Current evidence suggests that delta oscillations (0.5–4 Hz) in the brain are generated by intrinsic network mechanisms involving cortical and thalamic circuits. Here we report that delta band oscillation in spike and local field potential (LFP) activity in the whisker barrel cortex of awake mice is phase locked to respiration. Furthermore, LFP oscillations in the gamma frequency band (30–80 Hz) are amplitude modulated in phase with the respiratory rhythm. Removal of the olfactory bulb eliminates respiration-locked delta oscillations and delta-gamma phase-amplitude coupling. Our findings thus suggest respiration-locked olfactory bulb activity as a main driving force behind delta oscillations and gamma power modulation in the whisker barrel cortex in the awake state.
experimental study using a suspension of n-eicosane microcapsules in water was conducted in order to evaluate the heat transfer characteristics of phase change material suspensions. Experiments were done for laminar, hydrodynamically fully developed flows in a circular duct with a constant wall heat flux. The temperature of the suspension entering the test section was maintained at or below the melting point of the phase change material. The primary parameters in the study were the bulk Stefan number and the volumetric concentration. In addition, a few experiments were conducted to evaluate the effect of particle diameter and degree of homogeneity of the suspension. The heat fluxes chosen for the experiments were typical of low temperature applications (below 60°C). Results show that use of phase change material suspensions can reduce the rise in wall temperature by up to 50% as compared to a single phase fluid for the same non-dimensional parameters. The most dominant parameter influencing the heat transfer was found to be the bulk Stefan number. The effect of concentration was found to be insignificant by itself, though its influence is felt indirectly through the bulk Stefan number. An increase in particle diameter by a factor of 2.5 was found to further reduce the wall temperature rise by 15%. The degree of homogeneity of the suspension had no observable effect on the wall temperatures.
Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3–17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80 % of cases) and loss of CDKN2A (68 % of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways.
Angelman syndrome (AS) is a childhood-onset neurogenetic disorder characterized by functionally severe developmental delay with mental retardation, deficits in expressive language, ataxia, appendicular action tremors and unique behaviors such as inappropriate laughter and stimulus-sensitive hyperexcitibility. Most cases of AS are caused by mutations which disrupt expression of maternal UBE3A. Although some progress has been made in understanding hippocampal-related memory and learning aspects of the disorder using Ube3a deficient mice, the numerous motoric abnormalities associated with AS (ataxia, action tremor, dysarthria, dysphagia, sialorrhea and excessive chewing/mouthing behaviors) have not been fully explored with mouse models. Here we use a novel quantifiable analysis of fluid consumption and licking behavior along with a battery of motor tests to examine cerebellar and other motor system defects in Ube3a deficient mice. Mice with a maternally inherited Ube3a deficiency (Ube3a(m-/p+)) show defects in fluid consumption behavior which are different from Ube3a(m-/p-) mice. The rhythm of fluid licking and number of licks per visit were significantly different among the three groups (m-/p-, m-/p+, m+/p+) and indicate that not only was fluid consumption dependent on Ube3a expression in the cerebellum, but may also depend on low levels of Ube3a expression in other brain regions. Additional neurological testing revealed defects in both Ube3a(m-/p+) and Ube3a(m-/p-) mice in rope climbing, grip strength, gait and a raised-beam task. Long-term observation of fluid consumption behavior is the first phenotype reported that differentiates between mice with a maternal loss of function versus complete loss of Ube3a in the brain. The neuronal and molecular mechanisms underlying mouse fluid consumption defects specifically associated with maternally inherited Ube3a deficiency may reveal important new insights into the pathobiology of AS in humans.
The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.
Purpose The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. Methods Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C8*2, *3 or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. Results 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR=1.722, p=0.018), however, the influence of the *2 and *4 SNPs were not independently significant (*2: p=0.847, *4: p=0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p=0.0008) but not in the non-Caucasian replication group (p=0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. Conclusions The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3.
Fragile X syndrome (FXS) is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1) gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP). Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO) mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs) when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT) littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.
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