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Intranigral dynorphin-1-13 suppresses kindled seizures by a naloxone-insensitive mechanism.

Numerous lines of evidence indicate that the substantia nigra (SN) facilitates the propagation of seizures in kindling and in other seizure models. Intranigral injection of dynorphin-1-13 exerted a potent seizure suppressant action in kindled rats. This seizure suppressant action was dose dependent, spatially specific for the area of the SN and was not blocked by naloxone (2 mg/kg i.p.). This finding extends previous work indicating that treatments which reduce SN output exert an anticonvulsant action and further suggests that opioid peptides endogenous to the SN may regulate seizure susceptibility in the kindling model.

Animals

Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat.

Prolonged neurological dysfunction that results from an insult to the brain is often attributed to irreversible structural damage such as loss of neurons or axonal degeneration. For example, following cerebral ischemia even partial hippocampal CA1 neuronal loss has been proposed to be sufficient to result in deficits in hippocampal dependent spatial memory. This study examined if hippocampal CA1 neuronal loss and/or axonal injury was necessary to produce prolonged spatial memory deficits resulting from traumatic brain injury (TBI). Prior to TBI Sprague-Dawley rats were trained on an 8-arm radial maze, a task sensitive to detecting specific lesions of the hippocampus or its extrinsic connections. Following a mild, moderate, or sham injury, rats were tested for working and reference memory for 25 days. After 25 days of maze testing, histological cell counts were made from consistent coronal sections of the mid-dorsal hippocampus. Rats subjected to mild or moderate TBI manifested working memory deficits for 5 and 15 days, respectively, after injury in the absence of overt (all brain regions) or quantitative (CA1 only) evidence of neuronal death. The number of CA1 pyramidal neurons of representative sections of the mid-dorsal hippocampi for injured maze-deficit rats and sham control rats were: 1626 (S.E.M. = +/- 66) and 1693 (S.E.M. = +/- 69) per 10(6) micron2, respectively. Additionally, no overt evidence of axonal injury was observed in any forebrain structure including major intrinsic or extrinsic connecting hippocampal pathways. These data strongly suggest that mild to moderate TBI is capable of producing prolonged spatial memory deficits in the rat without evidence of either neuronal cell death in the intrinsic hippocampus or overt axonal injury in hippocampal pathways.

Animals

DNA damage caused by ionizing radiation.

A survey is given of continuous-time Markov chain models for ionizing radiation damage to the genome of mammalian cells. In such models, immediate damage induced by the radiation is regarded as a batch-Poisson arrival process of DNA double-strand breaks (DSBs). Enzymatic modification of the immediate damage is modeled as a Markov process similar to those described by the master equation of stochastic chemical kinetics. An illustrative example is the restitution/complete-exchange model. The model postulates that, after being induced by radiation, DSBs subsequently either undergo enzymatically mediated restitution (repair) or participate pairwise in chromosome exchanges. Some of the exchanges make irremediable lesions such as dicentric chromosome aberrations. One may have rapid irradiation followed by enzymatic DSB processing or have prolonged irradiation with both DSB arrival and enzymatic DSB processing continuing throughout the irradiation period. Methods for analyzing the Markov chains include using an approximate model for expected values, the discrete-time Markov chain embedded at transitions, partial differential equations for generating functions, normal perturbation theory, singular perturbation theory with scaling, numerical computations, and certain matrix methods that combine Perron-Frobenius theory with variational estimates. Applications to experimental results on expected values, variances, and statistical distributions of DNA lesions are briefly outlined. Continuous-time Markov chains are the most systematic of those radiation damage models that treat DSB-DSB interactions within the cell nucleus as homogeneous (e.g., ignore diffusion limitations). They contain virtually all other relevant homogeneous models and semiempirical summaries as special cases, limiting cases, or approximations. However, the Markov models do not seem to be well suited for studying spatial dependence of DSB interactions, which is known to be important in some situations.

Animals

Polycyclic aromatic hydrocarbon (PAH) concentrations in ambient airborne particles from local traffic and distant sources; variation of the PAH profile.

The temporal and spatial dependence of the PAH profile, i.e. the relative concentrations of polycyclic aromatic hydrocarbons, was investigated for ambient airborne particles during a period with moderate photochemical air pollution. The concentrations of 14 PAH were measured; they differed in volatility, sensitivity to atmospheric chemical conversion and contributing sources. Multivariate analysis (principal-component analysis and factor analysis) revealed that temporal dependence was predominantly determined by five factors clearly linked with volatility, reactivity and sources of the PAH, the first being by far the most important. The results, therefore, indicate that volatilization, conversion and a varying contribution of local sources were the major causes of the variation of the profile with time. The contribution of local sources was investigated by comparison of samples that were taken simultaneously at three different sites, one a background site and two sites downwind of traffic. A marked site dependence was found. The comparison suggested that the differences were not only determined by sources, but also by volatilization and/or conversion during residence of the particles in the air.

Air Pollutants

Possible applications of digital analysis of ultrasonic images of the placenta.

Analysis of the digitised ultrasonic images of in vivo placentae at 15-18 weeks gestation has revealed various textural differences. These have been correlated with smoking, visual appearance and the subsequent development of hypertension. The total number of patients included in this study was 98, of which 70 had images suitable for analysis. There were no significant textural differences between the images of the placentae of smokers and non-smokers nor did the spatially dependent co-occurrence matrices correlate with visual appearance. Textural differences were however detected when the placentae of the normotensive group were compared to those of patients who subsequently developed hypertension (latent hypertension) in the third trimester of pregnancy (p less than 0.05 Mann Whitney 'U' test).

Female

Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.

Animals

Quasi-elastic light scattering from migrating chemotactic bands of Escherichia coli.

We report the observation of migrating chemotactic bands of Escherichia coli in a buffer solution. The temporal development of the bacterial density profile is observed by the scattered light intensity as the band migrates through a stationary laser beam. We have made a preliminary analysis of the observed band profile with help of the Keller-Segel theory. The model accounts for only some aspects of the observed time evolution of the density profile. The microscopic motility characteristics of the E. coli in the band are simultaneously studied by photon correlation. The measured correlation functions are analyzed to obtain the spatial dependence of the half-width within the band. A simple analytical model is proposed to account for the contribution of the twiddle motion to the correlation function. By analyzing the correlation function as a superposition of straight-line and twiddle motions, we obtain a satisfactory agreement between the theory and the measured angular dependence of the line shape. As a consequence we are able to extract a parameter beta, which measures the average fraction of twiddling bacteria in the center of the band at a given time.

Cell Movement

Current injection into a two-dimensional anisotropic bidomain.

A two-dimensional sheet of anisotropic cardiac tissue is represented with the bidomain model, and the finite element method is used to solve the bidomain equations. When the anisotropy ratios of the intracellular and extracellular spaces are not equal, the injection of current into the tissue induces a transmembrane potential that has a complicated spatial dependence, including adjacent regions of depolarized and hyperpolarized tissue. This behavior may have important implications for the electrical stimulation of cardiac tissue and for defibrillation.

Animals

SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.

The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.

RNA Polymerase II

Detection of cell-type-specific differentially methylated regions in epigenome-wide association studies.

MOTIVATION: DNA methylation at cytosine-phosphate-guanine (CpG) sites is one of the most important epigenetic markers. Therefore, epidemiologists are interested in investigating DNA methylation in large cohorts through epigenome-wide association studies (EWAS). However, the observed EWAS data are bulk data with signals aggregated from distinct cell types. Deconvolution of cell-type-specific signals from EWAS data is challenging because phenotypes can affect both cell-type proportions and cell-type-specific methylation levels. Recently, there has been active research on detecting cell-type-specific risk CpG sites for EWAS data. However, existing methods all assume that the methylation levels of different CpG sites are independent and perform association detection for each CpG site separately. Although these methods significantly improve the detection at the aggregated-level-identifying a CpG site as a risk CpG site as long as it is associated with the phenotype in any cell type, they have low power in detecting cell-type-specific associations for EWAS with typical sample sizes. RESULTS: Here, we develop a new method, Fine-scale inference for Differentially Methylated Regions (FineDMR), to borrow strengths of nearby CpG sites to improve the cell-type-specific association detection. Via a Bayesian hierarchical model built upon Gaussian process functional regression, FineDMR takes advantage of the spatial dependencies between CpG sites. FineDMR can provide cell-type-specific association detection as well as output subject-specific and cell-type-specific methylation profiles for each subject. Simulation studies and real data analysis show that FineDMR substantially improves the power in detecting cell-type-specific associations for EWAS data. AVAILABILITY AND IMPLEMENTATION: FineDMR is freely available at https://github.com/JiaRuofan/Detection-of-Cell-type-specific-DMRs-in-EWAS.

DNA Methylation

Phase and sensitivity of receiver coils in magnetic resonance imaging.

Receiver coil response is a major cause of nonuniformities in magnetic resonance images. The spatial dependence of the sensitivity and phase of single-saddle receiver coils has been investigated quantitatively by calculating the H1 field and comparing the results with measurements of a uniform phantom. Agreement between the measurements and calculations is excellent. A method is developed which corrects for both the nonuniform sensitivity and the phase shifts introduced by receiver coils.

Humans

Thermodynamics of movable inductively heated seeds for the treatment of brain tumors.

A thermodynamic study is presented of temperature distributions created by an inductively heated 6-mm-diam Ni sphere imbedded in vivo and in vitro into porcine brain tissue. This study was performed in support of the development of a system that creates localized heat-induced lesions in deep-seated brain tumors. In this system, a magnetic "seed" will be remotely repositioned within the brain by an externally produced magnetic field. Convective effects of a hot moving seed will produce a different thermodynamic situation than that arising from an array of static implants. In this work, a study is presented of part of the expected change, in which a static sphere is heated to high temperature. Measurements were made of the temporal and spatial dependence of the temperature rise in the vicinity of the heated sphere, in vivo in four animals and in one that was euthanized immediately prior to experimentation. These results are used for parameter estimation with a theoretical model based on a point source solution to a form of the thermal diffusion equation, i.e., the "bioheat transfer equation." With this model thermal distributions from a power source of arbitrary geometry can be found using appropriate integration methods, and the method has widespread applicability. Estimates of blood flow rates, tissue thermal conductivity, and seed power absorption were found using the parameter estimation algorithm. The estimated blood perfusion exhibits a step increase following the first heating in multiple heating experiments. Thermal conductivity estimated using data from the nonperfused (in vitro) animal is 0.6 W/m degrees C. Seed power absorption is estimated correspondingly to be 0.9 W, a result confirmed independently with calorimetry. Statistical uncertainty is established for the radial decrease of the tissue temperature rise created by this method. This result allows estimation of a cell death boundary uncertainty of 0.6 mm, caused by fluctuations in power delivered to the seed, uncertainty in the temperature probe placements, and thermal properties such as blood perfusion and tissue thermal conductivity.

Animals

Single-exposure dual-energy computed radiography: improved detection and processing.

Recent reports have emphasized the potential for dual-energy computed radiographic applications. An improved method for single-exposure material-selective imaging with a photostimulable phosphor computed radiography system was investigated. The essential elements of the technique are (a) prefiltration with gadolinium, which divides the incident broad-beam x-ray spectrum into low-energy and high-energy peaks; (b) a cassette consisting of four photostimulable phosphor plates that record images of increasing mean energies, with a computed energy separation of 23 keV from the front to the rear plate; (c) spatially dependent scatter and beam-hardening corrections; and (d) a noise-reduction algorithm based on noise correlations between bone-selective and soft-tissue-selective dual-energy images. These elements result in improved material cancellation and signal-to-noise ratio throughout the image.

Algorithms

Non invasive measurement of myocardial motion using magnetic resonance tagging.

Magnetic resonance imaging has become a key modality within the modern radiology department. In addition to the conventional slice images, three dimensional angiographic images, and quantitative flow measurements can be obtained. More recently methods have been developed which enable one to visualize the motion of objects through the application of magnetic resonance markers or tags. Generally the myocardium appears homogeneous with respect to magnetic resonance imaging. Thus at best the displacement of the myocardial surfaces can be observed, but rotational and shear motions are not discernable. With magnetic resonance tagging this all changing. Tagging involves modifying the ability of the tissue to produce a nuclear magnetic resonance signal, in a spatially dependent manner. Typically the pattern is a grid of reduced signal intensity. The tagging grid is applied prior to the heart contraction. Then images are made during systole and diastole. The rotation and shear of the myocardium can be inferred from the distortions of the tagging grid. Here our work in this field is reviewed.

Heart Diseases

Digital imaging and picture archiving and communication systems.

Great progress has been made in digital imaging of the chest. Most studies are dealing with computed radiography. Chest radiography in the intensive care unit may, in most cases, be performed using computed radiography. However, subtle pulmonary interstitial disease can be demonstrated less confidently using computed radiography. Significantly better detection of calcified lung nodules can be obtained by using simplified single-exposure dual-energy technique that uses storage phosphor. The wide latitude of computed radiography permits images of high quality in areas other than chest radiography. Encouraging results are presented especially in the diagnostic evaluation of scoliosis and other musculoskeletal abnormalities. An important technical innovation in digital radiography is an improved method for single-exposure dual-energy digital imaging using prefiltration with gadolinium, a cassette consisting of four photostimulable phosphor plates, spatially dependent scatter and beam hardening corrections, and noise reduction algorithm. Other groups tested algorithms for enhancement of digital images that allowed significant data compression. The implementation of picture archiving and communication systems (PACS) is inevitable; the question concerning PACS implementation is not why, but when. A comparison of the cost-effectiveness of PACS with conventional film archiving and communication systems shows that PACS should provide indirect savings when regarding the hidden costs of conventional systems. Much more experience will be needed before there is general agreement on the best design for the radiologist's workstation. Teleradiology should contribute to radiologic consultation for remote locations, because it improves the efficacy of management of patients in such locations.

Child

Panoramic zonography of the midface: a clinician's guide to vertical magnification.

Surgical procedures involving the maxilla require details regarding the topography of the nasal floor and that of the maxillary sinus. Panoramic zonography can provide this information with a minimum of radiation exposure and may be used in certain instances when other imaging modalities cannot. Spatially dependent variations in vertical magnification inherent to panoramic zonography using the midface program were determined. Radiographic lengths of marker wires attached at seven locations along the maxillary arch of dry skulls were measured. Radiographs were obtained at 0, -10 and -20 mm shifts. Analysis of variance and ranking did not reveal any significant differences in magnification between skulls. However, a dichotomy between the anterior and posterior portions of the maxillary arch in terms of vertical magnification was found at all three shift positions. In addition, at all marker locations, the magnification diminished as a function of decreasing shift position. These variations are due to the fact that teeth within the arch are not all located at the central plane of the focal trough generated by the unit. The results provide the clinician with vertical magnification factors from which actual measurements can be derived from zonographs.

Alveolar Process

Magnetic resonance angiography in the head and neck.

Magnetic resonance angiography (MRA) provides a means to visualize vessel structure without the use of contrast agents and consequently without the risks and discomfort associated with contrast media. We have developed a flow encoding procedure which exploits the spatial dependence in the phase of spin magnetization generated by a gradient pulse. This technique yields image information for only those spins having macroscopic motion (i.e. flowing blood). Excellent suppression of non-moving spins can be obtained despite the overwhelming abundance of stationary spins. Data are presented in a projection format similar to that of traditional subtraction angiography.

Blood Vessels

Context dependent processing in spatial hyperacuity.

The importance of comparison processes in spatial hyperacuity tasks was investigated by means of a new relative nonalignment discrimination task. Vernier-type configuations nonaligned to either left or right, were presented in succession, and the subject had to decide which configuation exhibited a larger nonalignment. The relative nonalignment thresholds were found to be more strongly dependent on the spatial arrangement of the two lines than the thresholds corresponding to "ordinary" spatial hyperacuity performances. This context dependency is attributed to the active role played in the processing by comparison mechanisms.

Discrimination, Psychological