A Novel Transgenic Mouse Model to Investigate the Cell-Autonomous Effects of torsinA(ΔE) Expression in Striatal Output Neurons.

Dystonia is a disabling neurological syndrome characterized by abnormal movements and postures that result from intermittent or sustained involuntary muscle contractions; mutations of DYT1/TOR1A are the most common cause of childhood-onset, generalized, inherited dystonia. Patient and mouse model data strongly support dysregulation of the nigrostriatal dopamine neurotransmission circuit in the presence of the DYT1-causing mutation. To determine striatal medium spiny neuron (MSN) cell-autonomous and non-cell autonomous effects relevant to dopamine transmission, we created a transgenic mouse in which expression of mutant torsinA in forebrain is restricted to MSNs.

Validating Antibodies for Quantitative Western Blot Measurements with Microwestern Array.

Fluorescence-based western blots are quantitative in principal, but require determining linear range for each antibody. Here, we use microwestern array to rapidly evaluate suitable conditions for quantitative western blotting, with up to 192 antibody/dilution/replicate combinations on a single standard size gel with a seven-point, two-fold lysate dilution series (~100-fold range). Pilot experiments demonstrate a high proportion of investigated antibodies (17/24) are suitable for quantitative use; however this sample of antibodies is not yet comprehensive across companies, molecular weights, and other important antibody properties, so the ubiquity of this property cannot yet be determined.

A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens.

Most cancer cells harbor multiple drivers whose epistasis and interactions with expression context clouds drug and drug combination sensitivity prediction. We constructed a mechanistic computational model that is context-tailored by omics data to capture regulation of stochastic proliferation and death by pan-cancer driver pathways. Simulations and experiments explore how the coordinated dynamics of RAF/MEK/ERK and PI-3K/AKT kinase activities in response to synergistic mitogen or drug combinations control cell fate in a specific cellular context.

The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations.

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies.

Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ.

Effects of subthalamic nucleus lesions and stimulation upon corticostriatal afferents in the 6-hydroxydopamine-lesioned rat.

Abnormalities of striatal glutamate neurotransmission may play a role in the pathophysiology of Parkinson's disease and may respond to neurosurgical interventions, specifically stimulation or lesioning of the subthalamic nucleus (STN). The major glutamatergic afferent pathways to the striatum are from the cortex and thalamus, and are thus likely to be sources of striatal neuronally-released glutamate. Corticostriatal terminals can be distinguished within the striatum at the electron microscopic level as their synaptic vesicles contain the vesicular glutamate transporter, VGLUT1.

Effects of zona incerta lesions on striatal neurochemistry and behavioral asymmetry in 6-hydroxydopamine-lesioned rats.

Analysis of optimal sites for neurosurgical interventions in patients with Parkinson's disease (PD) suggests that significant clinical benefits may be achieved by involvement of the zona incerta (ZI). Unilateral electrolytic ZI lesions were made in intact and ipsilaterally 6-hydroxydopamine (6OHDA)-lesioned rats. Extracellular levels of glutamate, dopamine, and its metabolites in the ipsilateral striatum of awake rats were measured by using microdialysis, and tests of behavioral asymmetry were performed.

Effects of subthalamic nucleus lesions and stimulation upon glutamate levels in the dopamine-depleted rat striatum.

It is not known how neurosurgical interventions benefit patients with Parkinson's disease. We compared the effects of electrical stimulation and electrolytic lesions of the subthalamic nucleus upon striatal extracellular glutamate levels in awake rats, either intact or which had undergone unilateral 6-hydroxydopamine lesions. Two hours of subthalamic nucleus stimulation had no effect in either group.

Subthalamic nucleus stimulation and lesioning have distinct state-dependent effects upon striatal dopamine metabolism.

The mechanism by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) achieves its effects in Parkinson's disease (PD) is not known. In animal models of PD, stimulation and lesioning of the STN have some effects which are the same, but others which differ, in reversing cellular and behavioral changes induced by dopamine depletion. We compared the effects of short-term STN stimulation and lesions upon extracellular levels of dopamine and metabolites using in vivo microdialysis of the dorsal striatum of awake, intact and unilateral 6-hydroxydopamine (6OHDA)-lesioned rats.

Value of vasodilator stress myocardial contrast echocardiography and magnetic resonance imaging for the differential diagnosis of ischemic versus nonischemic cardiomyopathy.

Objective: Noninvasive differentiation of ischemic versus nonischemic cardiomyopathy (CM) remains challenging because of the low specificity of imaging-based tests in these patients. We hypothesized that myocardial contrast echocardiography (MCE) and cardiac magnetic resonance (CMR), combined with vasodilator stress, could provide accurate alternatives for determining the cause of CM.

Methods: To allow side-by-side comparisons between these techniques with coronary angiography as a reference, we studied 16 patients referred for coronary angiography after abnormal nuclear perfusion studies.

Improved semiautomated quantification of left ventricular volumes and ejection fraction using 3-dimensional echocardiography with a full matrix-array transducer: comparison with magnetic resonance imaging.

Our goals were to: (1) develop a technique for 3-dimensional (3D) direct, model-independent quantitative assessment of left ventricular (LV) volume and ejection fraction based on semiautomated detection of LV endocardial surface from transthoracic near real-time full matrix-array 3D echocardiographic (FM3DE) imaging; (2) evaluate the accuracy of LV volumes obtained with this technique, using cardiac magnetic resonance imaging (MRI) measurements as the reference for comparison; and (3) determine the effects of contrast enhancement on the accuracy of FM3DE measurements. A total of 46 patients underwent 2-dimensional echocardiography, FM3DE, and cardiac MRI. End-diastolic volume, end-systolic volume, and ejection fraction were derived from endocardial borders manually traced from 2-dimensional echocardiographic images and from semiautomatically detected LV cavity from FM3DE data.

Fast measurement of left ventricular mass with real-time three-dimensional echocardiography: comparison with magnetic resonance imaging.

Background: Left ventricular (LV) mass is an important predictor of morbidity and mortality, especially in patients with systemic hypertension. However, the accuracy of 2D echocardiographic LV mass measurements is limited because acquiring anatomically correct apical views is often difficult. We tested the hypothesis that LV mass could be measured more accurately from real-time 3D (RT3D) data sets, which allow offline selection of nonforeshortened apical views, by comparing 2D and RT3D measurements against cardiac MR (CMR) measurements.

Stroke in patient with an intervalvular fibrosa pseudoaneurysm and aortic pseudoaneurysm.

We describe a case of an intervalvular fibrosa pseudoaneurysm associated with a cerebrovascular accident. This case in unusual as the likely source of embolic stroke was thrombus from within the pseudoaneurysm. Transesophageal echocardiography also demonstrated a communication between the intervalvular fibrosa and the proximal aorta.

Interferon-regulated pathways that control hepatitis B virus replication in transgenic mice.

We previously showed that the intrahepatic induction of cytokines such as alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) inhibits hepatitis B virus (HBV) replication noncytopathically in the livers of transgenic mice. The intracellular pathway(s) responsible for this effect is still poorly understood. To identify interferon (IFN)-inducible intracellular genes that could play a role in our system, we crossed HBV transgenic mice with mice deficient in IFN regulatory factor 1 (IRF-1), the double-stranded RNA-activated protein kinase (PKR), or RNase L (RNase L) (IRF-1(-/-), PKR(-/-), or RNase L(-/-) mice, respectively), three well-characterized IFN-inducible genes that mediate antiviral activity.

Color Kinesis: Principles of Operation and Technical Guidelines.

Color kinesis is a new echocardiographic technique that aids in the assessment of global and regional left ventricular performance during either systole or diastole. Color kinesis uses automated border detection technology based on backscatter data to display both the magnitude and timing of endocardial motion in real time. The color kinesis display superimposes a color overlay on the two-dimensional echocardiographic image; the number of color pixels represents the magnitude of endocardial motion, while the different colors represent the timing of endocardial motion according to a predefined color scheme.