The Role of Gene Expression in the Lateral Hypothalamus on the Development of Allodynia after Cisplatin Treatment

Advances in cancer treatment have led to an increase in cancer survivorship as the number of individuals living beyond cancer diagnosis and treatment rises each year. Yet, as this number rises, so does the number of people who live with the side-effects of cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect of neurotoxic chemotherapeutic drugs that is characterized by sensations of numbness and tingling that begin in the distal extremities and can develop into chronic neuropathic pain. There are no recommended preventative measures for CIPN and the only recommended treatment is the serotonin-norepinephrine reuptake inhibitor, duloxetine, which does not offer relief to all patients. The lateral hypothalamus (LH) is part of a descending system that modulates pain in the spinal cord dorsal horn. The chemotherapeutic drug cisplatin accumulates in the dorsal root ganglion of the primary afferent neuron and promotes abnormal pain signaling that may disrupt the genome of LH cells, via the spinohypothalamic ascending tract, contributing to the development of painful CIPN. This dissertation study investigated the role of the LH in the development of cisplatin-related mechanical allodynia, a sign of neuropathic pain. The goal was to detect changes in LH-derived gene expression and examine the association of these changes with development and persistence of mechanical allodynia in different strains of mice. Results of nocifensive behavioral von Frey testing have shown that different strains of mice (C57BL/6J, BALB/cJ, DBA/2J, A/J, FVB/NJ, and CD-1) develop allodynia at different rates post cisplatin treatment. Based on these results, the two strains that represented the highest (C57BL/6J) and lowest (A/J) responders to allodynia development were selected for further gene expression and protein analysis. Analysis of microarray data from the LH transcriptome of C57BL/6J and A/J mice showed very few gene expression changes within each strain after cisplatin treatment, but we discovered 1311 differentially expressed genes (DEGs) between the strains prior to treatment. Using Ingenuity Pathway Analysis (IPA) to characterize these DEGs, we discovered that the top biological pathways affected by the DEGs included “Synaptic Long-Term Potentiation” and “Neuropathic Pain Signaling in Dorsal Horn Neurons.” Using IPA, we identified nine genes with documented function in pain development for further target gene expression validation with quantitative real-time polymerase chain reaction (qPCR). The results of the qPCR were used to verify the gene expression direction in seven of the DEGs. Western blot confirmed two of the genes were present at the protein level. The results of this pre-clinical study are suggestive that the gene expression profile prior to cisplatin treatment may predispose the development of painful CIPN in mice. These pre-clinical findings may ultimately guide precision health by using gene expression profiles to predict patients at risk for painful CIPN and identify patients who will benefit from preventative measures.PHDNursingUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/146007/1/mawag_1.pd

Precision Physics at the LHC

A large number of precision measurements will be possible with the ATLAS and CMS experiments at the CERN Large Hadron Collider (LHC). Examples from W physics, Drell-Yan production of lepton pairs, Triple-Gauge Couplings,top physics, Higgs and Supersymmetry are discussed.Comment: 13 pages, 9 figures, presented ate the 5th Zeuthen Workshop on Elementary Particle Theory on "Loops and Legs in Quantum Field Theory" Bastel/Konigstein, Germany, April 200

Primary Chondroblastic Osteosarcoma of the Lung

Purpose. Primary extra-osseous osteosarcomas are uncommon lesions, and those originating within the lung are especially rare, with few case reports existing in the literature

Using NLP technology in CALL

This paper outlines the research and guiding research principles of the (I)CALL group at Dublin City University, Ireland. Our research activities include the development of (I)CALL systems targeted at a variety of user groups including advanced Romance language learners, intermediate to advanced German learners, primary and secondary school students as well as students with L1 learning disabilities requiring a variety of system types which cater to individual user needs and abilities. Suitable CL/NLP technology is incorporated where appropriate for the learner

Distance Learning Courses: New Opportunities for the Development of University Education

DL is a new means of implementing the learning process, which is based on the use of modern information and telecommunication technologies that allow studying at a distance without personal contact between the teacher and the student. DL is one of the main ways of computerization and automation of education and the use of the latest technologies in training and serves to increase the effectiveness of education as such. The organization of high-quality distance education will increase educational capacities and positively affect the intellectual potential of the state. This paper discusses the features of distance learning. The authors also describe the basic functional modules of modern distance learning management systems that contain access to educational materials and the means to ensure communication between participants in the distance learning process. According to the formulated modules, the authors perform a review and comparison of the availability and implementation of distance learning modules in such distance learning systems as Moodle, Claronline, ATutor, SharePointLMS, Live @ EDU, and eFront

Spectrophotometric determination of rosuvastatin in pharmaceutical formulations using quinalizarin

This work presents the development of a methodology based on the formation of a charge transfer complex between quinalizarin and rosuvastatin, allowing for the spectrophotometric determination of rosuvastatin at 579 nm. The factors involved in the sensitivity of the technique were studied (nature and proportion of the solvent, reaction time, pH of aqueous phase and quinalizarin concentration). The proposed spectrophotometric procedures were validated with respect to linearity, ranges, precision, accuracy, detection and quantification limits. Calibration curves of the formed color products showed good linear relationships over the concentration range of 6-15 mg L-1. The proposed method has been successfully applied, which can be confirmed by interference test (comparison between the standard curves and addition of analyte), method precision (RSD 2.3% to 6 mg L-1), and by accuracy (statistically equivalent results between the proposed method and a chromatographic method of reference)

Interactions via electrical coupling in axial and appendicular motor networks during metamorphosis in Xenopus laevis tadpoles

The spinal locomotor networks in Xenopus laevis frog tadpoles undergo a remarkable transformation during metamorphosis to accommodate a switch from axial-based swimming to a limb-based kicking locomotor strategy. For a brief period during ontogeny, both the axial- and limb-based systems are present and functional, but reliant on different central pattern generators (CPGs) that are simultaneously active. However, the mechanisms controlling the functional coupling both within and between these locomotor networks are unknown. At metamorphosing larval stages (52-58), retrograde motoneuron (MN) backfilling from both axial (11th-12th post-otic segments) and hindlimb muscles with fluorescent rhodamine- and fluorescein-conjugated dextran dyes revealed two discrete MN populations (axial and appendicular) within the spinal cord. The co-labelling of both axial and appendicular cells provides evidence that the two MN pools in the lumbar enlargement are coupled. Electrophysiological data from animals at the same larval stages suggest that axial CPG excitability is modified as burst durations were increased by gap junction (GJ) blockers (18-β-glycyrrhetinic (18-β-GA) acid 100µM; CBNX 200µM), however, limb CPG burst parameters were not altered by GJ block. For spontaneous fictive locomotor bouts, the number of axial episodes initially increased, but then sharply decreased from control levels ~15-30 minutes after drug application. Coordinated and simultaneous axial and limb CPG output was observed with electrical stimulation to the optic tectum, an axial ventral root (VR), and a limb VR; GJ block did not affect the coordinated output from optic tectum stimulation, however, it decreased simultaneous output when the axial VR was stimulated. This novel finding that antidromic stimulation of an axial VR is sufficient to activate a different CPG for the limbs suggests there is synaptic coupling in the direction of axial to limb. These data suggest that axial CPG output is in part regulated by GJs. The anatomical data also suggest a connection exists between the axial and limb MN pools, and may be involved in the initial cycle-by-cycle coupling of the two CPG outputs. Thus the rhythm of the appendicular CPG is initially highly dependent on that of the axial CPG, which in turn is dependent on its own GJ connections within the spinal circuit. It appears that the immature limb MN pools in the lumbar spinal cord possess functional connections via electrical synapses to the axial locomotor system, which are presumably “pruned” as metamorphosis proceeds, and eventually lost completely by the adult stages when the limb network has become completely independent