cssi/SciSciGPT-SciSciNet huggingface dataset:
Of monkeys and men: analysis of the phase 2 double-blind, sham-surgery controlled, randomized trial of AAV2-neurturin gene therapy for Parkinson's disease.

Introduction: The development of new biological therapies for Parkinson’s disease (PD), such as direct brain protein infusions, gene transfer therapies, and cellular therapies, has been an area of tremendous interest and rapid growth over the past decade. This growth is driven by the urgent need for neuroprotective and neurorestorative therapies. Neurotrophic factor and gene transfer therapies have been safely translated from animal model studies to clinical trials in patients, including direct putamenal infusion of glial cell–derived neurotrophic factor (GDNF), which was unsuccessful, and adeno-associated virus 2glutamic acid decarboxylase (AAV2-GAD) gene delivery to the subthalamic nucleus, which has demonstrated some symptomatic improvement [1, 2]. The clinical trial of AAV2-neurturin gene therapy (CERE-120; Ceregene, San Diego, CA) discussed here is the first phase 2, double-blind, randomized, sham surgery controlled trial of a gene therapy for PD. It is a major milestone in many respects, but also highlights some of the key challenges facing the development of effective neurosurgically delivered biological therapies for PD. The background for this trial includes a sizable literature of animal studies that found that the neurotrophic factors GDNF and its analogue neurturin protect dopaminergic neurons of the substantia nigra pars compacta (SNpc) when exposed to neurotoxins such as 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) [3, 4]. The preclinical study of AAV2-neurturin gene therapy in MPTP-treated monkeys demonstrated robust expression of neurturin in targeted areas 8 months after administration, and an 80% to 90% improvement in motor scores 4 months post-therapy [5]. Statistically significant increases in F-fluorodopa positron emission tomography (PET) signal on the injected side of the brain compared with the non-injected side were found at both 4 months and 8 months post-injection in aged monkeys [6]. Primate studies were performed with injection of AAV2-neurturin to the striatum only [6], or to both the striatum and the substantia nigra simultaneously [5]. These findings and the results of a successful phase 1 open trial led to the phase 2 trial discussed here.
Dikes of the McClure mountain — Iron mountain alkalic complex, Fremont county, Colorado, U.S.A.

The McClure Mountain — Iron Mountain alkalic complex, the largest of three Precambrian alkalic complexes in south-central Colorado, is an irregularly ovoid body about 8×6.5 kilometers in plan. It contains major petrologic units (in age sequence): 1) peridotite and ilmenite-magnetite lenses, 2) gabbro, 3) hornblende syenite, 4) ijolite and 5) nepheline syenite, whose internal arrangement is irregular. Dikes are numerous and varied both within the complex and in the surrounding Precambrian metasediments and meta-volcanics (Idaho Springs formation), granitoids and migmatites to a distance of 27 kilometers from the complex. Fenitization has only locally affected these wall rocks at their contacts with the complex. Dikes within the complex are chiefly light colored and of syenitic or nepheline syenitic composition. Texturally they range from aphanitic, through porphyritic with an aphanitic to fine-grained matrix, to uniformly medium-grained. Most of the intracomplex dikes (save the few carbonatites) are represented by compositionally equivalent major units within the complex. In contrast, the extracomplex dikes are chiefly lamprophyres and carbonatites, none of which has a compositionally similar unit within the complex. The carbonatite dikes are younger than the lamprophyres; where the two types co-occupy the same fracture, the lamprophyre has been carbonatized. The lamprophyres are represented by an extraordinary number of textural varieties, involving phenocrysts and phenocryst combinations of augite, barkevikite, olivine and plagioclase in varying matrix combinations of olivine, augite, barkevikite, biotite, magnetite, apatite, plagioclase and orthoclase. Many of the dikes can be classed as camptonites or olivine camptonites. The Goldie lamprophyres contain local marginal phases spectacularly marked by concentrically zoned ovoids. The Cabin dike is studded by megaphenocrysts of augite. The carbonatites are of three main types: Many carbonatites and Th-RE veins emit, when broken, a fetid gas consisting of a mixture of fluorinated hydrocarbons of the C5 and C6 types along with F2, HF, and F2O. The fluorine has been derived from structurally degraded radioactive fluorite; the hydrocarbon gases appear to represent primary inclusions. Within the dike halo are two small breccia pipes consisting of fenitized, locally derived Precambrian gneiss blocks with minor fragments of transported biotitized lamprophyre in a subordinate calcitic matrix also containing aegirine, crocidolite, potash feldspar and hematite. The abundance of the lamprophyres, the great width of the dike halo, the lack of ring structure within the complex, the restriction of carbonatite to dikes, and the subordinate fenitization effects all combine to suggest that the McClure Mountain — Iron Mountain complex is now exposed at a relatively deep niveau, possibly near the mesozone — catazone boundary.
Polarimetric Detection of Land Sediment Runoff into the Ocean Using Space Shuttle Imagery

A new technique employing optical polarization is used to examine polarized radiation scattered by the sea in a region west of the Island of Hawaii. The technique is a very sensitive indicator of land sediment runoff following a storm. Polarization data acquisition details are described with an approach easily adapted to simplified instrumentation.
An analysis of carrier-facilitated transport through thin films of hemoglobin and myoglobin

Abstract The problem of carrier-facilitated transport through a thin film is examined in the asymptotic limit of small Damkohler number σ. In this limit, a regular perturbation solution is developed for the facilitated flux, correct to O (σ 6 ). The results are applied to the process of oxygen transfer through thin films of hemoglobin and myoglobin solutions. In these systems, the perturbation solution is found to be quite accurate for very thin films (i.e. small σ) with thickness substantially less than 1 μ m; but it tends to diverge, leading to large errors, as the thickness increases. We have used the method of Pade approximants to accelerate the convergence of this series solution. The accelerated solution predicts the facilitated flux accurately for films of thickness up to about 3 μ m in hemoglobin and about 5.5 μ m in myoglobin.
An Iterative Approach for Steady State Handling Analysis of Vehicles

In this paper, we present an iterative approach for analyzing the steady state handling behavior of a two-axled vehicle. This approach computes lateral forces iteratively from two separate submodels. The first submodel is an appropriate tire model that computes per wheel lateral forces as functions of slip angles, from formulations preferably expressed in a non-dimensional format. The second is a lateral weight transfer submodel that computes per-axle lateral force contributions for a given lateral acceleration. The combination then allows for the estimation of the required steer angles for the prevailing lateral acceleration. Subsequent corrections are then applied to take into account steer effects such as roll steer, lateral force compliance steer and aligning moment compliance steer. The usefulness of the approach is demonstrated by comparing simulation results with test data for a small passenger car.Copyright © 2008 by ASME
The placebo effect

Historically the term placebo harks back to the 116th psalm in the Hebrew bible. The ninth verse of this psalm begins with the word “et-ha-lech” (I shall walk), which was strangely translated into the Septuagint Greek as “euarestiso” and then into its Vulgate Latin equivalent of “placebo,” the first-person singular future tense of the verb meaning to please. In the twelfth century the word entered the English language as the name commonly given to the vespers for the dead. A few centuries later, placebo began to take on secular meanings, almost all of them derisive. For example, it was used to denote a servile flatterer and toady, and professional mourners were hired to “sing placebos“ at the bier of the deceased, as substitutes for members of the family. In medicine the first definition appeared in 1785 in Motherby’s New Medicul Dictionary as “a commonplace method or medicine.” By the 1795 edition the description had been expanded to include the words “calculated to amuse for a time, rather than for any other purpose.” The next dictionary change added the implication that the placebo was both inert and harmless. a “make-believe medicine,” devoid of effect. While the word placebo has for a long time been associated in the minds of physicians with deception or pandering to the desires of misguided and neurotic patients, for centuries most of the therapies in vogue were actually placebos, pharmacologic ciphers helpful primarily because of the mystique surrounding their use. Unicorn’s horn; bezoar “stone” from animal stomachs; the mish-mash known as theriac, with its principal ingredient of viper flesh; moss from the skull of a hanged criminal; eunuch fat; dried mummythese were at best inadvertently fraudulent remedies, for all their popularity. Even in the eighteenth and nineteenth centuries much of what the medical profession did in the way of therapy depended on the credulity of both doctor and patient and on the healing powers of time. For example, there was little reason for rejoicing around the turn of the nineteenth century over the attempts
SERT Ileu425Val in autism, Asperger syndrome and obsessive-compulsive disorder.

BackgroundSERT I425V, an uncommon missense single nucleotide polymorphism producing a gain-of-function of the serotonin transporter (SERT), was originally found to segregate with a primarily obsessive–compulsive disorder (OCD) but complexly comorbid phenotype in two unrelated families.ObjectiveAs tw
Associations between diabetes patients’ medication beliefs and adherence

Objective: To clarify the role of diabetes patients’ medication beliefs in explaining their medication adherence levels. Design: Cross sectional. Methods: Diabetes patients from Veterans Affairs settings reported their beliefs about the perceived necessity and potential harmfulness of their diabetes medications, along with their medication adherence and sociodemographic variables. Results: One-third of the 303 patients in the sample were nonadherent to medication A linear regression model adjusted for age, income, medical comorbidity, functional health literacy, depressive symptoms, and diabetes-related distress indicated that degree of nonadherence was significantly associated with the degree to which patients believed that their diabetes medication was unnecessary (β = − 0.19, p = 0.13, p = 0.021). Similar findings emerged when nonadherence was analyzed as a binary outcome in a logistic regression. Conclusions. In order to be maximally effective, interventions to improve diabetes medication adherence should evaluate patients’ perceptions about both the necessity and safety of taking medication. Implications for intervention accordingly are presented.
A smartphone-based chip-scale microscope using ambient illumination

Portable chip-scale microscopy devices can potentially address various imaging needs in mobile healthcare and environmental monitoring. Here, we demonstrate the adaptation of a smartphone's camera to function as a compact lensless microscope. Unlike other chip-scale microscopy schemes, this method uses ambient illumination as its light source and does not require the incorporation of a dedicated light source. The method is based on the shadow imaging technique where the sample is placed on the surface of the image sensor, which captures direct shadow images under illumination. To improve the image resolution beyond the pixel size, we perform pixel super-resolution reconstruction with multiple images at different angles of illumination, which are captured while the user is manually tilting the device around any ambient light source, such as the sun or a lamp. The lensless imaging scheme allows for sub-micron resolution imaging over an ultra-wide field-of-view (FOV). Image acquisition and reconstruction are performed on the device using a custom-built Android application, constructing a stand-alone imaging device for field applications. We discuss the construction of the device using a commercial smartphone and demonstrate the imaging capabilities of our system.
Collaborative Bluetooth-based location authentication on smart phones

Third-party location-based services are independent of wireless carriers and receive the user location from mobile devices GPS. A major problem in this context is how to prevent service abuse by malicious users who submit false locations by tampering with their phones. This paper presents LINK (Location authentication through Immediate Neighbors Knowledge), a location authentication protocol working independent of wireless carriers, in which nearby users help authenticate each other's location claims using Bluetooth communication. Simulation results demonstrate that LINK thwarts individual user attacks and a number of colluding users attacks. Experimental results over Android phones show that LINK works well at walking speeds and phone battery is not impacted significantly even for relatively high usage.
The Early Use and Development of Graphic Formulas: Two Case Study Reports of Graphic Formula Production by 2- to 3-year-old Children

Graphic formulas are an important denotational device in the drawing repertoires of adults and school-age children. They provide a stable basis for working out, modifying, and elaborating various aspects of graphic-representation. As such, they might also serve as useful graphic devices for very young children who are just beginning to use drawing as a representational medium. However, there are very few studies which have examined graphic formula production in the earliest phases of drawing. The case study reports presented here focus on the use and elaboration of graphic formulas by two 2- to 3-year-old children. They provide strong evidence, first, that graphic formulas are indeed available to even very young children. Secondly, they provide insight into the developmental processes by which the elaboration and reorganisation of graphic formulas occurs
Tryptophan Phosphorescence Study of Enzyme Flexibility and Unfolding in Laboratory-Evolved Thermostable Esterases†

Directed evolution of p-nitrobenzyl esterase (pNB E) has yielded eight generations of increasingly thermostable variants. The most stable esterase, 8G8, has 13 amino acid substitutions, a melting temperature 17 °C higher than the wild-type enzyme, and increased hydrolytic activity toward p-nitrophenyl acetate (pNPA), the substrate used for evolution, at all temperatures. Room-temperature activities of the evolved thermostable variants range from 3.5 times greater to 4.0 times less than wild type. The relationships between enzyme stability, catalytic activity, and flexibility for the esterases were investigated using tryptophan phosphorescence. We observed no correlation between catalytic activity and enzyme flexibility in the vicinity of the tryptophan (Trp) residues. Increases in stability, however, are often accompanied by decreases in flexibility, as measured by Trp phosphorescence. Phosphorescence data also suggest that the N- and C-terminal regions of pNB E unfold independently. The N-terminal region...
Improving transitions of care for patients on warfarin: The safe transitions anticoagulation report.

Adverse drug events are common during the transition period after hospitalization, and anticoagulants are among the medication classes for which the incidence is highest. We aimed to develop a concise report to improve the timeliness of international normalized ratio (INR) testing and quality of warfarin management posthospitalization. We developed the Safe Transitions Anticoagulation Report (STAR), which contains essential information on anticoagulation and is embedded in the discharge summary, and implemented the report and associated workflow in a tertiary care hospital within an integrated healthcare system. We performed a retrospective administrative database review of 505 patients in the preintervention period and 292 patients in the intervention period who were discharged on warfarin and were established patients at an affiliated ambulatory practice. There was no change in the frequency of obtaining an INR value within 10 days of discharge (41.4% and 47.6%, respectively, P = 0.09), and no increase in attaining a therapeutic INR level within 10 days of discharge (17.0% and 21.2%, respectively, P = 0.14). Ambulatory clinicians reported that the STAR improved "workflow and efficiency" (58%) and "patient safety" (77%), and led to an altered warfarin dose for 34% of survey respondents. Our study found that a concise anticoagulation report embedded in the discharge summary was perceived by ambulatory physicians as improving patient safety, but had no impact on clinical outcomes, suggesting that this electronic medical record tool would need to be a component of a broader multifaceted intervention to be effective.
Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Silencing gene expression by RNAi is a powerful method for exploring gene function and validating drug targets and potentially for therapy. Lymphocytes and other primary blood cells are resistant to lipid-based transfection in vitro and are difficult to target in vivo. We show here that antibody-protamine fusion proteins targeting the human integrin lymphocyte function-associated antigen-1 (LFA-1) efficiently deliver siRNAs and specifically induce silencing in primary lymphocytes, monocytes, and dendritic cells. Moreover, a fusion protein constructed from an antibody that preferentially recognizes activation-dependent conformational changes in LFA-1 selectively targets activated leukocytes and can be used to suppress gene expression and cell proliferation only in activated lymphocytes. The siRNA-fusion protein complexes do not cause lymphocyte activation or induce IFN responses. K562 cells expressing latent WT or constitutively activated LFA-1 engrafted in the lungs of SCID mice are selectively targeted by intravenously injected fusion protein–siRNA complexes, demonstrating the potential in vivo applicability of LFA-1-directed siRNA delivery.
Reliability of SiO 2 gate dielectric with semi-recessed oxide isolation

This paper reports the results of a study to minimize defects in the gate oxide and in the single crystal substrate of semirecessed oxide (Semi-ROX) structures. It is shown that both an increase in oxidation mask thickness and a decrease in wet field oxidation temperature markedly reduce the incidence of low voltage breakdown in the gate oxide. Microscopic studies of samples which exhibited low voltage breakdown showed that the Si3N4 oxidation mask had failed to protect the surface of the region in which the gate oxide was grown. Semi-ROX processing also exhibited edge breakdown, most likely due to the Kooi effect (nitrided Si surface). The use of a thicker "pad" oxide and a decrease in the wet field oxide thickness were beneficial in reducing the magnitude of degradation in gate breakdown due to this edge effect.
Evaluation of the Lumbar Spine in Patients with Glycogen Storage Disease: CT Demonstration of Patterns of Paraspinal Muscle Atrophy

CT studies of the lumbar spine were performed in 19 patients with glycogen storage disease. Nine of 10 patients with McArdle's disease and seven of nine patients with acid maltase deficiency demonstrated posterior paraspinal muscle atrophy out of proportion to their ages. In addition, the psoas muscles were spared in all 10 patients with McArdle's disease and were involved with atrophy in seven of the nine patients with acid maltase deficiency. We conclude that when patients with low back pain-or asymptomatic patients-demonstrate otherwise unexplained atrophy of the paraspinal muscles the diagnosis of glycogen storage disease should be considered. Furthermore, when the psoas muscles are spared, the specific diagnosis of McArdle's disease is suggested.
Measurement of shear stress between single-wall carbon nanotubes and substrates using NEMS devices

This paper presents a novel and easily controllable method for measurement of the interaction of single-wall carbon nanotubes (SWNTs) with surfaces using simple cantilever beams, a nanomanipulator, and a scanning electron microscope (SEM). A small SWNT bundle is assembled across two cantilevers by dielectrophoresis, with one cantilever much more flexible than the other. The flexible cantilever is then pushed away from the stiffer cantilever in order to produce slip between the SWNTs and the cantilever surface. When the cantilever returns to its initial position, axial slack is observed in the SWNTs. A theoretical model has been developed to calculate the shear stress between the SWNT bundle and the cantilever surface, based on the measured axial slack. For a gold cantilever surface, an average interfacial shear stress of 113 MPa was obtained.
Contribution of very low-density lipoprotein triglyceride fatty acids to postabsorptive free fatty acid flux in obese humans

Objective In the fasting state, plasma free fatty acids (FFA) are thought to derive almost exclusively from adipose tissue lipolysis. However, there are mixed reports as to whether the spillover of fatty acids (FA) from very low-density lipoprotein triglyceride (VLDL–TG) hydrolysis contributes significantly to the plasma FFA pool. Because substantial VLDL–TG fatty acid spillover into the plasma FFA pool would profoundly impact the interpretation of isotope dilution measures of FFA flux, we investigated the contribution of VLDL–TG spillover to plasma FFA appearance.
Diagnostic measurements on explosive emission cathodes operating at high current densities and UHV pressures

Vacuum diodes utilizing explosive emission cathodes generally suffer from non-uniform emission, gap closure by anode and cathode plasma expansion, and outgassing. Also, the Child-Langmuir relation does not apply at the edge of the emission area. This results in a high current density sheath at the edge of the emission area. Each of these phenomena presents its own technical challenge in HPM source design and optimization. Diagnostic techniques and particle in cell simulations for a vacuum diode, to be operated as a greater than 100 MW class vircator, have been used in order to compare the characteristics of the electron beam produced by various cathode materials and geometries. Uniform current density plays a key role in vircator performance and efficiency, as well as in the lifetime of the diode. The diode under investigation has an emission area of 20.3 cm2, and operates at a current density on the order of 300 A/cm2 at 200 kV. The background vacuum level and the associated adsorbed and absorbed gases at the surface play a major role in the behavior of an explosive emission cathode. This vircator source is operated as a sealed tube, requiring no vacuum pumping until the device is repetitively operated. The small amount of gas generated during operation is pumped down in between shots, if needed, utilizing an integrated small sputter-ion pump. The background pressure in the diode is in the ultra-high vacuum (UHV) range, on the order of 10−9 Torr to 10−8 Torr. Particle in cell simulations were performed to investigate current density distributions at the surface of both the anode and cathode due to various field shaping profiles. Additionally, scintillator images were taken to compare the beam profile of a machined aluminum cathode with a CsI coated carbon fiber cathode.
Structured optimal and robust control with multiple criteria: a convex solution

In this paper, the design of controllers that incorporate structural and multiobjective performance requirements is considered. The control structures under study cover nested, chained, hierarchical, delayed interaction and communications, and symmetric systems. Such structures are strongly related to several modern-day and future applications including integrated flight propulsion systems, platoons of vehicles, micro-electro-mechanical systems, networked control, control of networks, production lines and chemical processes. It is shown that the system classes presented have the common feature that all stabilizing controllers can be characterized by convex constraints on the Youla-Kucera parameter. Using this feature, a solution to a general optimal performance problem that incorporates time domain and frequency domain constraints is obtained. A synthesis procedure is provided which at every step yields a feasible controller together with a measure of its performance with respect to the optimal. Convergence to the optimal performance is established. An example of a multinode network congestion control problem is provided that illustrates the effectiveness of the developed methodology.
Determination of attenuation‐velocity products in a layered homogeneous medium

Attenuation imaging has the promise to become a measurement technique for ultrasound imaging systems more sophisticated than those we currently possess; however, the difficulties in using the presently available methods tend to limit this potential for the non-specialist. In our recent work, we have investigated the attenuation imaging problem, and have had some success with an alternative technique, namely, attenuation-velocity product imaging. In certain cases this can be an acceptable substitute for purely attenuation imaging, particularly for the soft tissues encountered in some diagnostic medical situations where the acoustic velocities of the various layers are all of approximately the same value. This article discusses our technique in detail, beginning with fundamental considerations. We make no unreasonable assumptions about the object under study, and yet are able to show the uniqueness of the solution and also deal effectively with the problem of multiple reflections. The data encountered in this experimental configuration have several intriguing properties, which allow us to draw some conclusions about acoustic imaging in general.
Abstract A33: Combination immunotherapy with anti-CD40 mAb and MPL results in T cell-independent antitumor effects against B16 melanoma in mice.

Combination immunotherapies are promising candidates for clinical testing. In this study, monophosphoryl lipid A (MPL), a nontoxic derivative of LPS and agonist of Toll-like receptor (TLR) 4, was tested in combination with an agonistic anti-CD40 monoclonal antibody (anti-CD40) to assess the antitumor synergy between the two agents. We show that anti-CD40 is capable of priming mouse macrophages for subsequent ex vivo activation by MPL to an extent comparable to a TLR9 agonist, CpG. When given intratumorally (i.t.) to C57BL/6 mice bearing subcutaneous B16 melanoma, anti-CD40 and MPL induced synergistic antitumor effects. When administered i.t. into a primary tumor, anti-CD40 and MPL also slowed the growth of a secondary tumor growing simultaneously at a distant site in both immunocompetent mice and mice depleted of T cells. Taken together, our results show that the antitumor effects of anti-CD40 are enhanced by subsequent treatment with MPL, even in T cell-deficient hosts. These data suggest that anti-CD40+MPL could be a clinically promising immunotherapy for immunosuppressed cancer patients. Citation Format: Tyler Van De Voort, Paul Sondel, Mildred Felder, Richard Young, Nicholas Kalogriopoulos, Alexander Rakhmilevich. Combination immunotherapy with anti-CD40 mAb and MPL results in T cell-independent antitumor effects against B16 melanoma in mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A33.
Neurobiology of the Gustatory–Salivary Reflex

All neural information resulting from chemical stimulation of taste buds in the oral cavity, pharynx and larynx travels via the facial (VII), glossopharyngeal (IX) and vagus (X) nerves to terminate in the nucleus of the solitary tract (NST) in the brainstem. The NST is responsible for initial processing and distribution of chemosensory information. At higher relays in the central nervous system the processes of detection, discrimination and affective responses occur resulting in the sensation we call taste and the behavioral reactions to that sensation. In addition, the NST connects to efferent motor systems involved in oral facial motor reflexes and systems controlling the initiation and flow of saliva. Thus, the NST plays a pivotal role in the neural processing of chemosensory information derived from stimulation of taste buds. Beginning in 1961 (Pfaffmann et al., 1961) a large number of investigators in different laboratories have examined the NST using anatomical, and neurophysiological techniques. The topographical projections of the VII, IX and Xth nerves conveying sensory information to the NST have been determined using different methods in several species (Torvik, 1956; Norgren, 1981; Whitehead and Frank, 1983; Hamilton and Norgren, 1984). The morphology of the NST has been studied and the neuronal architecture defined (Whitehead, 1988). Neurons in the NST have been described as belonging to three major anatomical types—multipolar, elongate and ovoid (Whitehead, 1988; Lasiter and Kachele, 1988; King and Bradley, 1994; Mistretta and Labyak, 1994), and using immunocytochemistry the presence of GABA and other neuropeptides has been described (Lasiter and Kachele, 1988; Barry et al., 1993).
Preferential budding of vesicular stomatitis virus from the basolateral surface of polarized epithelial cells is not solely directed by matrix protein or glycoprotein

Vesicular stomatitis virus has been shown to bud basolaterally, and the matrix protein, but not glycoprotein, was proposed to mediate this asymmetry. Using polarized T84 monolayers, we demonstrate that no single viral protein is sufficient for polarized budding. Particles are released from the apical and basolateral surfaces and are indistinguishable, indicating that there is no apical assembly defect. We propose that aspects of host cell polarity create a more efficient budding process at the basolateral surface.
Chemistry and Biochemistry of Oxidative Stress in Neurodegenerative Disease

The age-related neurodegenerative diseases exemplified by Alzheimerhs disease (AD), Lewy body diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntingtonhs disease are characterized by the deposition of abnormal forms of specific proteins in the brain. Although several factors appear to underlie the pathological depositions, the cause of neuronal death in each disease appears to be multifactorial. In this regard, evidence in each case for a role of oxidative stress is provided by the finding that the pathological deposits are immunoreactive to antibodies recognizing protein side-chains modified either directly by reactive oxygen or nitrogen species, or by products of lipid peroxidation or glycoxidation. Although the source(s) of increased oxidative damage are not entirely clear, the findings of increased localization of redox-active transition metals in the brain regions most affected is consistent with their contribution to oxidative stress. It is tempting to speculate that free radical oxygen chemistry plays a pathogenetic role in all these neurodegenerative conditions, though it is as yet undetermined what types of oxidative damage occur early in pathogenesis, and what types are secondary manifestations of dying neurons. Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.
Disease Expression in Usher Syndrome Caused by VLGR1 Gene Mutation (USH2C) and Comparison with USH2A Phenotype

PURPOSE. To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. METHODS. Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). RESULTS. The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. CONCLUSIONS. USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.
Simple Negotiating Agents in Complex Games: Emergent Equilibria and Dominance of Strategies

We present a simple model of distributed multi-agent multi-issued contract negotiation for open systems where interactions are competitive and information is private and not shared. We then investigate via simulations two different approximate optimization strategies and quantify the contribution and costs of each towards the quality of the solutions reached. To evaluate the role of knowledge the obtained results are compared to more cooperative strategies where agents share more information. Interesting social dilemmas emerge that suggest the design of incentive mechanisms.
Crossatron switch as thyratron replacement in high repetition rate, high average power modulators

Four prototype crossatron devices were evaluated with respect to their performance and lifetime in high-repetition-rate, high-average-power pulse modulators that had previously been equipped with hydrogen thyratrons. Various grid-drive, keep-alive power levels and triggering schemes were used in the tests. Switch parameters such as trigger time, anode fall time, jitter recovery time, peak di/dt, switch efficiency, and the gas pumping effect of the discharge were observed. One crossatron prototype was also subjected to lifetime tests that accumulated tens of billions of pulses. Lifetime data are compared to those of various models tested similarly. It is concluded that the crossatron can be used as an efficient, low-jitter, high-repetition-rate closing switch for high-average-power modulators. The lifetime of the switch appears to be on a par with several thyratrons of similar rating. >
Elucidation of the role of peptide linker in calcium-sensing receptor activation process.

Abstract Family 3 G-protein-coupled receptors (GPCRs), which includes metabotropic glutamate receptors (mGluRs), sweet and “umami” taste receptors (T1Rs), and the extracellular calcium-sensing receptor (CaR), represent a distinct group among the superfamily of GPCRs characterized by large amino-terminal extracellular ligand-binding domains (ECD) with homology to bacterial periplasmic amino acid-binding proteins that are responsible for signal detection and receptor activation through as yet unresolved mechanism(s) via the seven-transmembrane helical domain (7TMD) common to all GPCRs. To address the mechanism(s) by which ligand-induced conformational changes are conveyed from the ECD to the 7TMD for G-protein activation, we altered the length and composition of a 14-amino acid linker segment common to all family 3 GPCRs except GABAB receptor, in the CaR by insertion, deletion, and site-directed mutagenesis of specific highly conserved residues. Small alterations in the length and composition of the linker impaired cell surface expression and abrogated signaling of the chimeric receptors. The exchange of nine amino acids within the linker of CaR with the homologous sequence of mGluR1, however, preserved receptor function. Ala substitution for the four highly conserved residues within this amino acid sequence identified a Leu at position 606 of the CaR critical for cell surface expression and signaling. Substitution of Leu606 for Ala resulted in impaired cell surface expression. However, Ile and Val substitutions displayed strong activating phenotypes. Disruption of the linker by insertion of nine amino acids of a random-coiled structure uncoupled the ECD from regulating the 7TMD. These data are consistent with a model of receptor activation in which the peptide linker, and particularly Leu606, provides a critical interaction for the CaR signal transmission, a finding likely to be relevant for all family 3 GPCRs containing this conserved motif.
An external focus of attention enhances manual tracking of occluded and visible targets.

The present study investigated the enhancement effects of an external focus-of-attention (FOA) in the context of a manual-tracking task, in which participants tracked both visible and occluded targets. Three conditions were compared, which manipulated the distance of the FOA from the participant as well as the external/internal dimension. As expected, an external FOA resulted in lower tracking errors than an internal FOA. In addition, analyses of participants' movement patterns revealed a systematic shift toward higher-frequency movements in the external FOA condition, consistent with the idea that an external FOA exploits the natural movement dynamics available during skilled action. Finally, target visibility did not influence the effect of focused attention on tracking performance, which provides evidence for the proposal that the mechanisms that underlie FOA do not depend directly on vision.
Effects of Species, Density, Patch-type, and Season on Post-dispersal Seed Predation in a Puerto Rican Pasture1

An experimental study of seed removal of four woody species in an abandoned pasture revealed significant main effects of species, density (higher densities survived more than lower densities), and patch-type (seeds under shrub patches survived more than in grass patches), but no effects of season. Rates of seed loss decreased with seed size across species. Significant interactions between species and density and between species and patch-type were also observed.
On the Relationships and Adaptations of Kenyapithecus, a Large-Bodied Hominoid from the Middle Miocene of Eastern Africa

The phylogenetic relationships and adaptations of Kenyapithecus have been of special interest since Leakey (1962, p. 696) first described the genus as possessing a number of characters exhibiting “a marked tendency in the direction of the Hominidae.” Expectations regarding the hominid affinities of Kenyapithecus influenced the reconstruction of many functionally and phylogenetically significant aspects of its anatomy in the absence of tangible fossil evidence. The type species Kenyapithecus wickeri is represented by four jaw fragments, 11 isolated teeth, and a distal humerus collected from a single site, Fort Ternan (Pickford, 1985). As of 1985, the hypodigm of the referred species Kenyapithecus africanus consisted of the type maxilla together with 46 isolated teeth, four incomplete postcranial pieces, and a poorly preserved mandible collected from the Maboko Formation and an isolated lower molar from Nyakach (Pickford, 1985). Features for which little or no fossil evidence existed, but which Kenyapithecus was said to share with hominids, include: small lower incisors relative to cheek tooth size, reduced incisor procumbency, arcuate dental arcade, short rostrum, and a humerus that is longer than the femur (Simons and Pilbeam, 1972). The supposed reduction in upper canine and lower incisor size, and facial abbreviation, in combination with thickenameled molars in Kenyapithecus was interpreted as being related to an australopithecine-like emphasis on molar grinding resulting from the consumption of hard objects (Andrews and Walker, 1976), with incisors being “relatively unimportant in food preparation” (Simons and Pilbeam, 1978, pp. 149, 152).
Interleukin-17 Could Promote Breast Cancer Progression at Several Stages of the Disease

Metastatic disease accounts for more than 90% of deaths from breast cancer. Yet the factors that trigger metastasis, often years after primary tumor removal, are not understood well. Recently the proinflammatory cytokine interleukin- (IL-) 17 family has been associated with poor prognosis in breast cancer. Here we review current literature on the pathogenic mechanisms driven by IL-17 during breast cancer progression and connect these findings to metastasis. These include (1) direct effects of IL-17 on tumor cells promoting tumor cell survival and invasiveness, (2) regulation of tumor angiogenesis, and (3) interaction with myeloid derived suppressor cells (MDSCs) to inhibit antitumor immune response and collaborate at the distant metastatic site. Furthermore, IL-17 might also be a culprit in bone destruction caused by late stage bone metastasis. Interestingly, in addition to these potential prometastasis functions, there is also evidence for an opposite, antitumor role of IL-17 during cancer therapies. We hypothesize that these contradictory roles may be due to chronic, imbalanced versus acute transient nature of the immune reactions, as well as differences in the cells that interact with IL-17(+) cells under different circumstances.
Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene

Transgenic mice were generated containing a cytomegaloviral promoter driven construct (CMV43) expressing the gap junction polylpeptide connexin 43. RNA and protein analysis confirmed that the transgene was being expressed. In situ hybridization analysis of embryo sections revealed that transgene expression was targeted to the dorsal neural tube and in subpopulations of neural crest cells. This expression pattern was identical to that seen in transgenic mice harboring other constructs driven by the cytomegaloviral promoter (Kothary, R., Barton, S. C., Franz, T., Norris, M. L., Hettle, S. and Surani, M. A. H. (1991) Mech. Develop. 35, 25–31; Koedood, M., Fitchel, A., Meier, P. and Mitchell, P. (1995) J. Virol. 69, 2194–2207), and corresponded to a subset of the endogenous Cx43 expression domains. Significantly, dye injection studies showed that transgene expression resulted in an increase in gap junctional communication. Though viable and fertile, these transgenic mice exhibited reduced postnatal viability. Examination of embryos at various stages of development revealed developmental perturbations consisting of cranial neural tube defects (NTD) and heart malformations. Interestingly, breeding of the CMV43 transgene into the Cx43 knockout mice extended postnatal viability of mice homozygote for the Cx43 knockout allele, indicating that the CMV43 trangsene may partially complement the Cx43 deletion. Both the Cx43 knockout and the CMV43 transgenic mice exhibit heart defects associated with malformations in the conotruncus, a region of the heart in which neural crest derivatives are known to have important roles during development. Together with our results indicating neural-crest-specific expression of the transgene in our CMV-based constructs, these observations strongly suggest a role for Cx43-mediated gap junctional communication in neural crest development. Furthermore, these observations indicate that the precise level of Cx43 function may be of critical importance in downstream events involving these migratory cell populations. As such, the CMV43 mouse may represent a powerful new model system for examining the role of extracardiac cell populations in cardiac morphogenesis and other developmental processes.
Analysis of passive thermal storage opportunities for heating system design

Heating and cooling load calculations are critical to size HVAC systems and determine energy use of their operations. The ASHRAE recommended heating load calculation model is most commonly used for heating load calculations. It adopts a simplified approach by considering only steady-state conductive heat transfer. However, due to thermal storage effect, heat generated in daytime may still be stored in buildings and released at a later time. Such assumption leads to significantly over-sized heating systems which are usually accompanied by high initial cost and higher cost of energy use. This study therefore examines the thermal response and passive storage characteristic of heavy construction for typical office building in continental United States. By allowing space air to drift to reasonably lower values, buildings need to be warmed up before being occupied in the morning. The worst case conditions might happen during warm-up or beginning of occupied hours. This article evaluates the optimal size of heat...
Improved Fog Collection Using Turf Reinforcement Mats

AbstractImpoverished communities are particularly vulnerable to increasing water scarcity. The development of low-cost technologies that improve access to unconventional water sources, such as the freshwater contained in fog, is one way to address water scarcity. Passive fog collectors, sited to maximize exposure to orographic and advection fog, are typically constructed using 35% Raschel mesh stretched within a structural frame. To assess improvements to this technology, the fog collection potential of nonwoven turf reinforcement mats (TRM), underwent preliminary testing in a laboratory fog tunnel and more conclusive testing at a field site in Lima, Peru. In fog tunnel tests, both of the two tested TRM specimens increased fog collection yields over 35% Raschel mesh by 26 and 33% respectively. At one field site, the tested mats increased fog collection yields over 35% Raschel mesh by 62 and 75% respectively. At a second field site, these materials increased collection volumes over the 35% Raschel mesh by ...
Prospective study of plasma urate and risk of Parkinson disease in men and women.

Objective: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate–PD relationship. Methods: We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. Results: In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; p trend = 0.049) in men and 1.04 (95% CI 0.61, 1.78; p trend = 0.44) in women ( p heterogeneity = 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women. Conclusion: We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease.