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Brantley Coleman, Irini Topalidou, Michael Ailion
The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cb, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of or in parallel to the Gq-Rho pathway...
April 3, 2018: Genetics
Dharini van der Hoeven, Kwang-Jin Cho, Yong Zhou, Xiaoping Ma, Wei Chen, Ali Naji, Dina Montufar-Solis, Yan Zuo, Sarah E Kovar, Kandice R Levental, Jeffrey A Frost, Ransome van der Hoeven, John F Hancock
KRAS must localize to the plasma membrane (PM) for biological activity. We show here that multiple acid sphingomyelinase (ASM) inhibitors, including tricyclic antidepressants, mislocalized phosphatidylserine (PtdSer) and KRASG12V from the PM; resulting in abrogation of KRASG12V signaling and potent, selective growth inhibition of mutant KRAS transformed cancer cells. Concordantly, in nude mice, the ASM inhibitor fendiline decreased the rate of growth of oncogenic KRAS-expressing MiaPaCa-2 tumors, but had no effect on the growth of the wild-type KRAS-expressing BxPC-3 tumors...
November 20, 2017: Molecular and Cellular Biology
Mark G Sterken, Linda van Bemmelen van der Plaat, Joost A G Riksen, Miriam Rodriguez, Tobias Schmid, Alex Hajnal, Jan E Kammenga, Basten L Snoek
The oncogenic Ras/MAPK pathway is evolutionarily conserved across metazoans. Yet, almost all our knowledge on this pathway comes from studies using single genetic backgrounds, whereas mutational effects can be highly background dependent. Therefore, we lack insight in the interplay between genetic backgrounds and the Ras/MAPK-signaling pathway. Here, we used a Caenorhabditis elegans RIL population containing a gain-of-function mutation in the Ras/MAPK-pathway gene let-60 and measured how gene expression regulation is affected by this mutation...
September 7, 2017: G3: Genes—Genomes—Genetics
Yan Liu, Dejuan Zhi, Menghui Li, Dongling Liu, Xin Wang, Zhengrong Wu, Zhanxin Zhang, Dongqing Fei, Yang Li, Hongmei Zhu, Qingjian Xie, Hui Yang, Hongyu Li
Since about 30% of all human cancers contain mutationally activated Ras, down regulating the over-activation of Ras/MAPK pathway represents a viable approach for treating cancers. Over-activation of Ras/MAPK pathway is accompanied by accumulation of reactive oxygen species (ROS). One approach for developing anti-cancer drugs is to target ROS production and their accumulation. To test this idea, we have employed C. elegans of let-60 (gf) mutant, which contain over-activated let-60 (the homolog of mammalian ras) and exhibit tumor-like symptom of multivulva phenotype, to determine whether anti-oxidants can affect their tumor-like phenotype...
December 16, 2016: Scientific Reports
María Eugenia Goya, Andrés Romanowski, Carlos S Caldart, Claire Y Bénard, Diego A Golombek
Circadian rhythms are based on endogenous clocks that allow organisms to adjust their physiology and behavior by entrainment to the solar day and, in turn, to select the optimal times for most biological variables. Diverse model systems-including mice, flies, fungi, plants, and bacteria-have provided important insights into the mechanisms of circadian rhythmicity. However, the general principles that govern the circadian clock of Caenorhabditis elegans have remained largely elusive. Here we report robust molecular circadian rhythms in C elegans recorded with a bioluminescence assay in vivo and demonstrate the main features of the circadian system of the nematode...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Matt Crook, Awani Upadhyay, Liyana J Ido, Wendy Hanna-Rose
Identification of pro-cell-survival signaling pathways has implications for cancer, cardiovascular and neurodegenerative disease. We show that the Caenorhaditis elegans epidermal growth factor receptor LET-23 has a pro-survival function in counteracting excitotoxicity, and we identify novel molecular players required for this pro-survival signaling. uv1 sensory cells in the C. elegans uterus undergo excitotoxic death in response to activation of the OSM-9/OCR-4 TRPV channel by the endogenous agonist nicotinamide...
September 7, 2016: G3: Genes—Genomes—Genetics
Rajani Kanteti, Immanuel Dhanasingh, Essam El-Hashani, Jacob J Riehm, Thomas Stricker, Stanislav Nagy, Alexander Zaborin, Olga Zaborina, David Biron, John C Alverdy, Hae Kyung Im, Shahid Siddiqui, Pamela A Padilla, Ravi Salgia
We previously investigated MET and its oncogenic mutants relevant to lung cancer in C. elegans. The inactive orthlogues of the receptor tyrosine kinase Eph and MET, namely vab-1 and RB2088 respectively, the temperature sensitive constitutively active form of KRAS, SD551 (let-60; GA89) and the inactive c-CBL equivalent mutants in sli-1 (PS2728, PS1258, and MT13032) when subjected to chronic exposure of nicotine resulted in a significant loss in egg-laying capacity and fertility. While the vab-1 mutant revealed increased circular motion in response to nicotine, the other mutant strains failed to show any effect...
2016: Cancer Biology & Therapy
M Dávid Gyurkó, Péter Csermely, Csaba Sőti, Attila Steták
The Ras GTPase activating proteins (RasGAPs) are regulators of the conserved Ras/MAPK pathway. Various roles of some of the RasGAPs in learning and memory have been reported in different model systems, yet, there is no comprehensive study to characterize all gap genes in any organism. Here, using reverse genetics and neurobehavioural tests, we studied the role of all known genes of the rasgap family in C. elegans in associative learning and memory. We demonstrated that their proteins are implicated in different parts of the learning and memory processes...
October 15, 2015: Scientific Reports
Eduardo G Yukihara, Brandon A Doull, Md Ahmed, Stephan Brons, Thomas Tessonnier, Oliver Jäkel, Steffen Greilich
The objective of this study was to characterize the time-resolved (TR) optically stimulated luminescence (OSL) from Al2O3:C detectors and investigate methodologies to improve the accuracy of these detectors in ion beam therapy dosimetry, addressing the reduction in relative response to high linear energy transfer (LET) particles common to solid-state detectors. Al2O3:C OSL detectors (OSLDs) were exposed to proton, (4)He, (12)C and (16)O beams in 22 particle/energy combinations and read using a custom-built TR-OSL reader...
September 7, 2015: Physics in Medicine and Biology
Stephanie Schoeppe, Mitch J Duncan, Hannah M Badland, Stephanie Alley, Susan Williams, Amanda L Rebar, Corneel Vandelanotte
BACKGROUND: In developed countries, children's independent mobility levels are low. Built environmental factors and parental safety concerns are well-known to predict the level of independent mobility adults grant to children. In contrast, the influence of adults' socio-demographic characteristics and neighbourhood social cohesion on children's independent mobility is largely unexplored. This study investigated the influence of adults' socio-demographic factors and neighbourhood social cohesion on distances they would permit children for independent travel and outdoor play...
2015: BMC Public Health
Julia E Szymczak, Sarah Smathers, Cindy Hoegg, Sarah Klieger, Susan E Coffin, Julia S Sammons
IMPORTANCE: When clinicians work with symptoms of infection, they can put patients and colleagues at risk. Little is known about the reasons why attending physicians and advanced practice clinicians (APCs) work while sick. OBJECTIVE: To identify a comprehensive understanding of the reasons why attending physicians and APCs work while sick. DESIGN, SETTING, AND PARTICIPANTS: We performed a mixed-methods analysis of a cross-sectional, anonymous survey administered from January 15 through March 20, 2014, in a large children's hospital in Philadelphia, Pennsylvania...
September 2015: JAMA Pediatrics
James F Geary, Raquel Lovato, Samuel Wanji, Ron Guderian, Maeghan O'Neill, Sabine Specht, Nicole Madrill, Timothy G Geary, Charles D Mackenzie
BACKGROUND: Control and elimination of filarial pathogens is a central focus of major global health efforts directed at parasitic diseases of developing countries. Accomplishment of these goals would be markedly enhanced by the enhanced destruction of the adult stage of filariae. The identification of new, more quantitative biomarkers that correlate with mortality or chemotherapeutic damage to adult filariae, would greatly facilitate, for example, the development of new macrofilaricides...
2015: Parasites & Vectors
L Wootton, C Holmes, N Sahoo, S Beddar
PURPOSE: To assess the feasibility of using a commercial plastic scintillation detector, the Exradin W1, for precise, accurate entrance dosimetry in a passively scattered proton beam METHODS: Measurements of passively scattered proton beam entrance dose were performed using an Exradin W1 calibrated on a Cobalt-60 unit, and a calibrated parallel plane ion chamber at energies from 140 to 250 MeV. A fixed spread out Bragg peak (SOBP) width of 8 cm was used at all energies except 140 and 225 MeV, where selected SOBP widths spanning all those available were used...
June 2015: Medical Physics
F Therriault-Proulx, L Wootton, S Beddar
PURPOSE: To evaluate a measurement method that renders plastic scintillation detectors temperature independent and capable of recovering dose and temperature information simultaneously. METHODS: A novel approach was developed to account for the temperature dependence of plastic scintillation detectors (PSDs) without prior knowledge of the temperature. To enable this, the optical response of the scintillating element is separated into two sub-components, one being the response at a given temperature and the other accounting for the change in the optical emission spectrum with temperature...
June 2015: Medical Physics
P Pater, G Backstrom, S Enger, F Villegas, A Ahnesjo, J Seuntjens, I El Naqa
PURPOSE: To investigate the relationship between linear energy transfer (LET) and relative biological effectiveness (RBE) for protons and light ions, and the corresponding role of LET as a descriptor of radiation quality of hadron therapy. METHODS: Monte Carlo (MC) proton and light ion (He, Li, C) tracks with LET < 30 eV nm(-1) were generated in an event-by-event mode. They were overlaid on a cell nucleus model containing 6×10(9) nucleotide base pairs using an isotropic irradiation procedure that provides electronic equilibrium...
June 2015: Medical Physics
F Alsanea, L Wootton, R Kudchadker, M Usama, S Beddar
PURPOSE: To evaluate the accuracy and usefulness of plastic scintillation detectors used for skin dosimetry of patients undergoing passive scatter proton therapy. METHODS: Following an IRB approved protocol, six patients undergoing passively scattered proton beam therapy for prostate cancer were selected for in vivo skin dosimetry using the Exradin W1 plastic scintillator. The detector was calibrated on a Cobalt-60 unit, and phantom measurements in the proton beam with the W1 and a calibrated parallel plate ion chamber were used to account for the under-response due to high LET at energies used for treatment...
June 2015: Medical Physics
M Yeh, Y Wang, H Weng
UNLABELLED: Introduction National diagnostic reference levels (NDRLs) can be used as a reference dose of radiological examination can provide radiation dose as the basis of patient dose optimization. Local diagnostic reference levels (LDRLs) by periodically view and check doses, more efficiency to improve the way of examination. Therefore, the important first step is establishing a diagnostic reference level. Computed Tomography in Taiwan had been built up the radiation dose limit value,in addition, many studies report shows that CT scan contributed most of the radiation dose in different medical...
June 2015: Medical Physics
K O Inozemtsev, V V Kushin, R V Tolochek, V A Shurshakov
The paper presents the results of measuring biologically significant characteristics of space radiation (spectra of linear energy transfer (LET), absorbed and equivalent doses and averaged quality factors) inside the descend capsule of biosatellite Bion-M1 in space experiment Bioradiation. Measurements combined the use of thermoluminescent detectors DTG-4 (TDL) and solid state nuclear track detectors CR-39 (Tastrak) (SSNTD). Differential and integral LET spectra of high-LET space radiation were determined in 4 points inside spacecraft using passive detectors assembles (PDA)...
2015: Aviakosmicheskaia i Ekologicheskaia Meditsina, Aerospace and Environmental Medicine
Debbie Rand, Gabi Zeilig, Rachel Kizony
BACKGROUND: Impaired dexterity of the weaker upper extremity is common post stroke and it is recommended that these individuals practice many repetitions of movement to regain function. However, stroke rehabilitation methods do not achieve the required intensity to be effective. Touchscreen tablet technology may be used as a motivating tool for self-training impaired dexterity of the weaker upper extremity post stroke. METHODS/DESIGN: Rehab-let is a self-training protocol utilizing game apps on a touchscreen for practicing movement of the weaker upper extremity...
June 18, 2015: Trials
Rui Peng, Handeng Liu, Huimin Peng, Ji Zhou, He Zha, Xin Chen, Luyu Zhang, Yan Sun, Pin Yin, Li Wen, Tianhui Wu, Zheng Zhang
Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus (DM). Recent researches show that DNA methylation plays a role in DN. However, the exact mechanism is not fully understood. MicroRNAs (miRNAs) are a group of endogenous non-coding small RNAs that are involved in the regulation of the development of DN. We have previously demonstrated that let-7a was down-expressed in DN by microarray, but the mechanism is unclear. In this study, let-7a-3 was found to be the only gene with the CpG island in the promoter region among the three let-7a members (let-7a-1, let-7a-2 and let-7a-3) by bioinformatic methods...
October 1, 2015: Gene
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