Faculty Bibliography
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school:SOM
Department/Unit:Neuroscience Institute
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13474
Small molecule antagonists of RAGE-DIAPH1: Novel therapeutic opportunities in metabolic and chronic disease [Meeting Abstract]
Our previous work has shown that the cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1, or DIAPH1. Given the complex, multi-ligand nature of ligands binding to the extracellular domains of RAGE, we sought to discover small molecule inhibitors of the interaction of ctRAGE with DIAPH1. Prompted by our identification of 13 small molecules that block the interaction of ctRAGE-DIAPH1, we pursued structure-activity relationship experiments to identify analogues potentially able to delay or prevent the progression of RAGE-related chronic diseases, such as diabetes. In vitro binding studies Native tryptophan fluorescence experiments were conducted using 1mM of compound dissolved in phosphate buffer and DMSO. 10 nM ctRAGE solution was titrated from 0.1 nM-100 muM and the dissociation constants, Kd, were estimated from the changes in peak fluorescence intensities as a function of the free compound concentration. NMR experiments were performed operating at 1H frequencies of 500 MHz and 700 MHz. NMR samples contained 50 muM of [U-15N] ctRAGE and 10 muM of the compound. All spectra were collected at 298K, which yielded high quality NMR spectra of [U-15N] RAGE tail. Compound binding to ctRAGE was identified as at least a 0.01 ppm change in the ctRAGE chemical shift. Small molecule leads were identified and referred to as NYU 1-5 (Table 1). Ex vivo biological activity assays Inhibition of smooth muscle cell (SMC) migration induced by RAGE ligands after incubation with indicated NYU compounds. SMCs were grown to confluence and starved overnight. The next morning, the medium was removed, compounds were added and the monolayer was wounded using a p200 pipette tip and allowed to incubate for 1.5h. Following incubation, compounds were removed and fresh medium containing the RAGE ligand, CML-AGE (10 mug/ml) was added for 4h. Images were taken, measured and an area ingrowth of effective migrating cells was calculated (Table 1). In vivo studies (A) Delayed type hypersensitivity. Female CF-1 mice were sensitized over the left inguinal lymph node with a methylated bovine serum albumin emulsion. On day 19 and 20 after sensitization, mice received, by oral gavage, the test compounds (5 mg/kg/bw) or vehicle twice daily. Post-final compound injection, mBSA was injected into the left hind paw. Inflammation was assessed using a semiquantitative scoring system (Figure 1). (B) Myocardial infarction in diabetic mice. Male C57BL/6 mice were rendered diabetic with STZ and were diabetic for 2 months. Mice were subjected to left anterior descending coronary artery occlusion followed by reperfusion (LAD/reperfusion). After 48h, the hearts were excised. TTC and Evan's blue staining was used to measure infarct area. Mice received a total of 7 doses of either VEHICLE or an NYU compound (Figure 2). In summary, refined compounds that inhibit the interaction of ctRAGE with DIAPH1, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications and chronic inflammation. We conclude that these identified compounds hold significant potential as druggable scaffolds for further development and testing for the treatment of RAGE-related disorders
EMBASE:622545638
ISSN: 1530-6860
CID: 3160432
Transcranial Doppler in autonomic testing: standards and clinical applications
When cerebral blood flow falls below a critical limit, syncope occurs and, if prolonged, ischemia leads to neuronal death. The cerebral circulation has its own complex finely tuned autoregulatory mechanisms to ensure blood supply to the brain can meet the high metabolic demands of the underlying neuronal tissue. This involves the interplay between myogenic and metabolic mechanisms, input from noradrenergic and cholinergic neurons, and the release of vasoactive substrates, including adenosine from astrocytes and nitric oxide from the endothelium. Transcranial Doppler (TCD) is a non-invasive technique that provides real-time measurements of cerebral blood flow velocity. TCD can be very useful in the work-up of a patient with recurrent syncope. Cerebral autoregulatory mechanisms help defend the brain against hypoperfusion when perfusion pressure falls on standing. Syncope occurs when hypotension is severe, and susceptibility increases with hyperventilation, hypocapnia, and cerebral vasoconstriction. Here we review clinical standards for the acquisition and analysis of TCD signals in the autonomic laboratory and the multiple methods available to assess cerebral autoregulation. We also describe the control of cerebral blood flow in autonomic disorders and functional syndromes.
PMCID:5891134
PMID: 28821991
ISSN: 1619-1560
CID: 2670622
Future prospects and challenges for Alzheimer's disease drug development in the era of the NIA-AA Research Framework [Editorial]
PMID: 29653605
ISSN: 1552-5279
CID: 3058942
Assessment of the combination of temperature and relative humidity on kidney stone presentations
Temperature and relative humidity have opposing effects on evaporative water loss, the likely mediator of the temperature-dependence of nephrolithiasis. However, prior studies considered only dry-bulb temperatures when estimating the temperature-dependence of nephrolithiasis. We used distributed lag non-linear models and repeated 10-fold cross-validation to determine the daily temperature metric and corresponding adjustment for relative humidity that most accurately predicted kidney stone presentations during hot and cold periods in South Carolina from 1997 to 2015. We examined three metrics for wet-bulb temperatures and heat index, both of which measure the combination of temperature and humidity, and for dry-bulb temperatures: (1) daytime mean temperature; (2) 24-h mean temperature; and (3) most extreme 24-h temperature. For models using dry-bulb temperatures, we considered four treatments of relative humidity. Among 188,531 patients who presented with kidney stones, 24-h wet bulb temperature best predicted kidney stone presentation during summer. Mean cross-validated residuals were generally lower in summer for wet-bulb temperatures and heat index than the corresponding dry-bulb temperature metric, regardless of type of adjustment for relative humidity. Those dry-bulb models that additionally adjusted for relative humidity had higher mean residuals than other temperature metrics. The relative risk of kidney stone presentations at the 99th percentile of each temperature metric compared to the respective median temperature in summer months differed by temperature metric and relative humidity adjustment, and ranged from an excess risk of 8-14%. All metrics performed similarly in winter. The combination of temperature and relative humidity determine the risk of kidney stone presentations, particularly during periods of high heat and humidity. These results suggest that metrics that measure moist heat stress should be used to estimate the temperature-dependence of kidney stone presentations, but that the particular metric is relatively unimportant.
PMCID:5811384
PMID: 29289860
ISSN: 1096-0953
CID: 2899692
Phase-controlled, speckle-free holographic projection with applications in precision optogenetics
Holographic speckle is a major impediment to computer-generated holographic (CGH) projections in applications ranging from display, optical tweezers, and machining to optogenetic neural control. We present an iterative phase retrieval algorithm that allows the projection of amplitude-controlled speckle-free one-dimensional patterns with a high degree of pattern uniformity. The algorithm, termed the weighted Gerchberg-Saxton with phase-control (GSW-PC), is shown to have the ability to simultaneously control both the phase and amplitude of projected patterns with high diffraction efficiencies. Furthermore, we show that the framework can address the challenge of projecting volumetric phase and amplitude-controlled patterns, by incorporating GSW-PC with the angular spectrum method. The algorithms' performance is numerically and experimentally tested, and further compared with conventional and modern CGH techniques.
PMCID:5852266
PMID: 29564366
ISSN: 2329-423x
CID: 3000982
CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation (MCS)
Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a viable therapeutic, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.
PMCID:5874173
PMID: 29394516
ISSN: 1098-1063
CID: 2933942
High-Density Stretchable Electrode Grids for Chronic Neural Recording
Electrical interfacing with neural tissue is key to advancing diagnosis and therapies for neurological disorders, as well as providing detailed information about neural signals. A challenge for creating long-term stable interfaces between electronics and neural tissue is the huge mechanical mismatch between the systems. So far, materials and fabrication processes have restricted the development of soft electrode grids able to combine high performance, long-term stability, and high electrode density, aspects all essential for neural interfacing. Here, this challenge is addressed by developing a soft, high-density, stretchable electrode grid based on an inert, high-performance composite material comprising gold-coated titanium dioxide nanowires embedded in a silicone matrix. The developed grid can resolve high spatiotemporal neural signals from the surface of the cortex in freely moving rats with stable neural recording quality and preserved electrode signal coherence during 3 months of implantation. Due to its flexible and stretchable nature, it is possible to minimize the size of the craniotomy required for placement, further reducing the level of invasiveness. The material and device technology presented herein have potential for a wide range of emerging biomedical applications.
PMCID:5948103
PMID: 29488263
ISSN: 1521-4095
CID: 3192982
18F-florbetapir Positron Emission Tomography-determined Cerebral beta-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery
BACKGROUND:Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS:Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS:The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS:In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.
PMCID:5849499
PMID: 29389750
ISSN: 1528-1175
CID: 2994312
Cherub versus brat
A long non-coding RNA molecule called cherub is a driver of tumor development.
PMCID:5871327
PMID: 29580383
ISSN: 2050-084x
CID: 3011912
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2018:115(13):3392-3397.DOI: 10.1073/pnas.1717815115
Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation
The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation ofSmo(SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, withSmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as moreSmoM2orPtch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression.
PMCID:5879676
PMID: 29531057
ISSN: 1091-6490
CID: 2992582
