well other than self-limiting transaminitis. At the end of treatment, the patient enjoyed intact neurology and satisfactory developmental progress. Our case report illustrates the value a multi-pronged approach to characterizing rare pediatric CNS tumors. The precise delineation of breakpoints in fusion-driven tumors might be of value in the design of cfDNA-based assays. (APYL and CTLC contributed equally to the submission)
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Marazziti, Donatella, Jorge Perez, and Giovanni B. Cassano. "Is Obsessive-Compulsive Disorder Caused by a Second-Messenger Imbalance?" CNS Spectrums 6, no. 3 (March 2001): 206–9. http://dx.doi.org/10.1017/s1092852900008579.
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AbstractAlthough the precise etiologic nature of obsessive-compulsive disorder (OCD), one of the most common psychiatric conditions, is unknown, several findings indicate involvement of the serotonin (5-HT) transporter. Apart from the specific effects of selective 5-HT reuptake inhibitors, other studies show decreased functionality of the platelet 5-HT transporter in OCD. In this report, the authors combine data from two independent studies of patients with OCD, showing both an increased activity of protein kinase type C (PKC) and a decreased activity of protein kinase type A (PKA). The authors propose a unifying hypothesis that OCD might be determined by an imbalance between PKC and PKA, with a prevalence of the former and, more generally, of the phosphoinositide over the cyclic adenosine monophosphate (cAMP) pathway. Should this hypothesis prove correct, the path would be open for new therapeutic interventions in the treatment of OCD.
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McNeil, Craig, Eric D’Asaro, Bruce Johnson, and Matthew Horn. "A Gas Tension Device with Response Times of Minutes." Journal of Atmospheric and Oceanic Technology 23, no. 11 (November 1, 2006): 1539–58. http://dx.doi.org/10.1175/jtech1974.1.
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Abstract The development and testing of a new, fast response, profiling gas tension device (GTD) that measures total dissolved air pressure is presented. The new GTD equilibrates a sample volume of air using a newly developed (patent pending) tubular silicone polydimethylsiloxane (PDMS) membrane interface. The membrane interface is long, flexible, tubular, and is contained within a seawater-flushed hose. The membrane interface communicates pressure to a precise pressure gauge using low dead-volume stainless steel tubing. The pressure sensor and associated electronics are located remotely from the membrane interface. The new GTD has an operating depth in seawater of 0–300 m. The sensor was integrated onto an upper-ocean mixed layer, neutrally buoyant float, and used in air–sea gas exchange studies. Results of laboratory and pressure tank tests are presented to show response characteristics of the device. A significant hydrostatic response of the instrument was observed over the depth range of 0–9 m, and explained in terms of expulsion (or absorption) of dissolved air from the membrane after it is compressed (or decompressed). This undesirable feature of the device is unavoidable since a large exposed surface area of membrane is required to provide a rapid response. The minimum isothermal response time varies from (2 ± 1) min near the sea surface to (8 ± 2) min at 60-m depth. Results of field tests, performed in Puget Sound, Washington, during the summer of 2004, are reported, and include preliminary comparisons with mass-spectrometric analysis of in situ water samples analyzed for dissolved N2 and Ar. These tests served as preparations for deployment of two floats by aircraft into the advancing path of Hurricane Frances during September 2004 in the northwest Atlantic. The sensors performed remarkably well in the field. A model of the dynamical response of the GTD to changing hydrostatic pressure that accounts for membrane compressibility effects is presented. The model is used to correct the transient response of the GTD to enable a more precise measurement of gas tension when the float was profiling in the upper-ocean mixed layer beneath the hurricane.
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Ferreyra, Carola F., Cristina S. Ortiz, and María M. de Bertorello. "Qualitative and Quantitative Reversed-Phase Liquid Chromatography of a New Bisisoxazolylnaphthoquinone." Journal of AOAC INTERNATIONAL 85, no. 2 (March 1, 2002): 349–54. http://dx.doi.org/10.1093/jaoac/85.2.349.
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Abstract The main objective of this study was to develop and test the applicability of a sensitive, accurate, and precise liquid chromatographic (LC) method for evaluating the stability characteristics of a new bisisoxazolylnaphthoquinone, 2-(3,5-dimethyl-4-isoxazolylamino)-N-(3,5-dimethyl-4-isoxazolyl)-1,4-naphthoquinone-4-imine compound 1. The method was shown to be selective and stability-indicating. Isocratic elution with a mobile phase of methanol–water (75 + 25, v/v) on a reversed-phase column with UV detection at ambient temperature completely resolved compound 1 from its degradation products. The LC system was calibrated by plotting peak responses versus known concentrations of a reference standard by using an internal standardization procedure. Complete elution occurred after 12 min with a peak symmetry factor of 0.95 for the drug peak. The kinetic degradation of compound 1 was studied over a pH range of 0.88–14.00 to determine the kinetic parameters involved in its decomposition path in aqueous solution.
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Akram, Zubair, Ali Raza, Muhammad Mehdi, Anam Arshad, Xiling Deng, and Shiguo Sun. "Recent Advancements in Metal and Non-Metal Mixed-Doped Carbon Quantum Dots: Synthesis and Emerging Potential Applications." Nanomaterials 13, no. 16 (August 14, 2023): 2336. http://dx.doi.org/10.3390/nano13162336.
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In nanotechnology, the synthesis of carbon quantum dots (CQDs) by mixed doping with metals and non-metals has emerged as an appealing path of investigation. This review offers comprehensive insights into the synthesis, properties, and emerging applications of mixed-doped CQDs, underlining their potential for revolutionary advancements in chemical sensing, biosensing, bioimaging, and, thereby, contributing to advancements in diagnostics, therapeutics, and the under standing of complex biological processes. This synergistic combination enhances their sensitivity and selectivity towards specific chemical analytes. The resulting CQDs exhibit remarkable fluorescence properties that can be involved in precise chemical sensing applications. These metal-modified CQDs show their ability in the selective and sensitive detection from Hg to Fe and Mn ions. By influencing their exceptional fluorescence properties, they enable precise detection and monitoring of biomolecules, such as uric acid, cholesterol, and many antibiotics. Moreover, when it comes to bioimaging, these doped CQDs show unique behavior towards detecting cell lines. Their ability to emit light across a wide spectrum enables high-resolution imaging with minimal background noise. We uncover their potential in visualizing different cancer cell lines, offering valuable insights into cancer research and diagnostics. In conclusion, the synthesis of mixed-doped CQDs opens the way for revolutionary advancements in chemical sensing, biosensing, and bioimaging. As we investigate deeper into this field, we unlock new possibilities for diagnostics, therapeutics, and understanding complex biological processes.
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Haidar, Mouna, Aida Viden, and Bradley J. Turner. "Advances in Gene Delivery Methods to Label and Modulate Activity of Upper Motor Neurons: Implications for Amyotrophic Lateral Sclerosis." Brain Sciences 11, no. 9 (August 24, 2021): 1112. http://dx.doi.org/10.3390/brainsci11091112.
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The selective degeneration of both upper motor neurons (UMNs) and lower motor neurons (LMNs) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Unlike the simple organisation of LMNs in the brainstem and spinal cord, UMNs are embedded in the complex cytoarchitecture of the primary motor cortex, which complicates their identification. UMNs therefore remain a challenging neuronal population to study in ALS research, particularly in the early pre-symptomatic stages of animal models. A better understanding of the mechanisms that lead to selective UMN degeneration requires unequivocal visualization and cellular identification of vulnerable UMNs within the heterogeneous cortical neuronal population and circuitry. Here, we review recent novel gene delivery methods developed to cellularly identify vulnerable UMNs and modulate their activity in various mouse models. A critical overview of retrograde tracers, viral vectors encoding reporter genes and transgenic reporter mice used to visualize UMNs in mouse models of ALS is provided. Functional targeting of UMNs in vivo with the advent of optogenetic and chemogenetic technology is also discussed. These exciting gene delivery techniques will facilitate improved anatomical mapping, cell-specific gene expression profiling and targeted manipulation of UMN activity in mice. These advancements in the field pave the way for future work to uncover the precise role of UMNs in ALS and improve future therapeutic targeting of UMNs.
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Buček, Jan, Marek Zatloukal, Libor Havlíček, Lucie Plíhalová, Tomáš Pospíšil, Ondřej Novák, Karel Doležal, and Miroslav Strnad. "Total synthesis of [ 15 N]-labelled C6-substituted purines from [ 15 N]-formamide—easy preparation of isotopically labelled cytokinins and derivatives." Royal Society Open Science 5, no. 11 (November 2018): 181322. http://dx.doi.org/10.1098/rsos.181322.
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Cytokinins (CKs) and their metabolites and derivatives are essential for cell division, plant growth regulation and development. They are typically found at minute concentrations in plant tissues containing very complicated biological matrices. Therefore, defined standards labelled with stable isotopes are required for precise metabolic profiling and quantification of CKs, as well as in vivo elucidation of CK biosynthesis in various plant species. In this work, 11 [ 15 N]-labelled C6-purine derivatives were prepared, among them 5 aromatic ( 4, 5, 6, 7, 8 ) and 3 isoprenoid ( 9, 10, 11 ) CKs. Compared to current methods, optimized syntheses of 6-amino-9H-[ 15 N 5 ]-purine (adenine) and 6-chloro-9H-[ 15 N 4 ]-purine (6-chloropurine) were performed to achieve more effective, selective and generally easier approaches. The chemical identity and purity of prepared compounds were confirmed by physico-chemical analyses (TLC; HRMS; HPLC–MS; 1 H, 13 C, 15 N NMR). The presented approach is applicable for the synthesis of any other desired [ 15 N 4 ]-labelled C6-substituted purine derivatives.
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Navarro, Maria N., Linda V. Sinclair, Carmen Feijoo-Carnero, Rosemary Clarke, Sharon A. Matthews, and Doreen A. Cantrell. "Protein kinase D2 has a restricted but critical role in T-cell antigen receptor signalling in mature T-cells." Biochemical Journal 442, no. 3 (February 24, 2012): 649–59. http://dx.doi.org/10.1042/bj20111700.
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PKD (protein kinase D) 2 is a serine/threonine kinase activated by diacylglycerol in response to engagement of antigen receptors in lymphocytes. To explore PKD2 regulation and function in TCR (T-cell antigen receptor) signal transduction we expressed TCR complexes with fixed affinity for self antigens in the T-cells of PKD2-null mice or mice deficient in PKD2 catalytic activity. We also developed a single cell assay to quantify PKD2 activation as T-cells respond to developmental stimuli or engagement of α/β TCR complexes in vivo. Strikingly, PKD2 loss caused increases in thymic output, lymphadenopathy and splenomegaly in TCR transgenic mice. The precise magnitude and timing of PKD2 activation during T-cell development is thus critical to regulate thymic homoeostasis. PKD2-null T-cells that exit the thymus have a normal transcriptome, but show a limited and abnormal transcriptional response to antigen. Transcriptional profiling reveals the full consequences of PKD2 loss and maps in detail the selective, but critical, function for PKD2 in signalling by α/β mature TCR complexes in peripheral T-cells.
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Pierre, Alexandre, Daniel Weger, Arnaud Perrot, and Dirk Lowke. "Additive Manufacturing of Cementitious Materials by Selective Paste Intrusion: Numerical Modeling of the Flow Using a 2D Axisymmetric Phase Field Method." Materials 13, no. 21 (November 7, 2020): 5024. http://dx.doi.org/10.3390/ma13215024.
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The 3D printing of concrete has now entered a new era and a transformation of the construction sector is expected to reshape fabrication with concrete. This work focuses on the selective paste intrusion method, which consists of bonding dry particles of aggregate with a cement paste. This innovative technique could lead to the production of very precise component for specific applications. The main obstacle to tackle in order to reach a high shape accuracy of high mechanical performances of 3D printing elements by selectively activating the material is the control of the distribution of the cement paste through the particle bed. With the aim to better understand the path followed by the solution as it penetrates a cut-section of the granular packing, two-dimensional numerical modeling is carried out using Comsol software. A phase-field method combined with a continuous visco-plastic model has been used to study the influence of the average grain diameter, the contact angle, and the rheological properties of cement pastes on the penetration depth. We compare the numerical modeling results to existing experimental results from 3D experiments and a one-dimensional analytical model. We then highlight that the proposed numerical approach is reliable to predict the final penetration of the cement pastes.
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Wang, Xu, Jingtian Zheng, Maheshwar Adiraj Iyer, Adam Henry Szmelter, David T. Eddington, and Steve Seung-Young Lee. "Spatially selective cell treatment and collection for integrative drug testing using hydrodynamic flow focusing and shifting." PLOS ONE 18, no. 1 (January 17, 2023): e0279102. http://dx.doi.org/10.1371/journal.pone.0279102.
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Hydrodynamic focusing capable of readily producing and controlling laminar flow facilitates drug treatment of cells in existing microfluidic culture devices. However, to expand applications of such devices to multiparameter drug testing, critical limitations in current hydrodynamic focusing microfluidics must be addressed. Here we describe hydrodynamic focusing and shifting as an advanced microfluidics tool for spatially selective drug delivery and integrative cell-based drug testing. We designed and fabricated a co-flow focusing, three-channel microfluidic device with a wide cell culture chamber. By controlling inlet flow rates of sample and two side solutions, we could generate hydrodynamic focusing and shifting that mediated precise regulation of the path and width of reagent and drug stream in the microfluidic device. We successfully validated a hydrodynamic focusing and shifting approach for spatially selective delivery of DiI, a lipophilic fluorophore, and doxorubicin, a chemotherapeutic agent, to tumor cells in our device. Moreover, subsequent flowing of a trypsin EDTA solution over the cells that were exposed to doxorubicin flow allowed us to selectively collect the treated cells. Our approach enabled downstream high-resolution microscopy of the cell suspension to confirm the nuclear delivery of doxorubicin into the tumor cells. In the device, we could also evaluate in situ the cytotoxic effect of doxorubicin to the tumor cells that were selectively treated by hydrodynamic flow focusing and shifting. These results show that hydrodynamic focusing and shifting enable a fast and robust approach to spatially treat and then collect cells in an optimized microfluidic device, offering an integrative assay tool for efficient drug screening and discovery.
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Alame-Emane, Amel Kévin, Catherine Pierre-Audigier, Oriane Cordelia Aboumegone-Biyogo, Amandine Nzoghe-Mveang, Véronique Cadet-Daniel, Christophe Sola, Joël Fleury Djoba-Siawaya, Brigitte Gicquel, and Howard E. Takiff. "Use of GeneXpert Remnants for Drug Resistance Profiling and Molecular Epidemiology of Tuberculosis in Libreville, Gabon." Journal of Clinical Microbiology 55, no. 7 (April 26, 2017): 2105–15. http://dx.doi.org/10.1128/jcm.02257-16.
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ABSTRACTMultidrug-resistant (MDR) and extensively drug resistant (XDR) strains ofMycobacterium tuberculosispose major problems for global health. The GeneXpert MTB/RIF (Xpert) assay rapidly detects resistance to rifampin (RIFr), but for detection of the additional resistance that defines MDR-TB (MDR tuberculosis) and XDR-TB, and for molecular epidemiology, specimen cultures and a biosafe infrastructure are generally required. We sought to determine whether the remnants of sputa prepared for the Xpert assay could be used directly to find mutations associated with drug resistance and to study molecular epidemiology, thus providing precise characterization of MDR-TB cases in countries lacking biosafety level 3 (BSL3) facilities forM. tuberculosiscultures. After sputa were processed and run on the Xpert instrument, the leftovers of the samples prepared for the Xpert assay were used for PCR amplification and sequencing or for a line probe assay to detect mutations associated with resistance to additional drugs, as well as for molecular epidemiology with spoligotyping and selective mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing. Of 130 sputum samples from Gabon tested with the Xpert assay, 124 yielded interpretable results; 21 (17%) of these were determined to be RIFr. Amplification and sequencing or a line probe assay of the Xpert remnants confirmed 18/21 samples as MDR, corresponding to 12/116 (9.5%) new and 6/8 (75%) previously treated TB patients. Spoligotyping and MIRU typing with hypervariable loci identified an MDR Beijing strain present in five samples. We conclude that the remnants of samples processed for the Xpert assay can be used in PCRs to find mutations associated with the resistance to the additional drugs that defines MDR and XDR-TB and to study molecular epidemiology without the need for culturing or a biosafe infrastructure.
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Wong, Queenie Hoi-Wing, Gabriel Chun-Hei Wong, Aden Ka-Yin Chan, Wai Sang Poon, Danny Tat-Ming Chan, Hong Chen, Zhen-yu Zhang, et al. "PATH-23. GENOMIC LANDSCAPE OF IDH-MUTANT PRIMARY GLIOBLASTOMAS SHOWS DISTINCT CLINICAL AND MOLECULAR FEATURES AND THAT CDKN2A SHOULD BE SUPPLEMENTED WITH MGMTp AND G-CIMP FOR PRECISE PROGNOSTICATION." Neuro-Oncology 22, Supplement_2 (November 2020): ii169. http://dx.doi.org/10.1093/neuonc/noaa215.704.
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Abstract There have only been rare studies of IDH-mutant primary glioblastomas (IDH-mutant astrocytoma IV); there were one or two studies on secondary glioblastomas. In a cohort of 70 cases, we conducted clinical analysis, methylation profiling, RNA sequencing, targeted sequencing, and TERTp seqeuncing on available FFPE tissues. Median follow-up was 58.2 months (n= 60). IDH-mutant primary glioblastomas had longer median OS (30.4 months) and median PFS (25.9 months) than IDH-mutant secondary glioblastomas as in the literature or established databases. MGMTp methylated cases had better OS (p= 0.001) and it was an independent prognosticator. We previously showed G-CIMP to be an independent prognostic marker for IDH-mutant glioblastomas (NOA 2019). Although CDKN2A deletion was an independent prognostic marker for poorer OS (p= 0.036) and PFS (p= 0.005), MGMTp methylation had a trend of superseding CDKN2A deletion (p= 0.055) for prognostication and G-CIMP subgroups could similarly partially supersede CDKN2A deletion (p= 0.582). Hence, CDKN2A deletion should be supplemented with these two biomarkers for finer prognostication. Targeted sequencing (n= 55) showed that there were more ATRX (35/55, 64%), TP53 (31/55, 56%), KMT2D (18/55, 33%), POLE (11/55, 20%) and MSH6 (7/55, 13%) mutations, but fewer TERTp (3/69, 4%) and PTEN (1/55, 2%) mutations than IDH-wildtype glioblastomas as from literature and databases. CNVs revealed by methylomes (n= 53) and mutations (n= 55) showed that there were more PDGFRA (amplification: 9/53, 17%, mutation: 10/55, 18%) alterations, but fewer MET (amplification: 3/53, 6%, mutation: 4/55, 7%) alterations and hypermutated (6/55, 11%) cases than IDH-mutant secondary glioblastomas from literature. GISTIC analysis revealed amplifications of CCND2, CDK4, MYC, and PDGFRA, deletions of CDKN2A, RB1, and chromosome 10q to be significant CNVs (q< 0.05). There were few EGFR amplifications (2/53, 4%), which was different from regular glioblastomas. RNA sequencing (n= 42) showed few fusions (4/42, 10%), which was different from IDH-mutant secondary glioblastomas.
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Qi, Jiyun, Fangfang Li, Lu Jia, Xiaoyuan Zhang, Shuduan Deng, Bei Luo, Yonghui Zhou, Mizi Fan, and Yan Xia. "Fungal Selectivity and Biodegradation Effects by White and Brown Rot Fungi for Wood Biomass Pretreatment." Polymers 15, no. 8 (April 20, 2023): 1957. http://dx.doi.org/10.3390/polym15081957.
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The biodegradation path and mechanism of wood varies depending on diverse fungi and tree species, as fungi possess selectivity in degradation of versatile wood components. This paper aims to clarify the actual and precise selectivity of white and brown rot fungi and the biodegradation effects on different tree species. Softwood (Pinus yunnanensis and Cunninghamia lanceolata) and hardwood (Populus yunnanensis and Hevea brasiliensis) were subjected to a biopretreating process by white rot fungus Trametes versicolor, and brown rot fungi Gloeophyllum trabeum and Rhodonia placenta with various conversion periods. The results showed that the white rot fungus Trametes versicolor had a selective biodegradation in softwood, which preferentially convert wood hemicellulose and lignin, but cellulose was retained selectively. Conversely, Trametes versicolor achieved simultaneous conversion of cellulose, hemicellulose and lignin in hardwood. Both brown rot fungi species preferentially converted carbohydrates, but R. placenta had a selectivity for the conversion of cellulose. In addition, morphological observation showed that the microstructures within wood changed significantly, and the enlarged pores and the improved accessibility could be beneficial for the penetration and accessibility of treating substrates. The research outcomes could serve as fundamental knowhows and offer potentials for effective bioenergy production and bioengineering of bioresources, and provide a reference for further application of fungal biotechnology.
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Pradat, Pierre-François, David Hayon, Sophie Blancho, Pauline Neveu, Mohammed Khamaysa, and Nicolas Guerout. "Advances in Spinal Cord Neuromodulation: The Integration of Neuroengineering, Computational Approaches, and Innovative Conceptual Frameworks." Journal of Personalized Medicine 13, no. 6 (June 13, 2023): 993. http://dx.doi.org/10.3390/jpm13060993.
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Spinal cord stimulation (SCS) is an approved treatment for intractable pain and has recently emerged as a promising area of research for restoring function after spinal cord lesion. This review will focus on the historical evolution of this transition and the path that remains to be taken for these methods to be rigorously evaluated for application in clinical practice. New developments in SCS are being driven by advances in the understanding of spinal cord lesions at the molecular, cellular, and neuronal levels, as well as the understanding of compensatory mechanisms. Advances in neuroengineering and the computational neurosciences have enabled the development of new conceptual SCS strategies, such as spatiotemporal neuromodulation, which allows spatially selective stimulation at precise time points during anticipated movement. It has also become increasingly clear that these methods are only effective when combined with intensive rehabilitation techniques, such as new task-oriented methods and robotic aids. The emergence of innovative approaches to spinal cord neuromodulation has sparked significant enthusiasm among patients and in the media. Non-invasive methods are perceived to offer improved safety, patient acceptance, and cost-effectiveness. There is an immediate need for well-designed clinical trials involving consumer or advocacy groups to evaluate and compare the effectiveness of various treatment modalities, assess safety considerations, and establish outcome priorities.
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Barton-Grimley, Rory A., Amin R. Nehrir, Susan A. Kooi, James E. Collins, David B. Harper, Anthony Notari, Joseph Lee, Joshua P. DiGangi, Yonghoon Choi, and Kenneth J. Davis. "Evaluation of the High Altitude Lidar Observatory (HALO) methane retrievals during the summer 2019 ACT-America campaign." Atmospheric Measurement Techniques 15, no. 15 (August 15, 2022): 4623–50. http://dx.doi.org/10.5194/amt-15-4623-2022.
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Abstract. The NASA Langley Research Center High Altitude Lidar Observatory (HALO) is a multi-functional and modular lidar developed to address the observational needs of NASA's weather, climate, carbon cycle, and atmospheric composition focus areas. HALO measures atmospheric H2O mixing ratios, CH4 mole fractions, and aerosol/cloud optical properties using the differential absorption lidar (DIAL) and high-spectral-resolution lidar (HSRL) techniques. In 2019 HALO participated in the NASA Atmospheric Carbon and Transport – America campaign on board the NASA C-130 to complement a suite of greenhouse gas in situ sensors and provide, for the first time, simultaneous measurements of column CH4 and aerosol/cloud profiles. HALO operated in 18 of 19 science flights where the DIAL and integrated path differential absorption (IPDA) lidar techniques at 1645 nm were used for column and multi-layer measurements of CH4 mole fractions, and the HSRL and backscatter techniques were used at 532 and 1064 nm, respectively, for retrievals of aerosol backscatter, extinction, depolarization, and mixing layer heights. In this paper we present HALO's measurement theory for the retrievals of column and multi-layer XCH4, retrieval accuracy, and precision including methods for bias correction and a comprehensive total column XCH4 validation comparison to in situ observations. Comparisons of HALO XCH4 to in situ-derived XCH4, collected during spiral ascents and descents, indicate a mean difference of 2.54 ppb and standard deviation (SD) of the differences of 16.66 ppb when employing 15 s along-track averaging (<3 km). A high correlation coefficient of R=0.9058 was observed for the 11 in situ spiral comparisons. Column XCH4 measured by HALO over regional scales covered by the ACT-America campaign is compared against in situ CH4 measurements carried out within the planetary boundary layer (PBL) from both the C-130 and B200 aircraft. Favorable correlation between the in situ point measurements within the PBL and the remote column measurements from HALO elucidates the sensitivity of a column-integrating lidar to CH4 variability within the PBL, where surface fluxes dominate the signal. Novel capabilities for CH4 profiling in regions of clear air using the DIAL technique are presented and validated for the first time. Additionally, profiling of CH4 is used to apportion the PBL absorption from the total column and is compared to previously reported IPDA cloud slicing techniques that estimate PBL columns using strong echoes from fair weather cumulus. The analysis presented here points towards HALO's ability to retrieve accurate and precise CH4 columns with the prospects for future multi-layer profiling in support of future suborbital campaigns.
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Mehler, Mark F., and John S. Mattick. "Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease." Physiological Reviews 87, no. 3 (July 2007): 799–823. http://dx.doi.org/10.1152/physrev.00036.2006.
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The progressive maturation and functional plasticity of the nervous system in health and disease involve a dynamic interplay between the transcriptome and the environment. There is a growing awareness that the previously unexplored molecular and functional interface mediating these complex gene-environmental interactions, particularly in brain, may encompass a sophisticated RNA regulatory network involving the twin processes of RNA editing and multifaceted actions of numerous subclasses of non-protein-coding RNAs. The mature nervous system encompasses a wide range of cell types and interconnections. Long-term changes in the strength of synaptic connections are thought to underlie memory retrieval, formation, stabilization, and effector functions. The evolving nervous system involves numerous developmental transitions, such as neurulation, neural tube patterning, neural stem cell expansion and maintenance, lineage elaboration, differentiation, axonal path finding, and synaptogenesis. Although the molecular bases for these processes are largely unknown, RNA-based epigenetic mechanisms appear to be essential for orchestrating these precise and versatile biological phenomena and in defining the etiology of a spectrum of neurological diseases. The concerted modulation of RNA editing and the selective expression of non-protein-coding RNAs during seminal as well as continuous state transitions may comprise the plastic molecular code needed to couple the intrinsic malleability of neural network connections to evolving environmental influences to establish diverse forms of short- and long-term memory, context-specific behavioral responses, and sophisticated cognitive capacities.
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Oleksa, Paulina, Mateusz Sobczyk, Piotr Wójcik, Daria Żuraw, Monika Rogowska, and Małgorzata Słaboń. "The insulinoma as a diagnostically and therapeutically challenging neoplasm." Journal of Education, Health and Sport 11, no. 9 (September 24, 2021): 520–25. http://dx.doi.org/10.12775/jehs.2021.11.09.067.
Full textAbstract:
Introduction and purpose
An insulinoma is the most common neuroendocrine tumor of a pancreas. This tumor produces insulin, which in excess causes hypoglycemic attacks, provoked by hunger or physical effort. Delays in diagnostic processes of the insulinoma are associated with the misattribution of symptoms to cardiac, psychiatric or neurological disorders. Thus, the suitable diagnostic procedures play a significant role as they ensure quick introduction of treatment. The purpose of this work is to evaluate advances in demanding diagnostically and therapeutically insulinoma.
A brief description of the state of knowledge
The used method was a literature review. The basic and the most common method of treating the insulinoma is a surgery. Due to this, finding precise location of the tumor preoperatively is crucial. In the diagnostics of the insulinoma both basic CT and MRI contrast enhanced and an endoscopic ultrasound, a selective arterial calcium stimulation test and the latest molecular imaging are used. In treatment process not only traditional surgical excisions were performed, but also laparoscopic and robotic surgeries turned out to be success.
Conclusions
Summing up, the insulinoma is a neoplasm with a wide range of therapeutic and diagnostic solutions, thanks to the progress that has been made in recent years. Although there are many difficulties on a diagnostic path of the insulinoma, new solutions and appropriate aproach make this process easier. Nevertheless, doctor’s diagnostic vigilance is essential, because consideration in the differential diagnosis the insulinoma is an essential step and without this step any further actions can be taken.
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Marcelli, M., A. Di Maio, D. Donis, U. Mainardi, and G. M. R. Manzella. "Development of a new expendable probe for the study of pelagic ecosystems from voluntary observing ships." Ocean Science 3, no. 2 (June 4, 2007): 311–20. http://dx.doi.org/10.5194/os-3-311-2007.
Full textAbstract:
Abstract. Physical and biological processes of the marine ecosystem have a high spatial and temporal variability, whose study is possible only through high resolution and synoptic observations. The Temperature and Fluorescence Launchable Probe was charted in order to answer to the claim of a cost effective temperature and fluorescence expendable profiler, to be used in ships of opportunity. The development of the expendable fluorometer has followed similar concepts of the XBT (a wire conducting the signal to a computer card), but differently from the latter it was developed with an electronic system which can be improved and adapted to several variables measure channels. To reach the aim of a low-cost probe, were utilized commercial components: a glass bulb temperature resistor for the temperature measurement, blue LEDs, a photodiode and available selective glass filters, for the fluorescence measurement. The measurement principle employed to detect phytoplankton's biomass is the active fluorescence. This method is an in vivo chlorophyll estimation, that can get the immediate biophysical reaction of phytoplankton inside the aquatic environment; it is a non-disruptive method which gives real time estimation and avoids the implicit errors due to the manipulation of samples. The possibility of using a continuous profiling probe, with an active fluorescence measurement, is very important in real time phytoplankton's study; it is the best way to follow the variability of sea productivity. In fact, because of the high time and space variability of phytoplankton, due to its capability to answer in a relatively short time to ecological variations in its environment and because of its characteristic patchiness, there isn't a precise quantitative estimation of the biomass present in the Mediterranean Sea.
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Wang, Han, Kathy Chan, Po Yi Lee, Alex WK Leung, Chi Kong Li, and Kam Tong Leung. "Integrative Drug and Genomic Profiling Identify Therapeutic Vulnerabilities and Inform Precision Medicine for Pediatric Acute Myeloid Leukemia." Blood 138, Supplement 1 (November 5, 2021): 2297. http://dx.doi.org/10.1182/blood-2021-147693.
Full textAbstract:
Abstract Background/Aims: Despite advances in chemotherapy-based treatment protocols, the outcomes of children with acute myeloid leukemia (AML) remain suboptimal. Implementation of targeted therapy based solely on genomics is challenging due to the complex mutational patterns and scarcity of pharmacologic agents for most lesions. In addition, pediatric and adult AML are genetically and biologically distinct, which poses a major hurdle for extrapolation of new agents approved for adult AML to the pediatric population. This study aims to adopt a functional approach that directly measure the response of patient-derived leukemic cells to targeted agents, and to establish the drug sensitivity pattern and identify candidates of immediate clinical relevance for precision usage in high-risk pediatric AML. Methods: A high-throughput drug screening, comprising 39 targeted agents (2 in Phase I, 10 in Phase II, 5 in Phase III, 22 FDA-approved) and 6 conventional chemotherapeutics, was performed on 30 pediatric AML samples collected at diagnosis or relapse using a serum-free, cytokine-supported culture system. A counter-screen of active drugs on cord blood hematopoietic stem cells was accomplished to reveal leukemia-selective activities. The robustness of the drug testing platform for predicting in vivo activities was validated in xenograft models. Genomic profiling was complementarily performed to identify the genetic markers and underlying mechanisms of drug sensitivity. Patients with refractory AML were treated with targeted agents based on drug profiling results, and assessed for clinical responses. Results: Unsupervised clustering revealed 5 distinct clusters of drug response: highly active compounds (IC50 <15 nM, 5 drugs); generally active compounds (IC50 <250 nM, 11 drugs); compounds with bimodal activities (wide IC50 ranges, 3 drugs); generally inactive compounds (16 drugs); and inactive compounds (IC50>2000 nM, 10 drugs). Targeted agents, including Bcl-2, HDAC, proteasome, HSP and survivin inhibitors, had substantially higher potency and selectivity over standard chemotherapeutic agents. New agents approved for adult AML were essentially inactive in pediatric AML. Drug sensitivity ex vivo accurately predicted in vivo single-agent and combinatorial activities with cytarabine in cell line- and patient-derived xenografts. Targeted resequencing of a 141-gene panel revealed novel mutations of prognostic relevance, such as KMT2C, in pediatric AML and their vulnerability to targeted agents. Whole-genome RNA-sequencing identified distinct gene expression signatures shaping the response to individual drugs. Administration of venetoclax to a child with refractory AML resulted in rapid blast clearance and achieved long-term remission. Complementary genomic profiling on serial specimens dictated the dynamic drug responses during disease evolution. Conclusions: Our study establishes a reliable drug testing platform and a pediatric-specific drug response profile of AML, which enables an evidence-based selection of targeted agents for patients without treatment options and endows therapies increasingly precise and personalized. The study also generates a valuable gene-drug-clinical dataset that could be leveraged to address the fundamental and translational biology of pediatric AML. It will ultimately impact the future design of clinical trials and protocols for managing this life-threatening malignancy. Disclosures No relevant conflicts of interest to declare.
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Ebert, Benjamin L., Ross L. Levine, Martha Wadleigh, Jean-Philippe Brunet, Jennifer L. Pretz, Lambert Buque, Stephanie J. Lee, D. Gary Gilliland, and Todd R. Golub. "Characterization of Distinct Molecular Signatures in Myeloproliferative Diseases with the JAK2V617F Mutation and Wild Type JAK2." Blood 106, no. 11 (November 16, 2005): 119. http://dx.doi.org/10.1182/blood.v106.11.119.119.
Full textAbstract:
Abstract The recently discovered JAK2V617F mutation provides a critical insight into the molecular pathogenesis of polycythemia vera and other myeloproliferative diseases (MPD). However, the mutations present in patients with wild type JAK2 have not been discovered, and the precise molecular consequences of JAK2 mutation have not been elucidated. We employed gene expression profiling to characterize the molecular phenotype of cells with the JAK2V617F mutation, to identify a distinct signature in cells without JAK2 mutations, and to refine a molecular taxonomy of MPDs. Using purified neutrophils from 70 patients with myeloproliferative diseases and 11 unaffected individuals, we performed gene expression profiling using oligonucleotide microarrays, sequencing of the JAK2 gene, quantitative genotyping by mass spectrometry and allele-specific quantitative PCR, and X-inactivation clonality assays. To reduce the confounding influence of normal neutrophils that are admixed with cells bearing disease-causing mutations, we examined the gene expression profiles of samples in which greater than 80% of JAK2 alleles bear the V617F mutation. PRV1, a previously identified marker of polycythemia vera, was powerfully overexpressed in neutrophils with a homozygous JAK2 mutation. In addition, cells with the JAK2 mutation had increased expression of a set of kinases, including JAK2, and decreased expression of a set of phosphatases. Cells that rely on JAK2 activation for clonal dominance may therefore derive a selective advantage from increased expression of the JAK2 gene. We next examined samples that have high clonality, and therefore relatively few normal neutrophils, but do not have a mutation in the JAK2 gene. These samples have a markedly different gene expression profile and overexpress a distinct set of kinases. The kinases overexpressed in cells with wild type JAK2 are candidates for further mutational analysis and are potential therapeutic targets. Utilizing these signatures and unsupervised analytical algorithms, the samples cluster according to their mutational status and the percentage of normal neutrophils in the sample. Our data demonstrate that the gene expression profiles of MPD samples are not uniform regardless of JAK2 genotype, implying that samples with and without JAK2 mutations have not activated the same pathway via alternative mechanisms. Moreover, we have identified a common signature in samples without JAK2 mutations that meets significance, indicating that one or a small number of mutations may play a critical role in these cells. Genotype and gene expression analyses are defining a molecular classification of myeloproliferative diseases with subtypes that have distinct therapeutic targets.
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Marcelli, M., A. Di Maio, D. Donis, U. Mainardi, and G. M. R. Manzella. "Development of a new expendable probe for the study of pelagic ecosystems from Voluntary Observing Ships." Ocean Science Discussions 3, no. 5 (September 11, 2006): 1515–41. http://dx.doi.org/10.5194/osd-3-1515-2006.
Full textAbstract:
Abstract. Physical and biological processes of the marine ecosystem have a high spatial and temporal variability, whose study is possible only through high resolution and synoptic observations. The T-FLAP (Temperature and Fluorescence LAunchable Probe) was charted in order to answer to the claim of a cost effective temperature and fluorescence expendable profiler, to be used in ships of opportunity. The development of the expendable fluorimeter has followed similar concepts of the XBT (a wire conducting the signal to a computer card), but differently from that, T-FLAP was developed with an electronic system that can be improved and adapted to several variables measure channels. Commercial components were utilized to reach the aim of a low-cost probe: a glass bulb temperature resistor for the temperature measurement, blue LEDs, a photodiode and available selective glass filters, for fluorescence measurement. The measurement principle employed to detect phytoplankton's biomass is the active fluorescence. This method is an in vivo chlorophyll measure, that can get the immediate biophysical reaction of the cell inside the aquatic ecosystem; it is a non-disruptive method which gives a real time measure and avoids the implicit errors due to the manipulation of samples. The possibility of using continuous profiling probe, with an active fluorescence measurement, is very important in the study of phytoplankton in real time; it is the best way to follow the variability of sea productivity. In fact, because of the high time and space variability of phytoplankton, due to its capability to answer in a relatively short time to ecological variations in its environment and because of its characteristic patchiness, there isn't a precise quantitative estimation of the biomass present in the Mediterranean sea.
30
Poulain, Laury, Adrien Grenier, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Rudy Birsen, et al. "PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2552. http://dx.doi.org/10.1182/blood-2019-123364.
Full textAbstract:
Acute myeloid leukemia (AML) is a myeloid progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Novel therapeutic approaches for AML are therefore critically needed. Adenosine monophosphate (AMP) activated protein kinase (AMPK) is a pleiotropic serine/threonine kinase promoting catabolism that represses anabolism and enhances autophagy in response to stress1. AMPK heterotrimers comprise catalytic α- and regulatory β- and γ-subunits, the latter harboring binding sites for AMP. Targets of AMPK include a host of metabolic pathway enzymes mediating carbohydrate, lipid and protein synthesis and metabolism. Accumulating evidence implicates AMPK in cancer biology, primarily as a tumor suppressor, although minimal AMPK activity may also be required for cancer cell growth under stress conditions2,3. Pharmacological activation of AMPK thus represents an attractive new strategy for targeting AML. We previously used the selective small molecule AMPK activator GSK621 to show that AMPK activation induces cytotoxicity in AML but not in normal hematopoietic cells, contingent on concomitant activation of the mammalian target of rapamycin complex 1 (mTORC1)4. However, the precise mechanisms of AMPK-induced AML cytotoxicity have remained unclear. We integrated gene expression profiling and bioinformatics proteomic analysis to identify the serine/threonine kinase PERK - one of the key effectors of the endoplasmic reticulum stress response - as a potential novel target of AMPK. We showed that PERK was directly phosphorylated by AMPK on at least two conserved residues (serine 439 and threonine 680) and that AMPK activators elicited a PERK/eIF2A signaling cascade independent of the endoplasmic reticulum stress response in AML cells. CRISPR/Cas9 depletion and complementation assays illuminated a critical role for PERK in apoptotic cell death induced by pharmacological AMPK activation. Indeed, GSK621 induced mitochondrial membrane depolarization and apoptosis in AML cells, an effect that was mitigated when cells were depleted of PERK or expressed PERK with a loss of function AMPK phosphorylation site mutation. We identified the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as a downstream target of the AMPK/PERK pathway, as its expression was enhanced in PERK knockdown AML cells. Moreover, selective pharmacologic activation of ALDH2 by the small molecule ALDA-1 recapitulated the protective effects of PERK depletion in the face of pharmacological AMPK activation. Corroborating the impact of the AMPK/PERK axis on mitochondrial apoptotic function, BH3 profiling showed marked Bcl-2 dependency in AML cells treated with GSK621. This dependency was abrogated in PERK-depleted cells, suggesting a role for PERK in mitochondrial priming to cell death. In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML. References 1. Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. 2018;27(2):299-313. 2. Hardie DG. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical Cancer Research. 2015;21(17):3836-3840. 3. Jeon S-M, Hay N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 2015;38(3):346-357. 4. Sujobert P, Poulain L, Paubelle E, et al. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015;11(9):1446-1457. Figure Disclosures Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.
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Camassa, Roberto, and Claudio Viotti. "On the response of large-amplitude internal waves to upstream disturbances." Journal of Fluid Mechanics 702 (May 22, 2012): 59–88. http://dx.doi.org/10.1017/jfm.2012.147.
Full textAbstract:
AbstractLarge-amplitude internal solitary waves generate shear flows that intensify from the wings of the waves to their maxima. Upstream perturbations of the hydrostatic equilibrium in the form of wave packets along the path of wave propagation are expected to trigger shear instability and ultimately generate Kelvin–Helmholtz roll-ups. In contrast, as shown here with accurate simulations of incompressible stratified Euler equations, large internal waves can act as suppressors of perturbations. The precise understanding of the mechanisms leading to different outcomes, including whether instability is excited, is the focus of this work. Under the action of shear flows, small-amplitude wave packets undergo stretching and filamentation, which lead to significant absorption of perturbation energy into the background shear. It is found that this typical behaviour is present in the self-induced shear by internal waves, regardless of whether the shear is stable or unstable, and can leave a quieter state in the wave’s wake for a wide range of perturbation parameters. In the unstable case, even once perturbations are selected to excite the instability, our results show that this absorption can act to reduce growth in the strong-shear region, effectively making roll-up development observable only downstream of the wave crest. Our approach is both analytical and numerical; a model valid for relatively thin pycnoclines and suitable for local spectral analysis is devised and used. Energy diagnostics on the simulations are implemented to validate the numerics and illustrate the energy exchanges between background wave flow and its shear. A link between the absorption mechanism and the clustering of local eigenvalues along the wave is proposed. This promotes an energetic coupling among neutral modes stronger than what may be expected to occur in slowly varying flows, and gives rise to multi-modal transient dynamics of the kind often referred to as non-normality effects. For those cases in which the wave-induced shear meets the conditions for local instability, it is found that the growth of disturbances is selective with respect to the sign of the mode excited upstream. Elements of this phenomenon are interpreted by asymptotic analysis for spatial growth in time-independent slowly varying media.
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Elmas, Z. G., M. Aquino, H. A. Marques, and J. F. G. Monico. "Higher order ionospheric effects in GNSS positioning in the European region." Annales Geophysicae 29, no. 8 (August 22, 2011): 1383–99. http://dx.doi.org/10.5194/angeo-29-1383-2011.
Full textAbstract:
Abstract. After removal of the Selective Availability in 2000, the ionosphere became the dominant error source for Global Navigation Satellite Systems (GNSS), especially for the high-accuracy (cm-mm) demanding applications like the Precise Point Positioning (PPP) and Real Time Kinematic (RTK) positioning. The common practice of eliminating the ionospheric error, e.g. by the ionosphere free (IF) observable, which is a linear combination of observables on two frequencies such as GPS L1 and L2, accounts for about 99 % of the total ionospheric effect, known as the first order ionospheric effect (Ion1). The remaining 1 % residual range errors (RREs) in the IF observable are due to the higher – second and third, order ionospheric effects, Ion2 and Ion3, respectively. Both terms are related with the electron content along the signal path; moreover Ion2 term is associated with the influence of the geomagnetic field on the ionospheric refractive index and Ion3 with the ray bending effect of the ionosphere, which can cause significant deviation in the ray trajectory (due to strong electron density gradients in the ionosphere) such that the error contribution of Ion3 can exceed that of Ion2 (Kim and Tinin, 2007). The higher order error terms do not cancel out in the (first order) ionospherically corrected observable and as such, when not accounted for, they can degrade the accuracy of GNSS positioning, depending on the level of the solar activity and geomagnetic and ionospheric conditions (Hoque and Jakowski, 2007). Simulation results from early 1990s show that Ion2 and Ion3 would contribute to the ionospheric error budget by less than 1 % of the Ion1 term at GPS frequencies (Datta-Barua et al., 2008). Although the IF observable may provide sufficient accuracy for most GNSS applications, Ion2 and Ion3 need to be considered for higher accuracy demanding applications especially at times of higher solar activity. This paper investigates the higher order ionospheric effects (Ion2 and Ion3, however excluding the ray bending effects associated with Ion3) in the European region in the GNSS positioning considering the precise point positioning (PPP) method. For this purpose observations from four European stations were considered. These observations were taken in four time intervals corresponding to various geophysical conditions: the active and quiet periods of the solar cycle, 2001 and 2006, respectively, excluding the effects of disturbances in the geomagnetic field (i.e. geomagnetic storms), as well as the years of 2001 and 2003, this time including the impact of geomagnetic disturbances. The program RINEX_HO (Marques et al., 2011) was used to calculate the magnitudes of Ion2 and Ion3 on the range measurements as well as the total electron content (TEC) observed on each receiver-satellite link. The program also corrects the GPS observation files for Ion2 and Ion3; thereafter it is possible to perform PPP with both the original and corrected GPS observation files to analyze the impact of the higher order ionospheric error terms excluding the ray bending effect which may become significant especially at low elevation angles (Ioannides and Strangeways, 2002) on the estimated station coordinates.
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Scott, David W., George W. Wright, Mickey Williams, Jason Lih, William Walsh, Elaine S. Jaffe, Andreas Rosenwald, et al. "Determining Cell-Of-Origin Subtypes In Diffuse Large B-Cell Lymphoma Using Gene Expression Profiling On Formalin-Fixed Paraffin-Embedded Tissue – An L.L.M.P.P. Project." Blood 122, no. 21 (November 15, 2013): 73. http://dx.doi.org/10.1182/blood.v122.21.73.73.
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Abstract The diffuse large B-cell lymphoma (DLBCL) cell-of-origin (COO) distinction into germinal center B cell (GCB) and activated B cell (ABC) subtypes, as molecularly described by our group, has profound biological, prognostic, and potential therapeutic implications. New therapeutic agents with selective activity in ABC and GCB DLBCL are under development. An accurate diagnostic assay is urgently needed to qualify patients for clinical trials using targeted agents and as a predictive biomarker. Although the subtypes were originally defined using gene expression profiling on snap-frozen tissues (frozen-GEP), it has become common practice to use less precise but relatively inexpensive and broadly applicable immunohistochemical (IHC) methods in formalin-fixed paraffin-embedded tissue (FFPET). We sought to create a robust, highly accurate molecular assay for COO distinction using new GEP techniques applicable to FFPET. Studies were performed on centrally reviewed DLBCL FFPET biopsies using cases that had “gold standard” COO assigned by frozen-GEP using Affymetrix U133 plus 2.0 microarrays. The training cohort consisted of 51 cases comprising 20 GCB, 19 ABC and 12 Unclassifiable (U) cases. An independent validation cohort, consisting of 68 cases (28 GCB, 30 ABC, 10 U) drawn from the validation cohort of Lenz et al (NEJM 2008) had the typical proportions of COO subtypes seen in DLBCL populations. Nucleic acids were extracted from 10um FFPET scrolls. Digital gene expression was performed on 200ng of RNA using NanoString technology (Seattle, WA). All FFPET GEP studies were performed in parallel at two independent sites (BC Cancer Agency, Vancouver, and NCI, Frederick, MD) using different FFPET scrolls to determine inter-site concordance and assess the robustness and portability of the assay. To assign COO by IHC, tissue microarrays were made using 0.6mm duplicate cores from 60/68 validation cohort cases, and stained for CD10, BCL6, MUM1, FOXP1, GCET1 and LMO2. Two hematopathologists independently assessed the proportion of tumor cells stained, with consensus on discordant cases reached with a third hematopathologist. For the validation studies, those producing and analyzing the GEP and IHC data were blinded to the “gold standard” COO. All 119 FFPET biopsies yielded sufficient RNA. A pilot study using the training cohort identified 20 genes (15 genes of interest and 5 house keeping genes) whose expression, measured using NanoString, would allow accurate replication of the COO assignment model of Lenz et al (NEJM 2008). NanoString was then used to quantitate these 20 genes in the training cohort, allowing the COO model to be optimized. Despite the age of the FFPET blocks (6-32 years old), 95% (49/51) of the training samples gave gene expression data of sufficient quality. The model, including coefficients, thresholds and QC parameters was then “locked” and applied to the independent validation cohort. Ninety-nine percent (67/68) of the samples from the validation cohort (5-12 years old) provided gene expression of adequate quality. Three cases did not give interpretable IHC results. When considering the “gold standard” ABC and GCB cases, the COO assignments by the NanoString assay at the NCI site were 93% concordant, with 5% labeled U and 1 ABC misclassified as GCB (see table). This 2% rate of misclassification of ABC and GCB cases compares favorably with the 9%, 6% and 17% rates for the interpretable cases from the Hans, Tally and Choi algorithms, respectively. Furthermore, the 98% concordance of COO assignment (95% if “gold standard” U cases are also included) between the NCI and BC Cancer Agency sites indicates that, in contrast to the IHC algorithms, the assay is reproducible.TableNanoString GEP assay - NCIHans algorithmTally algorithmChoi algorithmGCBUABCGCBNon-GCBGCBABCGCBABCFrozen GEPGCB2800210183192U721552864ABC1325422026620 In summary, 119 well-characterized DLBCL cases from the LLMPP, previously subtyped by our published disease-defining algorithm using frozen-GEP, were used to develop a highly accurate and robust NanoString 20 gene assay, applicable to RNA from FFPET that is routinely obtained for diagnosis. This new assay shows excellent performance in archival FFPET, and the rapid turn-around time (<36 hours from FFPET block to result) will allow prospective implementation in future therapeutic trials and, ultimately, clinical practice. Disclosures: No relevant conflicts of interest to declare.
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Freson, Kathleen, Veerle Labarque, Chantal Thys, Christine Wittevrongel, Rita De Vos, Richard Farndale, and Chris Van Geet. "Increased Bleeding Tendency in a Patient with Caffey Disease Due to a COL1A1 Mutation and a Defect in Platelet Morphology and Function." Blood 106, no. 11 (November 16, 2005): 736. http://dx.doi.org/10.1182/blood.v106.11.736.736.
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Abstract Caffey disease or infantile cortical hyperostosis is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of particularly the long bones. This autosomal dominant disorder in 4 unrelated families is caused by a similar missense mutation (R836C) in the gene for the alpha1 chain of type I collagen (COL1A1; Gentile et al, JCI, 2005). The precise link between this mutation and either the localized inflammation problems or the originally described thrombocytosis and easy bruising associated with Caffey disease (Lorber et al, 1979) was not evidenced. In the present study, we studied the platelets from a 6-year-old girl with Caffey disease due to a de novo COL1A1 R836C mutation because of her increased bleeding tendency. Apart from the typical skeletal deformities she also presented with easy bruising. This COL1A1 mutation modulates normal megakaryopoiesis since the patient presented with a relatively high number of platelets (+/−450.000/mL) and a decreased MPV (7-8 fL). All other hematological parameters were normal. Electron microscopy further revealed platelets with a proliferation of the dense tubular system, a pronounced open canalicular system and a reduced number of often smaller dense granules. Platelet ATP secretion was reduced after stimulation with 5 mg/ml Horm collagen (2 mM: nl 3-7 mM). The PFA100 response with either collagen/epinephrine or collagen/ADP was within the normal range. Aggregation studies were suggestive for a selective impairment of platelet activation to collagen since the patient platelets showed a reduced and retarded response towards Horm Collagen, convulxin and the collagen related peptide (CRP-XL) but a normal aggregation with ADP, U46019 and arachidonic acid. Membrane glycoprotein (GP) profiling by flow cytometry showed a normal antibody binding to integrin beta3, integrin alpha2beta1 and GPVI. Since R to C amino acid substitutions in COL1A1 are associated with an increased disulfide crosslinking within mutant collagen fibers (Gentile et al, JCI, 2005) but also with other cysteine-containing proteins as integrins, we hypothesized that the platelet integrins might be triggered when mature megakaryocytes are in contact with the collagen type I of the extracellular matrix of the patients bone marrow. Immunoblot analysis of platelet lysates from the patient indeed showed the presence of a 190 kDa COL1A1 band, which could not be detected in control samples. In addition, beta1 integrin could be co-immunoprecipitated with an anti-COL1A1 antibody in platelet lysates from the patient. Further studies are needed to determine whether this COL1A1 R836C binding to platelet collagen receptors is responsible for the defective collagen signaling in this patient by receptor desensitization. In conclusion, we here present the first collagen type I mutation that leads to a defective platelet ultra structure and function.
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Fons, Nathan R., Rhonda C. Kines, and John T. Schiller. "Abstract 6295: Belzupacap sarotalocan, an investigational virus-like drug conjugate, preferentially binds cancer cell glycosaminoglycans associated with the epithelial to mesenchymal transition." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6295. http://dx.doi.org/10.1158/1538-7445.am2023-6295.
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Abstract Human papillomaviruses (HPVs) are non-enveloped, double-stranded DNA viruses that utilize modified glycosaminogycans (GAGs) such as heparan sulfate proteoglycans, within the epidermal basement membrane as initial attachment factors prior to cell entry and infection. Similarly modified GAGs are also commonly found on the surface of tumor cells, enabling HPV capsids with tumor-selective binding properties. Belzupacap sarotalocan (bel-sar, formerly AU-011), is a virus-like drug conjugate composed of an HPV virus-like particle (VLP) conjugated to a cytotoxic payload (phthalocyanine dye) which upon light activation, causes rapid immunogenic tumor necrosis of bound tumor cells in vivo and has the potential to induce long-term anti-tumor immunity. Bel-sar has been shown to bind to and kill a wide variety of tumor types in preclinical models and is entering a Phase 3 clinical trial for the treatment of early-stage choroidal melanoma. To investigate the precise GAG modifications as well as the overall genetic signature which mediates the binding specificity of bel-sar, a large, multi-tumor type binding screen of bel-sar on 124 cancer cell lines was performed in vitro, where we identified a strong relationship between drug binding and pathways involved in the epithelial to mesenchymal transition (EMT). Additionally, through dose escalation treatments, HeLa subclones were generated which fail to bind and are resistant to the cytotoxic effects of bel-sar. Gene expression profiling and biochemical characterization of these resistant HeLa cell lines demonstrated a strong reduction in the expression of GAGs and a marked down-regulation of TGF-β signaling, ultimately resulting in the induction of a mesenchymal to epithelial transition (MET). Furthermore, gene-gene correlation studies showed that a variety of GAG biosynthesis genes are associated with TGF-β signaling and EMT progression, and that these genes are important determinates of bel-sar binding. Overall, these data suggest that the binding of bel-sar and HPV VLPs is strongly dependent on the expression and modification of GAGs that occurs during the EMT process. As many cancers, especially metastatic tumors, are thought to undergo at least partial EMT, these data provide mechanistic insights into the tumor-targeting ability of HPV VLP-conjugates such as bel-sar and suggest possible applications for such therapies across a wide variety of other tumor types. Citation Format: Nathan R. Fons, Rhonda C. Kines, John T. Schiller. Belzupacap sarotalocan, an investigational virus-like drug conjugate, preferentially binds cancer cell glycosaminoglycans associated with the epithelial to mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6295.
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Sugino, Noriko, Masahiro Kawahara, Takayoshi Suzuki, Yuya Nagai, Yayoi Shimazu, Sumie Fujii, Ryusuke Yamamoto, Masakatsu Hishizawa, and Akifumi Takaori-Kondo. "The Pharmacological Inhibition of KDM1A Displays Preclinical Efficacy in AML and MDS By Inducing Myelomonocytic Differentiation." Blood 124, no. 21 (December 6, 2014): 1010. http://dx.doi.org/10.1182/blood.v124.21.1010.1010.
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Abstract Background: Histone methylation is one of the major systems of epigenetics and reversibly regulated by lysine (K) specific methyltransferases (KMTs) and demethylases (KDMs). Dysregulation of KMTs such as EZH2 and MLL play a key role in the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) while the precise function of KDMs remains unclear.KDM1A is the first reported histone demethylase, which mainly catalyzes demethylation of mono- and di-methylated lysine 4 of histone 3 (H3K4me1 and me2 respectively). According to recent reports, the inhibition of KDM1A either alone or in combination of all-trans retinoic acid is effective for AML expressing MLL-AF9 or for several types of AML respectively, suggesting KDM1A could be a therapeutic target of AML. However, other reports argue that KDM1A is essential in hematopoiesis, raising concern that KDM1A-targeted therapy could lead to severe hematological toxicity. Here, we try to clarify what types of leukemia can be ameliorated by the pharmacological inhibition of KDM1A with a possible therapeutic window and what are functional and molecular mechanisms utilizing highly selective KDM1A inhibitors we have newly designed. Results: First we validated the effect of our novel inhibitors on murine leukemia cells harboring MLL-AF9. In accordance with a previous report, our novel KDM1A inhibitors suppressed cell proliferation, diminished clonogenic capacity and induced G1-S cell cycle arrest and myelomonocytic differentiation but not apoptosis in quite low concentration that clonogenicity of normal murine bone marrow cells was spared. Next we examined the effect of these drugs on diverse types of human myeloid leukemia cells and found that our drugs were particularly effective in erythroid leukemia cells (HEL), megakaryocytic leukemia cells (CMK11-5), and a blastic subline from a MDS patient with complex karyotype (MDS-L). MDS-L cells were changed phenotypically and morphologically towards myelomonocytic differentiation such as the increase of CD11b expression level and the induction of neutrophil-like cells. HEL and CMK cells which are negative for myelomonocytic markers also gained CD11b expression and decreased erythroid markers such as CD235a and CD71. These data suggest that the inhibition of KDM1A induces myeloid differentiation across various types of leukemia. To investigate an underlying molecular basis for the cell fate conversion in HEL and myeloid differentiation in MDS-L by the inhibition of KDM1A, we performed gene expression profiling and analyzed a change of gene signatures. The expression pattern of transcriptional factors was changed from the erythroid signature (e.g. GATA1 and TAL1) to the myeloid signature (e.g. SPI1 and CEBPA) in HEL. Gene Set Enrichment Analysis (GSEA) showed that the myeloid differentiation-associated gene signature was positively enriched and the leukemia stem cell-associated gene signature was negatively enriched in both HEL and MDS-L. Finally, we investigated the effect of our KDM1A inhibitors on primary human samples such as AML with MLL-AF9 and MDS in the phase of overt leukemia (MDS/AML) with complex karyotype. The colony formation capacity was clearly impaired in relatively low concentration that normal colonies were spared. We transplanted primary MDS/AML cells with complex karyotype to immunodeficient mice and treated with a KDM1A inhibitor or vehicles after confirming the engraftment. In one MDS/AML case, all mice treated with vehicles (n=4) died of anemia and the increase of human leukemia cells within four months while 3 of 4 mice treated with a KDM1A inhibitor have survived for more than six months. Also in another case, both of two vehicle-treated mice died while all drug-treated mice had survived for more than six months. At day 200 after transplantation, we sacrificed all survived mice treated with a KDM1A inhibitor and found that human blasts were displaced from the bone marrow of treated mice. Those data suggest that our KDM1A inhibitor is effective in vivo and have a possibility for the clinical application. Conclusion: Our study suggests that KDM1A involves with myeloid differentiation and the leukemia stem cell signature and that the pharmacological inhibition of KDM1A by highly selective inhibitors is a promising way to ameliorate AML with poor prognosis such as erythroleukemia and MDS/AML with complex karyotype, without impairing normal hematopoiesis. Disclosures No relevant conflicts of interest to declare.
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Krönke, Jan, Anupama Narla, Slater N. Hurst, Namrata Udeshi, Monica Schenone, Marie McConkey, Peter Grauman, et al. "Inhibition of the CRBN-DDB1-CUL4-ROC1 E3 Ubiquitin Ligase Mediates the Anti-Proliferative and Immunomodulatory Properties of Lenalidomide." Blood 120, no. 21 (November 16, 2012): 919. http://dx.doi.org/10.1182/blood.v120.21.919.919.
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Abstract Abstract 919 Lenalidomide is a highly effective drug for the treatment of del(5q) MDS and multiple myeloma, and its use in a range of other conditions is being actively explored. Despite its increasing use for the treatment of malignancies, the precise mechanism of action of lenalidomide has not been established. We sought to identify the direct protein targets of lenalidomide using a quantitative, mass spectrometry-based proteomic approach we developed. Using a validated derivative of lenalidomide immobilized to beads, we identified DDB1 as a target of the drug by affinity enrichment of protein binders and analysis by high performance LC-MS/MS. DDB1, together with CRBN, CUL4A, and ROC1, forms an E3 ubiquitin ligase known as CRBN-CRL4. We confirmed that members of the complex bind to the immobilized lenalidomide derivative, and could be competed off with soluble lenalidomide, further supporting the role of CRBN-CRL4 in the actions of lenalidomide. CRL4 targets multiple proteins for ubiquitination and subsequent proteasomal degradation, including the cell cycle regulators CDKN1A (p21) and CDKN1B (p27), as well as the DNA licensing factor CDT1. We hypothesized that lenalidomide disrupts the ubiquitination of these and other proteins, leading to increased levels of the respective targets. We found that treatment of the lenalidomide sensitive cell line MM1S and NCI-H929 increased protein levels of p21, p27 and CDT1 in a dose and time dependent manner. Furthermore, overexpression of these three targets led to growth inhibition. Similarly, knockdown of DDB1, CUL4A, ROC1 and CRBN by lentiviral shRNAs increased p21 and p27 protein levels and inhibited growth of these cell lines. Lenalidomide is also known to increase IL-2, promote erythropoiesis and inhibit TNF-alpha. We found that in activated primary human T cells, shRNA knockdown of DDB1 recapitulated the stimulatory effects of lenalidomide on IL-2 expression levels and release. We also found that shRNA knockdown of DDB1 and CRBN recapitulated the pro-erythropoietic effects of the drug with an increase in the number of colony-forming units-erythroid (CFU-E) compared to control knockdown. Experiments studying the effects on TNF-alpha are underway. To further establish that the CRBN-CRL4 complex is the target of lenalidomide, we tested a previously published mutant form of CRBN which prevents binding of the drug to the complex. Ectopic expression of this mutant CRBN conferred resistance to lenalidomide induced cell death to multiple myeloma cells. It also resulted in the loss of CFU-E production by lenalidomide. To gain further insight into how lenalidomide might disrupt the function of the CRBN-CRL4 complex, we did immunoprecipitation against CRBN with or without the drug and found that lenalidomide disrupts the formation of the complex by preventing binding of ROC1, the adaptor protein to ubiquitin charged E2 conjugating enzyme. Using in vivo and in vitro ubiquitination assays, we also demonstrated that lenalidomide inhibits the auto-ubiquitination of CRBN. We are currently performing a ubiquitin profiling experiment to identify other protein targets that might be affected by the disruption of the CRBN-CRL4 complex by lenalidomide. Our study establishes that lenalidomide's antiproliferative and immunomodulatory properties rely on binding to CRBN-CRL4 and inhibiting its function as ubiquitin ligase. Ito et al. showed 2010 that the same mechanism is also responsible for the teratogenic effects of thalidomide. The characterization of lenalidomide as a specific E3 ubiquitin ligase inhibitor will provide insight into the mechanism of therapeutic efficacy in MDS and multiple myeloma, and serves as a proof-of-concept that selective ubiquitin ligases are efficacious targets for cancer therapy. Disclosures: No relevant conflicts of interest to declare.
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Sajjadi, Elham, Konstantinos Venetis, Roberto Piciotti, Marco Invernizzi, Elena Guerini-Rocco, Svasti Haricharan, and Nicola Fusco. "Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization." Cancer Cell International 21, no. 1 (May 17, 2021). http://dx.doi.org/10.1186/s12935-021-01976-y.
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AbstractThe clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.
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Whiteley, Samuel, Adam Sorensen, John J. Vajo, Roy Sfadia, Thaddeus D. Ladd, Shanying Cui, and jason graetz. "Dopant Selective Photoelectrochemical Etching of SiC." Journal of The Electrochemical Society, March 17, 2023. http://dx.doi.org/10.1149/1945-7111/acc553.
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Abstract Single crystalline 4H-SiC is a wide-gap semiconductor with optical properties that are poised to enable new applications in microelectromechanical systems (MEMS) and quantum devices. A number of key hurdles remain with respect to the micro and nano-fabrication of SiC to prepare precise photonic structures with nanometer-scale precision. These challenges include development of a fast, scalable etching process for SiC capable of producing a sub-nanometer roughness semiconductor surface while simultaneously reducing the total thickness variation across a wafer. Our investigation into UV photoelectrochemical processing of SiC reveals high dopant-type selectivity and the advantage of multiple etch stops to reduce layer thickness variation. We demonstrate dopant-type selectivities >20:1 using a single step and a >100x reduction in surface variation by combining two etch stops. Moreover, the etch rate is fast (>4 μm/hr) and the etched surface is smooth (~1 nm RMS). These results demonstrate a scalable path to the fabrication of precise nanoscale SiC structures and electronic devices that will enable the next generation of MEMS and photonic quantum devices.
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Wang, Xiang-Dong, Qianghua Xie, Joe Hooker, Shifeng Lu, J. J. Lee, Phil Tobin, Wei Liu, and Linda Cross. "2D Dopant Profiling for Advanced Process Control." MRS Proceedings 745 (2002). http://dx.doi.org/10.1557/proc-745-n4.3.
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ABSTRACTAs the CMOS device dimensions continue to shrink, it is more and more critical to control the process parameters during mass production of advanced VLSI chips in order to achieve high yield and profitability. 2D dopant characterization is one of the critical techniques to resolve manufacturing excursions. A quick access to dopant distribution, especially precise delineation of p-n junction would readily provide critical information for many manufacturing issues, as well as device design and process development. Here we present our approaches to some of those issues with available techniques. The main techniques we used are dopant selective etching (DSE) and scanning probe microscopy based electrical measurements including scanning capacitance microscopy (SCM) and scanning spread resistance microscopy (SSRM). These techniques provided complementary results and showed strengths in solving different issues. We have successfully delineated junction of CMOS devices with 0.13 μm technology with source/drain extensions. Other applications, including diode leakage, well-well isolation, and buried layer delineation with the combination of these methods are presented.
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Tóth, Balázs, Iordan Iordanov, and László Csanády. "Selective profiling of N- and C-terminal nucleotide-binding sites in a TRPM2 channel." Journal of General Physiology 152, no. 5 (March 25, 2020). http://dx.doi.org/10.1085/jgp.201912533.
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Transient receptor potential melastatin 2 (TRPM2) is a homotetrameric Ca2+-permeable cation channel important for the immune response, body temperature regulation, and insulin secretion, and is activated by cytosolic Ca2+ and ADP ribose (ADPR). ADPR binds to two distinct locations, formed by large N- and C-terminal cytosolic domains, respectively, of the channel protein. In invertebrate TRPM2 channels, the C-terminal site is not required for channel activity but acts as an active ADPR phosphohydrolase that cleaves the activating ligand. In vertebrate TRPM2 channels, the C-terminal site is catalytically inactive but cooperates with the N-terminal site in channel activation. The precise functional contributions to channel gating and the nucleotide selectivities of the two sites in various species have not yet been deciphered. For TRPM2 of the sea anemone Nematostella vectensis (nvTRPM2), catalytic activity is solely attributable to the C-terminal site. Here, we show that nvTRPM2 channel gating properties remain unaltered upon deletion of the C-terminal domain, indicating that the N-terminal site is single-handedly responsible for channel gating. Exploiting such functional independence of the N- and C-terminal sites, we selectively measure their affinity profiles for a series of ADPR analogues, as reflected by apparent affinities for channel activation and catalysis, respectively. Using site-directed mutagenesis, we confirm that the same N-terminal site observed in vertebrate TRPM2 channels was already present in ancient cnidarians. Finally, by characterizing the functional effects of six amino acid side chain truncations in the N-terminal site, we provide first insights into the mechanistic contributions of those side chains to TRPM2 channel gating.
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Shen, Congzhen, Duoteng Zhang, Fang Xu, Yang Yang, Yi Tan, Qian Zhao, Lin Li, Ke Ding, and Zhengqiu Li. "Two-photon fluorescent turn-on probes for highly efficient detection and profiling of thiols in live cells and tissues." Biological Chemistry, September 9, 2021. http://dx.doi.org/10.1515/hsz-2021-0189.
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Abstract Thiols are important units in amino acids such as cysteine and peptides like glutathione. Development of chemical sensors capable of precise detection of thiols is important in cancer diagnosis and therapy. We have developed novel two-photon fluorescent turn-on probes for selective detection of thiols. The probes displayed excellent sensitivity and low detection limits. The dual-purpose probes have been demonstrated to be suitable for simultaneous imaging and proteome profiling in live cells and tumor tissues. The unique turn-on design endows the probes with excellent selectivity toward thiols in vitro and in situ, and can be further developed to support a thiol-quantification assay.
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KONDRA, SRINIVASU, BAPUJI A. T., D. GOWRI SANKAR, and POTTURI MURALI KRISHNAM RAJU. "IMPURITY PROFILING IMPURITY PROFILING OF THIAMINE HYDROCHLORIDE INJECTION BY RP-HPLC AND CHARACTERIZATION OF DEGRADATION PRODUCT BY LC-MS/MS/QTOF." International Journal of Applied Pharmaceutics, September 16, 2020, 151–61. http://dx.doi.org/10.22159/ijap.2020v12i6.38283.
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Objective: To propose a comprehensive, simple, and affordable RP-HPLC method for impurity profiling and characterization of unknown degradation products of thiamine hydrochloride injectable formulation.
Methods: The chromatographic separation employs gradient mode using the octadecyl silane column using a mobile phase consisting of phosphate buffer with ion pair reagent, acetonitrile, and methanol delivered flow rate at 1.2 ml/min. The detection was carried out at 248 nm using empower software. LC-MS/MS/QTOF hyphenated technique was used for isolation and characterization of unknown degradation impurity. The performance of the method was systematically validated as per ICH Q2 (R1) guidelines.
Results: Degradation product observed in accelerated stability was characterized by LC-MS/MS/QTOF hyphenated technique and found m/z value 351.1604 and postulated as an oxidative degradation product of thiamine due to excipient interaction. The validated method was sensitive, selective, and specific data proves the method is precise and accurate from LOQ to 150% level and results are within 95-108% and less than 4.5% RSD. The developed method is linear from 0.03-58.83 µg/ml with a correlation coefficient of more than 0.990 and LOD and LOQ value ranged from 0.03 to1.51 μg/ml.
Conclusion: An efficient RP-HPLC method for impurity profiling of thiamine injectable formulation was successfully developed and unknown degradation product observed instability condition samples characterized by LC-MS/MS/QTOF technique. The validated method can be successfully employed for the impurity profiling of thiamine injectable in the quality control department.
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Hager, Antonia, Lucas Guniat, Nicholas Morgan, Santhanu Panikar Ramanandan, Alok Rudra, Valerio Piazza, Anna Fontcuberta i Morral, and Didem Dede. "The implementation of thermal and UV nanoimprint lithography for selective area epitaxy." Nanotechnology, July 26, 2023. http://dx.doi.org/10.1088/1361-6528/acea87.
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Abstract Semiconductor nanowires in horizontal configuration could provide a path for scalable nanowire-based devices. Bottom-up large-scale manufacturing of these nanostructures by selective area epitaxy (SAE) relies on precise nanopatterning of various shapes on the growth masks. Electron beam lithography offers an extraordinary accuracy suited for the purpose. However, this technique is not economically viable for large production as it has a low throughput and requires high investment and operational costs. Nanoimprint lithography (NIL) has the potential to reduce fabrication time and costs significantly while requiring less sophisticated equipment. In this work, we utilize both thermal and UV NIL for patterning substrates for SAE, elucidating the advantages and disadvantages of each lithography technique. We demonstrate the epitaxial growth of Ge and GaAs NWs on these substrates, where we observe high-quality mono-crystalline structures. Even though both processes can produce small uniform structures suitable for SAE, our results show that UV NIL proves to be superior and enables reliable and efficient patterning of sub-100 nm mask features at the wafer scale.
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Xu, Bin, and Ryan Haley. "Development and validation of methods that enable high-quality droplet digital PCR and hematological profiling data from microvolume blood samples." Bioanalysis, November 4, 2022. http://dx.doi.org/10.4155/bio-2022-0162.
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Aim: Mouse models have been crucial to preclinical studies in the increasingly relevant fields of cell and gene therapy. However, only small quantities of mouse blood can be collected without producing adverse physiological effects that compromise data integrity. Results: To address this limitation, two combined methods were developed to create detailed droplet digital PCR (ddPCR) and hematological profiles using only ∼20 μl of mouse blood. The validation of these methods, which can serve as a foundation for a standardized regulatory pipeline for ddPCR, is discussed. Even when using small amounts of input, this ddPCR protocol is accurate, precise, selective, specific, stable and robust. Conclusion: These techniques enable more frequent sample collection for higher-resolution pharmacokinetic data that meets or exceeds quality standards.
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Guydosh, Nicholas R., Philipp Kimmig, Peter Walter, and Rachel Green. "Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe." eLife 6 (September 25, 2017). http://dx.doi.org/10.7554/elife.29216.
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The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.
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Wang, Zenan, Jun Tian, Ying Hu, and Jun Wei. "Surface Acoustic Wave (SAW)‐Based Sonoporation of Single‐Adherent‐Cell." Advanced Materials Technologies, August 30, 2023. http://dx.doi.org/10.1002/admt.202300573.
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AbstractSonoporation refers to the formation of tiny transient pores in cell plasma membranes by using ultrasound to increase the permeability to bioactive materials. Recently, the Sonoporation technique has been widely researched in cell treatment applications, such as gene transfection. However, due to the random distribution of microbubbles, it is challenging to perform controllable and precise localized sonoporation of a target cell. In this work, a device based on the surface acoustic wave is developed to achieve a selective manipulation and cavitation of microbubbles. The device consists of a pair of microbubble positioning slant‐finger interdigital transducers (SFITs) for moving a selected microbubble in a two‐dimensional plane. Meanwhile, another narrow‐frequency‐band SFIT is integrated into the device for local cavitation control of the same microbubble. As a result, a microbubble can be transported orthogonal to and along the acoustic transmission path by continuously adjusting the input frequency and relative phase. Upon reaching the target cell, the selected microbubble can be cavitated without exciting other microbubbles, resulting in local sonoporation. The resolution of phase‐based positioning and frequency‐based transportation are 8.3 and 7.0 µm with 45° and 10 kHz settings, respectively.
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Mathiyalagan, Prabhu, Yaxuan Liang, David Kim, Douglas W. Losordo, Roger J. Hajjar, and Susmita Sahoo. "Abstract 16109: A Selective Cargo of Non-coding RNAs Mediate Therapeutic Potential of Human CD34+ Stem Cell-derived Exosomes." Circulation 132, suppl_3 (November 10, 2015). http://dx.doi.org/10.1161/circ.132.suppl_3.16109.
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Introduction: Clinical application of human CD34+ stem cells is associated with improved exercise tolerance and therapeutic angiogenesis in patients with myocardial ischemia. We reported the first description of independent therapeutic potential of CD34+ stem cell-derived exosomes (CD34Exo) to that of parent cell by mechanisms that still remain poorly understood. Hypothesis: Herein, we tested the hypothesis that CD34Exo may selectively carry non-coding RNA (ncRNA) cargo targeted for pro-angiogenic signaling and ischemic tissue repair. Methods and Results: Murine models of myocardial ischemia employed throughout the study. Cell-free CD34Exo replicated the therapeutic activity of their parent cells by significantly improving myocardial ischemia (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis, 27±2 v 48±7%; p<0.05, n=7-12) compared with a PBS control. Confocal imaging and flow cytometry analyses revealed that CD34Exo was selectively internalized into endothelial cells and cardiomyocytes in the CD34Exo-injected ischemic hearts. MicroRNA (miR) profiling identified several pro-angiogenic miRs including miR-126 that are selectively enriched in CD34Exo. Mice injected with CD34Exo show elevated miR-126 and several pro-angiogenic mRNAs in ischemic myocardium, however did not affect endogenous miR-126 synthesis suggestive of direct CD34Exo-mediated miR-126 transfer. Depletion of miR-126 reduced the therapeutic efficacy of CD34Exo both in vitro and in vivo indicating a critical role for miR-126. Using fluorescent-tagged miR-126, we monitored in real-time the uptake and transfer of miR-126 by endothelial cells both in vitro and in vivo. We finally provide novel insights underlying CD34Exo function in regulating endothelial proliferation through identification of novel pathways regulated by miR-126 in endothelial cells. Conclusion: Our results reveal specific CD34Exo-shuttled microRNAs and pathways regulated in the ischemic myocardium. Our work presents a molecular framework for CD34Exo mechanism and function in therapeutic angiogenesis. Precise understanding of CD34Exo mechanisms could significantly amplify the therapeutic benefits of CD34Exo in ischemic tissue regeneration and repair.
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Girme, Aboli, Prajkta Bhoj, Ganesh Saste, Sandeep Pawar, Amit Mirgal, Dipak Raut, Machindra Chavan, and Lal Hingorani. "Development and Validation of RP-HPLC Method for Vicenin-2, Orientin, Cynaroside, Betulinic Acid, Genistein, and Major 8 Bioactive Constituents with LC-ESI-MS/MS profiling in Ocimum genus." Journal of AOAC INTERNATIONAL, April 30, 2021. http://dx.doi.org/10.1093/jaoacint/qsab067.
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Abstract Background Ocimum genus known as Tulsi or Basil is a prominent botanical class in Asian culture, especially in India. The leaves have an immunomodulatory, antioxidant, stress-relieving, and adaptogenic role in traditional and modern medicine, with prominent usage in herbal teas and nutraceuticals. Objective The HPLC-PDA method was developed and validated for vicenin-2, orientin, cynaroside, betulinic acid, genistein, with syringic acid, rosmarinic acid, eugenol, carnosic acid, oleanolic acid, ursolic acid, luteolin, apigenin for quantification and confirmed using a novel ESI -MS/MS method in the Ocimum samples. Method The methodology parameters were developed on the RP-C18 column with a gradient elution of 1 mL/min flow rate for 0.1% o-phosphoric acid and acetonitrile at 210 and 340 nm wavelengths. Result The validation data for 13 bioactive compounds showed good linearity (r2> 0.99) with sensitive LOD (0.034-0.684 µg/mL) and LOQ (0.100-2.068 µg/mL) with recoveries (83.66-101.53%).The results were found precise (RSD,<5.0%) and accurate (RE, -0.60-1.06) for the quantification. The method performance was verified and found robust by analyzing ten samples of O. tenuiflorum from the ten geographical states of India (RSD, < 5.0%). Conclusion The validated HPLC-PDA method was found selective and suitable for analyzing thirteen compounds in O. tenuiflorum and twelve cultivars from the Ocimum genus as a quality control tool. This method can be used in routine analysis as an inexpensive alternative to advanced techniques. Highlights This work is the first to report for vicenin-2, orientin, cynaroside, betulinic acid, and genistein, with simultaneous analysis of eight bioactive compounds in the Ocimum genus.
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Ojo, Joseph S., Babatunde A. Alabi, and Moses O. Ajewole. "Characterization of Ka-band Radar Observations for Different Rain Types over Akure, Nigeria." Physical Science International Journal, May 16, 2020, 9–19. http://dx.doi.org/10.9734/psij/2020/v24i330180.
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Radar is a unique tool that can measure precipitation parameters over a large aerial coverage. Its application spans over study of climate change and radiowave propagation. Inter-relation between the rain parameters can also be derived with the height of radar especially on vertical profiling or aloft ground level. Hence effect of precipitation parameters can be assessed along the satellite propagation path with the help of space-borne radar. Satellite communication links operating at frequencies above 10 GHz are usually affected by hydrometeors especially rainfall. These effects are expected to be quite severe in the tropical region like Akure due to the nature of precipitation which is mainly convective and stratiform rain type. Therefore, information on vertical rain structure is important for precise quantitative estimation of precipitation. Thus, the focus of this work is to characterize the vertical profile of rain structures using vertically-pointing Ka-band Micro Rain Radar (MRR) at Akure, Nigeria. This has been achieved by using 2-year (2013 and 2014) data of rain parameters namely: rain rate, reflectivity, liquid water content and fall velocity obtained from MRR to determine the bright band heights under different rain types and its implications on satellite and radio waves propagation in this region. Rain rate in this region has been categorized into four groups namely: 0.02- 0.2 mm/h, 0.2- 2 mm/h, 2-40 mm/h, and 40 - 200 mm/h. The very low rain rate group is related to the stratiform rain types whereas highest rain rate groups are for the convective rain type. Study shows that parameters that are much associated with rain attained peak value at different height depending on the period of the year. The vertical profile of Z shows peak around 3 to 4.2 km height. The peak region is associated with the bright band height and contribution to the melting layer. This study revealed that the occurrence of bright band heights varies with rain types. The overall results will be useful for determining rain height needed for the prediction of rain attenuation in this region.