Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynorphin A (1–17) induces apoptosis in striatal neurons in vitro through AMPA/kainate receptor-mediated cytochrome c release and caspase-3 activation

Dynorphin A (1–17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1–17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using MK(+)801, a non-equilibrium N-methyl-D-aspartate (NMDA) antagonist; CNQX, a competitive α –amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (−)-naloxone, a general opioid antagonist. The results show that dynorphin A (1–17) (≥10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, Z-DEVD-FMK, further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-Benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors. are *P < 0.05 or **P < 0.01 versus untreated neurons; b P < 0.05 versus untreated, dynorphin A (1–17) (10 μM), or dynorphin A (1–17) (10 μM) + naloxone treated neurons.
Protein Kinase C- e Regulates Local Calcium Signaling in Airway Smooth Muscle Cells

ProteinkinaseC(PKC)isknowntoregulateryanodinereceptor(RyR)– mediated local Ca 2 1 signaling (Ca 2 1 spark) in airway and vascular smooth muscle cells (SMCs), but its speciﬁc molecular mechanisms andfunctionsstillremainelusive.Inthisstudy,werevealthat,inairwaySMCs,speciﬁcPKC e peptide inhibitor and gene deletion signiﬁcantly increased the frequency ofCa 2 1 sparks, and decreased the amplitude ofCa 2 1 sparksinthepresenceofxestospogin-Ctoeliminatefunctional inositol 1,4,5-triphosphate receptors. PKC e activation with phorbol- 12-myristate-13-acetate signiﬁcantly decreased Ca 2 1 spark frequency and increased Ca 2 1 spark amplitude. The effect of PKC e inhibition or activation on Ca 2 1 sparks was completely lost in PKC e 2 / 2 cells. PKC e inhibition or PKC e activation was unable to affect Ca 2 1 sparks in RyR1 2 / 2 and RyR1 1 / 2 cells. Modiﬁcation of RyR2 activity by FK506-binding protein 12.6 homozygous or RyR2 heterozygous gene de- letion did notprevent the effect ofPKC e inhibitionoractivation. RyR3 homogenousgenedeletiondidnotblocktheeffectofPKC e inhibition and activation, either. PKC e inhibition promotes agonist-induced airway muscle contraction, whereas PKC e activation produces an opposite effect. Taken together, these results indicate that PKC e regulates Ca 2 1 sparks by speciﬁcally interacting with RyR1, which playsanimportantroleinthecontrolofcontractileresponsesinairway SMCs. ) This study reveals that protein kinase C (PKC)- e regulates local Ca 2 1 signaling by speciﬁcally interacting with ryanodine receptor (RyR) 1, thereby modulating contractile responses in airway smooth muscle cells. Thus, PKC- e and RyR1 may become new therapeutic targets for asthma and other lung diseases.
Electrical Trees and Their Growth in Silicone Rubber at Various Voltage Frequencies

The insulation property at high voltage frequencies has become a tough challenge with the rapid development of high-voltage and high-frequency power electronics. In this paper, the electrical treeing behavior of silicone rubber (SIR) is examined and determined at various voltage frequencies, ranging from 50 Hz to 130 kHz. The results show that the initiation voltage of electrical trees decreased by 27.9% monotonically, and they became denser when the voltage frequency increased. A bubble-shaped deterioration phenomenon was observed when the voltage frequency exceeded 100 kHz. We analyze the typical treeing growth pattern at 50 Hz (including pine-like treeing growth and bush-like treeing growth) and the bubble-growing pattern at 130 kHz. Bubbles grew exponentially within several seconds. Moreover, bubble cavities were detected in electrical tree channels at 50 Hz. Combined with the bubble-growing characteristics at 130 kHz, a potential growing model for electrical trees and bubbles in SIR is proposed to explain the growing patterns at various voltage frequencies.
Case Report: Abducens Nerve Palsy and Meningitis by Rickettsia typhi

Patients with rickettsial infection may present with encephalitis or meningitis but neurologic involvement is rare in murine typhus. Here, we report two patients with Rickettsia typhi meningitis who presented with cranial neuropathy, presumably caused by two distinct disease processes. Recognition of the disease manifestations is important because rickettsial infections are potentially associated with significant morbidity. Simple effective treatments are available.
Post-transcriptional regulation of grooi, , a, and IL-8 mRNAs by IL-1:

Expression of the cytokine gene gro, also known as melanoma growth stimulatory activity, is induced by inflammatory stimuli, including IL-1. To determine whether gro expression is regulated at a post-transcriptional level, the effect of IL-1 on gro mRNA stability was examined. Treatment of fibroblasts with IL-1,B caused a dose-dependent induction of gro mRNA. When IL-1 was withdrawn, gro mRNA decayed rapidly with a half life of 1 hour. This decay occurred whether or not actinomycin D was added to block new transcription. In contrast, when IL-1 was present in the medium, the level of gro mRNA was stable over 8 hours following addition of actinomycin D. In addition, the stability of a related mRNA, IL-8, was found to be regulated by IL-1. To examine whether Northern results reflected expression of groa, or of the closely related genes, grofi and groy, RNA samples were analyzed by PCR. All three genes were found to be induced by IL-1 and all mRNAs were stabilized in the presence of IL-1. Northern analysis revealed a minor species of gro mRNA which lacked poly(A). The pattern of expression of this RNA suggested that it was a decay intermediate of one or more of the gro mRNAs. The findings indicate that mRNA stabilization is an important component of IL-1-induced gene expression.
Empirical Analyses Socioeconomic Gradients and Low Birth-Weight: Empirical and Policy Considerations

Objective. To examine whether socioeconomic status (SES) gradients emerge in health outcomes as early as birth and to examine the magnitude, potential sources, and explanations of any observed SES gradients. Data Sources. The National Maternal and Infant Health Survey conducted in 1988. Study Design. A multinomial logistic regression of trichotomized birth-weight categories was conducted for normal birth-weight (2,500–5,500 grams), low birth-weight (LBWT; o 2,500 grams), and heavy birth-weight ( 4 5,500 grams). Key variables included income, education, occupational grade, state-level income inequality, and length of participation in Women-Infants-Children (WIC) for pregnant mothers. Principal Findings. A socioeconomic gradient for low birth-weight was discovered for an adjusted household income measure, net of all covariates in the unrestricted models. A gross effect of maternal education was explained by maternal smoking behaviors,while noeffect ofoccupational grade was observed,net ofhousehold income. There were no signiﬁcant state-level income inequality effects (Gini coefﬁcient) for any of the models. In addition, participation in WIC was discovered to substantially ﬂatten income gradients for short-term participants and virtually eliminate an income gradient among long-term participants. Conclusions. Although a materialist explanation for early-life SES gradients seems the most plausible (vis-a`-vis psychosocial and occupational explanations), more research is needed to discover potential interventions. In addition, the notion of a monotonic gradient inwhich income is salutaryacrossthe full range of the distribution ischallenged by these data such that income may cease to be beneﬁcial after a given threshold. Finally, the success of WIC participation in ﬂattening SES gradients argues for either: (a) the experimental efﬁcacy of WIC, or (b) the biasing selection characteristics of WIC participants; either conclusion suggests that interventions or characteristics of participants deserves further study as a potential remedy for socioeconomic disparities in early-life health outcomes such as LBWT.
Expression of zinc-deficient human SOD1 in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction

More than 130 different mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been associated with Amyotrophic lateral sclerosis (ALS) but the mechanism of this toxicity remains controversial. To gain insight into the importance of the zinc site in the pathogenesis of SOD1 in vivo , we generated a Drosophila model with transgenic expression of a zinc-deficient human SOD1. Expression of zinc-deficient SOD1 in Drosophila resulted in a progressive movement defect with associated mitochondrial cristae vacuolization and reductions in ATP levels. Furthermore, these flies are sensitized to mitochondrial toxins, paraquat and zinc. Importantly, we show that the zinc-deficient SOD1-induced motor defect can be ameliorated by supplementing the endogenous fly respiratory chain machinery with the single-subunit NADH–ubiquinone oxidoreductase ( Ndi1 ) from yeast. These results demonstrate that zinc-deficient SOD1 is neurotoxic in vivo and suggest that mitochondrial dysfunction plays a critical role in this toxicity. The robust behavioral, pathological and biochemical phenotypes conferred by zinc-deficient SOD1 in Drosophila have general implications for the role of the zinc ion in both familial and sporadic ALS. mitochondrial Previous studies demonstrated that supplementation with nitric oxide synthase inhibitors neuronal loss and ameliorated phenotypes of G93A-mSOD1 These observations suggest that mitochondrial dysfunction may be a central mechanism of mutant SOD toxicity. Considering that zinc-deficient SOD neurotoxicity is also dependent on endogenous production of nitric oxide we hypothesized that mitochondrial dysfunction may be responsible for locomotor defects in our ALS flies. Our results demonstrate that a mutation affecting the zinc-binding site of SOD1 is sufficient to induce mitochondrial vacuolization and to reduce ATP levels. Furthermore, zinc-deficient SOD1-expressing flies are severely sensitized to mitochondrial toxins paraquat and zinc: paraquat lowers mitochondrial complex I activity while zinc ion interacts with nitric oxide to induce mitochondrial dysfunction and neuronal cell death superoxide dismutase (SOD2).
CEREBRAL CIRCULATION AND METABOLISM IN HYPERTHYROIDISM l

The nitrous oxide method for measuring cerebral blood flow has been previously described (7), and the modification used in this laboratory of drawing simultaneous "integrated" samples from the artery and internal jugular bulb, rather than five separate samples for each, has been reported, together with values obtained on normal young subjects (8). The oxygen content of arterial and venous blood samples was measured by the spectrophotometric method of Hickam and Frayser (9). Blood sugar values were measured by Nelson's modification of Somogyi's method (10). Each value for arterial-cerebral venous glucose difference is the average of four such differences. Arterial pressure was measured by the auscultatory method every two minutes throughout the blood flow procedure, the arm being held at heart level. Mean arterial pressure was computed by adding one-third the pulse pressure to the diastolic pressure. Cerebral venous oxygen tension was not measured directly, but was computed from the per cent oxygen saturation of the cerebral venous blood by the use of a standard oxy-hemoglobin dissociation curve drawn for pH 7.4. Cerebral oxygen consumption, cerebral glucose consumption, and cerebral vascular resistance were calculated as previously described (8).
Stability of audiometric thresholds for children with hearing aids applying the AAA Pediatric Amplification Guidelines: Implications for Safety

Background— Children who wear hearing aids may be at risk for further damage to their hearing from over-amplification. Previous research on amplification-induced hearing loss has included children using linear amplification or simulations of predicted threshold shifts based on nonlinear amplification formulae. A relationship between threshold shifts and the use of nonlinear hearing aids in children has not been empirically verified. Purpose— The purpose of the study was to compare predicted threshold shifts from amplification to longitudinal behavioral thresholds in a large group of children who wear hearing aids to determine the likelihood of amplification-induced hearing loss. Research design— An accelerated longitudinal design was used to collect behavioral threshold and amplification data prospectively. Study sample— Two-hundred and thirteen children with mild to profound hearing loss who wore hearing aids were included in the analysis. Data collection and analysis— Behavioral audiometric thresholds, hearing aid outputs and hearing aid use data were collected for each subject across four study visits. Individual ear- and frequency-specific safety limits were derived based on the Modified Power Law to determine the level at which increased amplification could result in permanent threshold shifts. Behavioral thresholds were used to estimate which children would be above the safety limit at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz using thresholds in dB HL and then in dB SPL in the ear canal. Changes in thresholds across visits were compared for children who were above and below the safety limits. Results— Behavioral thresholds decreased across study visits for all children, regardless of whether or not their amplification was above the safety limits. The magnitude of threshold change across time corresponded with changes in ear canal acoustics as measured by the real-ear-to-coupler difference. Conclusions— Predictions of threshold changes due to amplification for children with hearing loss did not correspond with observed changes in threshold over across two to four years of monitoring amplification. Use of dB HL thresholds and predictions of hearing aid output to set the safety limit resulted in a larger number of children being classified as above the safety limit than when safety limits were based on dB SPL thresholds and measured hearing aid output. Children above the safety limit for the dB SPL criteria tended to be fit above prescriptive targets. Additional research should seek to explain how the Modified Power Law predictions of threshold shift overestimated risk for children who wear hearing aids.
A DDITIVE P OISSON P ROCESS : L EARNING I NTENSITY OF H IGHER -O RDER I NTERACTION IN P OISSON P ROCESSES

We present the Additive Poisson Process (APP), a novel framework that can model the higher-order interaction effects of the intensity functions in Poisson processes using projections into lower-dimensional space. Our model combines the techniques from information geometry to model higher-order interactions on a statistical manifold and in generalized additive models to use lower-dimensional projections to overcome the effects from the curse of dimensionality. Our approach solves a convex optimization problem by minimizing the KL divergence from a sample distribution in lower-dimensional projections to the distribution modeled by an intensity function in the Poisson process. Our empirical results show that our model is able to use samples observed in the lower dimensional space to estimate the higher-order intensity function with extremely sparse observations
Synthesis and Identification of New 4-Arylidene Curcumin Analogs as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway

A series of curcumin analogues including new 4-arylidene curcumin analogs (4-arylidene-1,7bisaryl-hepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogs can effectively decrease the growth of a panel of lung cancer cells in suband low micromolar concentration ranges. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogs exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogs also reduced the tumorigenic potential of cancer cells in a clonogenic assay.
Combined piezoelectric and flexoelectric effects in resonant dynamics of nanocantilevers

We establish and analyze an analytical framework by accounting for both the piezoelectric and flexoelectric effects in bimorph cantilevers. The focus is placed on the development of governing electroelastodynamic piezoelectric–flexoelectric equations for the problems of resonant energy harvesting, sensing, and actuation. The coupled governing equations are analyzed to obtain closed-form frequency response expressions via modal analysis. The combined piezoelectric–flexoelectric coupling coefficient expression is identified and its size dependence is explored. Specifically, a typical atomistic value of the flexoelectric constant for barium titanate is employed in the model simulations along with its piezoelectric constant from the existing literature. It is shown that the effective electromechanical coupling of a piezoelectric material, such as barium titanate, is significantly enhanced for thickness levels below 100 nm. The electromechanical coupling coefficient of a barium titanate bimorph cantilever increases from the bulk piezoelectric value of 0.065 to the combined piezoelectric–flexoelectric value exceeding 0.3 toward nanometer thickness level. Electromechanical frequency response functions for resonant power generation and dynamic actuation also capture the size-dependent enhancement of the electromechanical coupling. The analytical framework given here can be used for parameter identification and design of nanoscale cantilevers that can be used as energy harvesters, sensors, and actuators.
Pioneer Vector Integration and Tumorigenesis

W ith some early molecular work in oncology and virology in Harald zur Hausen’s lab in Heidelberg, Germany, a background in internal medicine and oncology (courtesy of learning to treat Hodgkin’s disease from Volker Diehl, Cologne, Germany), I had developed a fascination with stem cell transplantation as a way to treat otherwise intractable diseases in humans. So I jumped at the opportunity to work on a gene therapy project in Rainer Storb’s division at the Hutch in Seattle, together with Hans-Peter Kiem and the late Friedrich Schuening. Gene therapy was all the rage of the day; many people convinced—or trying to convince others—that gene transfer would solve many of the major medical problems of humankind. My own view, under the influence of Rainer’s sharp scientific wit and guidance, was that perhaps the stably integrating retrovirus vectors, biologically inert as we thought they were, could at least help decipher the structure of human hematopoiesis. At the very least, they could help to understand its regeneration after hematopoietic stem cell transplantation— that meant as soon as we would succeed making them enter human blood-forming stem cells in significant numbers.
X-ray crystallographic and Solution State NMR Spectroscopic Investigations of NADP + Binding to Ferredoxin-NADP Reductase (FPR) from Pseudomonas aeruginosa , †,‡

The f erredoxin nicotinamide adenine dinucleotide p hosphate r eductase from Pseudomonas aeruginosa ( pa -FPR) in complex with NADP + has been characterized by X-ray crystallography and in solution by NMR spectroscopy. The structure of the complex revealed that pa -FPR harbors a pre-formed NADP + binding pocket where the cofactor binds with minimal structural perturbation of the enzyme. These findings were complemented by obtaining sequential backbone resonance assignments of this 29,518 kDa enzyme, which enabled the study of the pa -FPR-NADP complex by monitoring chemical shift perturbations induced by addition of NADP + or the inhibitor, adenine dinucleotide phosphate (ADP), to pa -FPR. The results are consistent with a pre-formed NADP + binding site and also demonstrate that the pa -FPR-NADP complex is largely stabilized by interactions between the protein and the 2 ′ P AMP portion of the cofactor. Analysis of the crystal tail is not dynamically active, even upon NADP + binding. These findings, which suggest that the C’-terminal extension will likely not be readily displaced to allow “productive” packing of the isoalloxazine and nicotinamide rings for direct hydride transfer, are discussed in the context of a possible multistep hydride transfer operative in the oxidation of NADPH by FPR enzymes.
CAP modulates acetylcholine release at the myoneural junction

Transient receptor potential (TRP) proteins are non-selective cation channel proteins that are expressed throughout the body. Previous studies demonstrated the expression of TRP Vanilloid 1 (TRPV1), capsaicin (CAP) receptor, in sensory neurons. Recently, we reported TRPV1 expression in mouse motor nerve terminals [MNTs; (Thyagarajan et al., 2009)], where we observed that CAP protected MNTs from botulinum neurotoxin A (BoNT/A). Phrenic nerve diaphragm nerve muscle preparations (NMP) isolated from isoflurane anesthetized adult mice were analyzed for twitch tension, spontaneous (mEPCs) and nerve stimulus evoked (EPCs) acetylcholine release. When acutely applied to isolated NMP, CAP produced a concentration-dependent decline of twitch tension and produced a significant decline in the amplitude of EPCs and quantal content without any effect on the mEPCs. The suppression of nerve stimulus evoked acetylcholine release by CAP was antagonized by capsazepine (CPZ), a TRPV1 antagonist. CAP did not suppress phrenic nerve stimulus evoked acetylcholine release in TRPV1 knockout mice. Also, CAP treatment, in vitro , interfered with the localization of adapter protein 2 in cholinergic Neuro 2a cells. Wortmannin, (WMN; non-selective phosphoinositol kinase inhibitor), mimicked the effects of CAP by inhibiting the acetylcholine exocytosis. Our data suggest that TRPV1 proteins expressed at the MNT are coupled to the exo-endocytic mechanisms to regulate neuromuscular functions.
Passively Q-Switched Operation of a Tm,Ho:LuVO4 Laser with a Graphene Saturable Absorber

A passively Q-switched (PQS) operation of Tm,Ho:LuVO4 laser is experimentally demonstrated with a graphene saturable absorber (SA) mirror. An average output power of 1034 mW at 54.5 kHz is acquired with an 8% optical–optical conversion efficiency. The energy per pulse of 40.4 μJ and a peak power of 56.07 W are achieved; the narrowest pulse width of 300 ns is acquired, and the output wavelengths of Tm,Ho:LuVO4 are 2075.02 nm in a continuous wave (CW) regime and 2057.03 nm in a PQS regime.