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Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis., Introduction Dystonia is a disabling hyperkinetic movement disorder characterized by an excess of sustained, often repetitive, involuntary twisting movements, and abnormal postures (1). Dystonia, after Parkinson's disease and essential tremor, [...]

A large-caliber railgun was developed to demonstrate the supersonic launch of 120-mm projectiles. A trade study that evaluated over 70 different railgun configurations and geometries resulted in the selection of a high-inductance-gradient multiturn configuration as the best overall choice. Subscale tests were performed on both the railgun and launch package configurations. A full-scale laboratory system was installed, which included a dedicated high-current large-caliber breech and gunline. A full-scale launcher was successfully tested to beyond the design conditions. This paper will describe the trade study and overall experimental program that included the subscale testing and full-scale design and experimental results. Index Terms--Component, high inductance gradient, large caliber, railgun.

The principal component analysis is used to identify and quantify spatial distributions of relative photoresponse as a function of the exposure time for a visible CCD array. The analysis shows a simple way to define an invariant photoresponse nonuniformity and compare it with the definition of this invariant pattern as the one obtained for long exposure times. Experimental data of radiant exposure from levels of irradiance obtained in a stable and well-controlled environment are used. OCIS codes: 120.5630, 040.1520.

We analyze in detail the apparent violation of the reciprocity law that occurs for an interline CCD array owing to its responsivity that varies with exposure time, and we investigate other parameters having an influence on this variation, such as the numerical aperture of the system or the illumination wavelength. The variation can be explained from a qualitative point of view by the charge leakage that occurs from the sense region to the register region during readout time. This change of the responsivity can be avoided either by using a synchronized external shutter or by limiting the numerical aperture while keeping relatively high exposure times. A detailed characterization for each particular CCD model must be carried out if it is to be employed in low-uncertainty radiometric measurements. OCIS codes: 120.5630, 040.1520.

What we believe to be a novel procedure to correct the nonuniformity that is inherent in all matrix detectors has been developed and experimentally validated. This correction method, unlike other nonuniformity-correction algorithms, consists of two steps that separate two of the usual problems that affect characterization of matrix detectors, i.e., nonlinearity and the relative variation of the pixels' responsivity across the array. The correction of the nonlinear behavior remains valid for any illumination wavelength employed, as long as the nonlinearity is not due to power dependence of the internal quantum efficiency. This method of correction of nonuniformity permits the immediate calculation of the correction factor for any given power level and for any illuminant that has a known spectral content once the nonuniform behavior has been characterized for a sufficient number of wavelengths. This procedure has a significant advantage compared with other traditional calibration-based methods, which require that a full characterization be carried out for each spectral distribution pattern of the incident optical radiation. The experimental application of this novel method has achieved a 20-fold increase in the uniformity of a CCD array for response levels close to saturation.

O,O-acetal can be activated to generate an alpha-heteroatom-substituted carbenium ion as a reactive intermediate, which reacts with a nucleophile to form a substitute product under acidic conditions. In this process, the acid coordinates to a lone pair of one of the heteroatoms to cleave the oxygen - carbon bond with the assistance of electron donation from a lone pair of the other oxygen atom.

A new expression for the internal quantum efficiency of a photodiode is presented. It is obtained from the analysis of the photocurrent generated within the diode, considering the power and the cross-sectional diameter of the incident beam. The model explains variations of the internal quantum efficiency with irradiance that are not explained by other existing models, although this experimental fact was already known. The well-known phenomenon of supra-responsivity is also explained with this model. Finally, we show the dependence of the internal quantum efficiency on the variables involved in the model. OCIS codes: 120.1880, 120.5630, 040.1880.

Visualizing the complex and counterintuitive phenomenology associated with rotordynamics has been problematic since Rankine first scientifically studied it in the early 1900s. To address this, a simple model capable of allowing visualization of the parameters and problematic aspects associated with an imbalanced rotor (Jeffcott rotor) will be proposed using bond graphs, which provide a structured and unified method for modeling a large class of nonlinear, multienergetic systems. The purpose of this paper is to provide a high-fidelity, experimentally proven bond graph model of the Jeffcott rotor to aid in the design and analysis of high-speed rotational machinery often associated with pulsesd energy systems. The intent of the model is the ability to use it as a modular and foundational piece in more complex rotordynamic models. Index Terms--Bond graph, Jeffcot rotor, pulsed power, rotordynamic models, rotordynamics.

Byline: Juan Antonio Marchal (1), Houria Boulaiz (2), Ines Suarez (2), Estrella Saniger (3), Joaquin Campos (3), Esmeralda Carrillo (1), Jose Prados (2), Miguel Angel Gallo (3), Antonio Espinosa (3), Antonia Aranega (2) Keywords: breast cancer; antitumour drugs; 5-fluoropyrimidine compounds; cell cycle; programmed cell death; DNA fragmentation Abstract: In this study we evaluate the antitumour activity, the cell cycle arrest and apoptotic properties of novel lipophilic benzene-fused seven-membered 5-fluorouracil (5-FU) analogs in comparison to 5-FU on MCF-7 human breast cancer cells. The lipophilicities of ESB-786B, ESB-252A and ESB-928A were predicted by using the CDR option of the PALLAS 2.0 program. Cytotoxic assays were evaluated in MCF-7 cells treated with the sulforhodamine B colorimetric method. Cell cycle perturbations were studied by flow cytometry. Apoptosis was determined by both DNA fragmentation and annexin V-FITC and propidium iodide staining. The novel derivatives were more lipophilic than 5-FU and induced a marked growth inhibition, in a dose-dependent manner. After treatment with IC.sub.50 value (ranged from 2.5 to 22 uM) for each compound, light microscopy observation showed modifications in the morphology of MCF-7 cells. In addition, the 5-FU analogs arrest cells in the G.sub.0/G.sub.1 phase of the cell cycle whereas 5-FU induced arrest in S-phase. Moreover, induction of apoptosis was demonstrated by the annexin-V-based assay and confirmed using DNA fragmentation analysis on MCF-7 cells, a cell line in which the induction of DNA laddering is very difficult. The novel benzannelated seven-membered 5-FU analogs can be considered as specific apoptotic inducers. These experimental findings provide support for the use of these novel compounds as new weapons in the fight against breast cancer. Author Affiliation: (1) Department of Health Sciences, University of Jaen, Jaen, 23071, Spain (2) Department of Anatomy and Human Embryology, Faculty of Medicine, University of Granada, Granada, 18012, Spain (3) Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada, 18071, Spain Article History: Registration Date: 02/10/2004