cssi/SciSciGPT-SciSciNet huggingface dataset:
Bone tissue specific transcriptional control: options for targeting gene therapy to the skeleton.

BACKGROUND The transplantation of multipotential bone marrow cells containing bone tissue specific promoter-controlled transgenes provides an efficacious approach to deliver therapeutic gene expression to osteoblasts for the treatment of patients with bone disorders or tumor metastasis to the skeleton. The specificity of tissue-restricted gene therapy can be refined by utilization of a 31-amino-acid segment of the hematopoietic and osteogenic AML/CBF transcription factors that direct the regulatory proteins to subnuclear sites that support gene expression. METHODS Unfractionated adherent bone marrow cells from transgenic mice constructed with the proximal 1.7 kb of the osteocalcin gene promoter fused to a CAT reporter were transplanted by intravenous infusion. Engraftment and expression at the single-cell level within the context of tissue organization was established by immunohistochemistry using an anti-CAT antibody. Sequences that support the intranuclear trafficking of AML/CBF transcription factors to subnuclear sites that support transcription were determined by the expression and visualization of mutated and epitope tagged AML/CBF proteins. RESULTS Immunohistochemical staining of an extensive series of tissue sections from mice posttransplantation using an anti-CAT antibody indicated that CAT-positive osteoblasts and osteocytes were present in bone sections. These findings indicate that donor bone marrow-derived cells engraft in bone tissue in an environment that supports maturation to the developmental stage at which a bone specific osteocalcin promoter is transcriptionally active. Characterization of functional domains in AML/CBF transcription factors has established that there are at least two regulated events that are required for targeting the factors to transcriptionally active nuclear domains: A nuclear localization signal in the amino terminal region controls nuclear import and retention, and a nuclear matrix targeting signal in the carboxyl region controls association with nuclear matrix-linked sites where transcription occurs. CONCLUSIONS The specificity of hematopoietic and bone phenotypic promoters, together with the additional level of specificity inherent in the AML/CBF family of hematopoietic and osteogenic intranuclear targeting signals, offers viable options for constructing gene therapy regimens that are targeted to the skeleton for the control of metastatic disease. It is realistic to anticipate that, as additional parameters of gene regulatory mechanisms are defined, particularly components of transcriptional control that are operative within a three-dimensional context of nuclear architecture, opportunities for enhancing the effectiveness of treating patients with tumors that metastasize to bone will be extended. Cancer 2000;88:2899–902. © 2000 American Cancer Society.
The Effects of a Group Supervision Intervention to Promote Wellness and Prevent Burnout

The authors evaluated the effects of a wellness intervention in group supervision on wellness and burnuot in counselors-in-training (n = 88). They found no differences between the treatment and control group at posttest. Additionally, Coping Self was negatively related to the Emotional Exhaustion subscale. The authors discuss results and implications for counselor education and supervision.
Assessment of the Effectiveness of the N.Y. State Drug Curriculum Guide with Respect to Drug Attitudes

The major purpose of this investigation was to assess the effectiveness of the revised edition of the New York State Curriculum Guide with respect to the affective domain dealing with the drug topic. Drug attitude test score comparisons were made between high school students who received the Curriculum Guide program and comparable students receiving a traditional program. Results of the attitude scores between the two groups evidenced a significantly higher score for the experimental group. However, closer analysis revealed that the program seemed to be effective for males but not females.
A statistical toolbox for metagenomics: assessing functional diversity in microbial communities

The 99% of bacteria in the environment that are recalcitrant to culturing have spurred the development of metagenomics, a culture-independent approach to sample and characterize microbial genomes. Massive datasets of metagenomic sequences have been accumulated, but analysis of these sequences has focused primarily on the descriptive comparison of the relative abundance of proteins that belong to specific functional categories. More robust statistical methods are needed to make inferences from metagenomic data. In this study, we developed and applied a suite of tools to describe and compare the richness, membership, and structure of microbial communities using peptide fragment sequences extracted from metagenomic sequence data. Application of these tools to acid mine drainage, soil, and whale fall metagenomic sequence collections revealed groups of peptide fragments with a relatively high abundance and no known function. When combined with analysis of 16S rRNA gene fragments from the same communities these tools enabled us to demonstrate that although there was no overlap in the types of 16S rRNA gene sequence observed, there was a core collection of operational protein families that was shared among the three environments. The results of comparisons between the three habitats were surprising considering the relatively low overlap of membership and the distinctively different characteristics of the three habitats. These tools will facilitate the use of metagenomics to pursue statistically sound genome-based ecological analyses.
Exact finite-range DWBA treatment of heavy-ion-induced reactions to unbound residual states

Abstract We show that when one considers heavy-ion-induced direct nuclear reactions, the narrowly localized reaction surface makes a traditional approximation used in analysis of light-ion reactions to particle-unbound states a very poor one. Even for unbound states having single-particle widths 10 −5 of their resonance energies, quite different heavy-ion angular distributions are predicted using weakly-bound states versus more realistic complex-energy eigenstates (Gamow states).
A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine

Ischemia-reperfusion injury has been implicated as playing a major role in the development of necrotizing enterocolitis, a major cause of morbidity and mortality in the newborn. A tungsten-supplemented molybdenum-free diet can reduce xanthine oxidase (XO) enzyme activity in the intestine, which in turn reduces the generation of oxygen radicals after an ischemia-reperfusion insult. This study evaluated the ability of this diet to be effective by indirect means, ie, transplacental and breast-feeding routes. XO activity of the intestine was measured in three groups of CD-1 white rats: I, weanlings fed the tungsten diet or standard chow for 1 week; II, 1-day-old rat pups whose mothers were maintained on the tungsten or standard chow for 7 to 10 days prior to term; and III, rat pups at 1 and 3 weeks after birth whose lactating mothers were maintained on the tungsten or standard chow. Some animals from group III also underwent either a 30- or 60-minute episode of occlusion of the superior mesenteric artery (SMA) to evaluate the protective effects of the diet. XO activity was significantly reduced in all groups receiving the tungsten diet (P less than .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P less than .05) and fibrosis (P less than .0001) in the tungsten-treated group than in the controls. In the 60-minute occlusion study all tungsten-group animals survived, whereas 7 of 12 in the control group died of intestinal infarction within 24 hours (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Exploratory behavior in active learning: : A between- and within-person examination

Abstract Despite being central to active learning theory, surprisingly little research has directly examined the antecedents and outcomes of exploratory behavior. This laboratory study addressed this gap using repeated measures to examine the role and dynamics of exploration in complex task learning. Findings showed task exploration was beneficial across a variety of learning outcomes. Dynamic effects were also observed: (a) exploration was positively related to practice performance at both between- and within-person levels, (b) exploration decreased across practice trials, and (c) decreases in exploration were mitigated by pre-training task-related knowledge. Although general mental ability (GMA) and pre-training task-related knowledge both exhibited effects on exploration, effects were stronger for pre-training task-related knowledge. Neither moderated the link between exploration and learning. Error framing moderated the GMA–exploration relationship such that higher-GMA learners explored more under approach versus avoid conditions. Results are discussed with respect to criticisms of discovery-based learning and implications for active learning.
Nucleon-nucleus inelastic scattering using a relativistic impulse approximation with exchange.

We formulate a microscopic relativistic treatment of nucleon-nucleus inelastic scattering in a distorted wave impulse approximation. The interaction is taken from a Lorentz invariant formulation with explicit direct and exchange terms constrained by fitting to experimental NN amplitudes. This procedure allows us to apply the theory in the lower range of intermediate energies (100--400 MeV) where exchange effects are likely to be important. Application to inelastic scattering uses this interaction for both the distorting potentials and the transition interaction. Effects of explicit exchange are studied and a preliminary analysis of $^{12}\mathrm{C}$(p,p') data is presented.
A Tale of Two Tests: tensions in assessment policy

Abstract A comparison of assessment policy in England and Vermont suggests the utility of viewing the assessment development process as resulting from the interplay of three loosely related games: policy making, assessment, and teaching. This process is characterized by two universal tensions. The technical one stems from the need to reconcile the goals of instructional improvement and accountability. The political tension stems from the differences in perspectives of policy makers, educationists, and educators. How tensions are resolved depends on the size of the unit, the introduction of broader ideological issues into the debate, and the quality of communication within and across games.
Wavelet coefficient analysis for the quantitative determination of damage in tendons and cables

Wires, bars, multi-wire strands made of steel or composite materials are widely used in civil infrastructures as tensioning members in cable-stayed bridges, suspension bridges and prestressed concrete. The health monitoring of these components is a long-standing challenge in the NDE community. In the last few years, the authors have been conducting a study on the application of ultrasonic guided waves for the structural health monitoring of bars and multi-wire strands. This paper presents an application of a signal processing technique based on the Discrete Wavelet Transform (DWT) for the detection and the quantification of damage (in the form of small notches) in loaded seven-wire steel strands. The DWT is applied to ultrasonic signals generated and detected via magnetostrictive transducers. The detection and the quantification of damage in the strands are accomplished by constructing and computing a damage index based on the variance and the root mean square of the wavelet coefficient vector of the ultrasonic damage signatures. It is shown that the logarithmic value of the damage index is linearly dependent on the damage size. In the last portion of the paper an eight-dimensional damage index is constructed and it is fed to an artificial neural network that classifies the size and the location of the notch.
Partial discharge monitoring in dielectric elastomer actuators

Dielectric elastomer actuators represent an interesting use of dielectric materials for two reasons. First, being a soft material that is designed to exert mechanical strains, the aging and dielectric breakdown mechanisms are often the result of mechanical phenomena less common in other high voltage insulating systems that use rigid dielectrics selected solely for their electrical properties. Secondly, these systems are rather unique in that realtime insulation health monitoring can provide meaningful insights to extend the working life of the system. Like most high voltage systems, dielectric breakdown results in the irreversible and catastrophic failure of the system. However, since the system can be used at lower operating voltages, albeit at a lower effectiveness, if the operating voltage can be lowered as the dielectric shows signs of aging, the useful life of the system can be extended. Partial discharge testing has been used to assess the health of the polymer films used in these systems, and the procedures for real-time monitoring of partial discharges are explored in this paper.
Exploring the Effects of Mood Checklist Pretesting on Experimental Mood Induction Procedures

Research was conducted to investigate the potential impact of mood checklist (MAACL) pretesting upon the Velten experimental mood induction procedure. Multivariate analyses (MANOVA and ANCOVA) of the three MAACL subscales (Depression, Anxiety, and Hostility) suggest that variance unique to Anxiety, and that shared between Anxiety and the other subscales, is affected by pretesting, including both a main effect and a pretesting X Velten interaction. In contrast, the Velten manipulation impacted only variance unique to Depression and variance shared between Depression and the other two subscales. Apart from their significance for mood induction research, these findings provide rare evidence for the discrimination validity of the MAAACL subscales. Implications of these findings are discussed along with methodological suggestions for future studies.
Quantitative interpretation of lumbar muscle myoelectric signals during rapid cyclic attempted trunk flexions and extensions

The quantitative relationship between lumbar myoelectric signals (MES) and rapidly varying isometric trunk muscle forces was investigated. Ten young adult males were asked to cycle harmonically between attempted trunk flexion and attempted trunk extension in an upright position at rates of 0.33,0.67 and 1.0 Hz to peak efforts of 20, 40 and 60% of maximum voluntary exertion levels. The forces voluntarily exerted against a load cell were measured and used along with acquired kinematic data to calculate the time course of the net sagittal moment at the level of the third lumbar vertebra during task performances. A 22 muscle double linear programming biomechanical model was used to predict the lumbar trunk muscle contraction forces from the calculated moments. Rectified and bidirectionally low-pass filtered myoelectric activities were acquired at the L3 level from four abdominal muscles and four back muscles. The processed MES were found to be well correlated (r10.90) with predicted muscle forces when the MES were time-shifted to account for electromechanical delay as well as the dynamic phase shift between muscle electrical activity and contraction force. Mean time shifts that maximized the linear MES-force relationship ranged from 111 to 218 ms, were greater for the trunk extensors than the trunk flexors and generally exhibited lateral symmetry. The corresponding approximate phase angles averaged 20" at the slowest rate and 50" at the fastest rate. MES-force phase angles decreased as effort level was increased indicating that the dynamic MES-force relationship is nonlinear. These results illustrate the importance of accounting for the phase lag between muscle electrical activity and force when using MES to quantify muscle loads during rapidly varying exertions.
Discovering Social Circles in Directed Graphs

We examine the problem of identifying social circles, or sets of cohesive and mutually aware nodes surrounding an initial query set, in directed graphs where the complete graph is not known beforehand. This problem differs from local community mining, in that the query set defines the circle of interest. We explicitly handle edge direction, as in many cases relationships are not symmetric, and focus on the local context because many real-world graphs cannot be feasibly known. We outline several issues that are unique to this context, introduce a quality function to measure the value of including a particular node in an emerging social circle, and describe a greedy social circle discovery algorithm. We demonstrate the effectiveness of this approach on artificial benchmarks, large networks with topical community labels, and several real-world case studies.
Role of gene regulation in song circuit development and song learning

songbirds, ordinary song-related activities such as ABSTRACT: The songbird has emerged as an im- singing and listening cause dramatic increases in gene portant model for study of brain-behavior relation- expression in brain areas specific to each activity. The ships by virtue of its rich natural advantages and from
Postendarterectomy Common Carotid Artery Pseudoaneurysm

Pseudoaneurysm (PSA) formation is an uncommon complication in carotid surgery. PSA of the carotid artery requires surgical or endovascular treatment to prevent PSA thrombosis, embolization from the thrombotic material within the PSA, hemorrhage after rupture, or compression on the adjacent structures. We present a case of a symptomatic common carotid PSA that occurred 14 months after routinely performed eversion carotid endarterectomy.
The Burroughs Wellcome Career Award in the Biomedical Sciences: challenges to and prospects for estimating the causal effects of career development programs.

The Career Award in Biomedical Sciences (CABS) was launched by the Burroughs Wellcome Fund to assist talented scientists to cross the “bridge” that connects postdoctoral training with independent i...
Incorporation of Molecular Oxygen during Microbial Utilization of Olefins

THE utilization of various alkanes by certain bacteria involves the incorporation of molecular oxygen into the conversion products1 and into the bacterial cells2. The attack of the olefin 1-hexadecene at the saturated end of the molecule3 probably is not different from that of the alkanes. Instances where the oxidative attack occurs at the double bond in olefins3,4 have now been examined with the use of oxygen-18. Also, the cells of an ethylene-utilizing bacterium were analysed similarly.
Prairiegrass–Brassica Hybrid Swards for Autumn Dry Matter Production

Stockpiling herbage can redistribute nutrient availability and supplement quantity for livestock, depending on production objectives. Brassicas (Brassica spp.) and improved prairiegrass (Bromus catharticus Vahl.) cultivars are adapted to growing conditions occurring in the Appalachian region and provide nutritionally valuable herbage in autumn; however, highly digestible brassica herbage may require supplementation with a fibrous companion species for efficient rumen microbe function and nutrient use by grazers. A prairiegrass– brassica hybrid [B. rapa L. 3 B. rapa subsp. pekinensis (Lour.) Hanelt.] mixture and pure stands of each were established to determine productivity and nutritive value of stockpiled stands in autumn. Field plots were established in late June of 2003 and 2004, and clipping began 74 and 63 d after planting, respectively. Prairiegrass coestablished with brassica hybrid and could be harvested in the establishment year. Sown species and year interacted to influence stand composition, dry matter productivity, and nutritive value. Dry conditions occurred shortly after planting in 2003 and slowed brassica hybrid establishment and productivity. Total dry matter varied for monospecificandmixedstands ofprairiegrassandbrassica hybrid each year, as did distribution during the season. Nutritive value varied with years and met or exceeded values suggested for efficient rumen microbe function. Herbage growth continued for about 80 d after the first clip in early September for all sward types and demonstrated the compatibility of co-seeded prairiegrass and brassica hybrid as well as the suitability of the mixture to provide adequate herbage mass and nutritive value when stockpiled in autumn.
Does external tocodynamometry increase maternal perception of uterine contractions

A prospective study was performed on 63 women at risk for preterm delivery who recorded maternally perceived contractions for 1 hour before and after placement of an external tocodynamometer. Fifteen women had an increase, 11 had a decrease, and 37 had no change (P not significant) in the number of perceived contractions after placement of the tocodynamometer.
Deriving DC Machine Toeque by the Principle of Virtual Work

The purpose of this paper is to fill a gap which exists in the "textbook" theory of dc machines. The paper shows that the usual expression for dc machine torque can be obtained from the direct application of the principle of virtual work to the machine, making the traditional assumptions. The method provides additional benefits in that it demonstrates the reluctance torque which results from the saliency of the field structure and shows that compensating windings have no effect on the torque under the assumed linear conditions.
Bullous Pulmonary Damage in Users of Intravenous Drugs

Among a large group of users of illicit intravenous drugs, the incidence of bullous pulmonary damage was noted to be 2 percent (6/387). Bullous damage was significantly different in the drug users than in those who did not use drugs. The drug users were significantly younger than the nonusers, their bullae were large and confined to the upper lobes, and alpha 1-antitrypsin deficiency was very unlikely. These features strongly implicate intravenous drug abuse in the pathogenesis of these patients' bullous pulmonary damage.
Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases

Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.
The use of robots in the undergraduate curriculum: experience reports

Using the robot as a metaphor for assisting students in understanding problem solving in general, the algorithmic process, and the relationship between algorithms and computing agents is not new. While simulated robot environments have existed for many years (e.g. Karel the Robot[3]) it is only recently that the technology for inexpensively supplying undergraduates with real robots has become available. Lego Mindstorms, MIT Handyboards, the Rug Warrior, and others are examples of such systems. Programmable in familiar languages, including C, Ada, and Java, these systems allow for the creative exploration of important computer science concepts. Representing a variety of institution types the panelists will discuss their experiences in using hands-on robot-based projects for illustrating various important computer science concepts.
Runoff of pyrethroid insecticides from concrete surfaces following simulated and natural rainfalls.

Abstract Intensive residential use of insecticides has resulted in their ubiquitous presence as contaminants in urban surface streams. For pest eradication, urban hard surfaces such as concrete are often directly treated with pesticides, and wind/water can also carry pesticides onto hard surfaces from surrounding areas. This study expanded on previous bench-scale studies by considering pesticide runoff caused by irrigation under dry weather conditions and rain during the wet season, and evaluated the effects of pesticide residence time on concrete, single versus recurring precipitations, precipitation intensity, and concrete surface conditions, on pesticide transferability to runoff water. Runoff from concrete 1 d after pesticide treatment contained high levels of bifenthrin (82 μg/L) and permethrin (5143 μg/L for cis and 5518 μg/L for trans ), indicating the importance of preventing water contact on concrete after pesticide treatments. Although the runoff transferability quickly decreased as the pesticide residence time on concrete increased, detectable residues were still found in runoff water after 3 months (89 d) exposure to hot and dry summer conditions. ANOVA analysis showed that precipitation intensities and concrete surface conditions (i.e., acid wash, silicone seal, stamping, and addition of microsilica) did not significantly affect the pesticide transferability to runoff. For concrete slabs subjected to natural rainfalls during the winter wet season, pesticide levels in the runoff decreased as the time interval between pesticide application and the rain event increased. However, bifenthrin and permethrin were still detected at 0.15–0.17 and 0.75–1.15 μg/L in the rain runoff after 7 months (221 d) from the initial treatment. In addition, pesticide concentrations showed no decrease between the two rainfall events, suggesting that concrete surfaces contaminated by pesticides may act as a reservoir for pesticide residues, leading to sustained urban runoff contamination.
Simulation and analysis of switched capacitor dc-dc converters for use in battery electric vehicles

This paper presents a switched capacitor dc-dc converter based electric drive system for battery electric vehicles. The main idea is to replace the traditional IGBT boost converter by modular battery cell tied MOSFET switched capacitor converters. The system topology is presented, including the drive train architecture. The modeling approach for each electrical component, including the battery set, dc-dc and dc-ac converters, ac machines, and their control is discussed. Upon successful simulations, various efficiency analyses are performed. Finally, potential hardware implementation, including economic and spacing constraints, is discussed.
Modeling For Forecasting Versus Modeling for Understanding: Observations from Energy Planning

The majority of energy modeling has been conducted for the purpose of forecasting the future. The experience has been, for the most part, a long record of erroneous forecasts misleading to public and private sector policymaking. An alternative use of models is for understanding and expansion of community debate. This article delineates some of the distinguishing features of the two modeling approaches and compares three sets of energy scenarios, generated in the mid-1970s using models developed as tools for understanding, to sets of energy forecasts. Comparisons are made for electricity and transportation energy use in Wisconsin and total primary energy for the U.S. Using the criteria of which of the two approaches has more closely matched actual outcomes, the modeling for understanding approach appears to be superior. Other advantages to a modeling for understanding approach are described, as are implications for planning education and practice.
New correlation functions for multi-particle processes

Abstract We propose a new family of correlation functions for the study of multi-particle processes, the “split-bin” correlation functions. Split-bin correlation functions are similar to scaled factorial moments, but they are less susceptible to some systematic errors, such as double-counting of particles. Unlike scaled factorial moments, split-bin correlation functions can be constructed using continuous variables, such as transverse energy. They can also be used to help differentiate between correlations due to jet-like and resonance-like sources.
Methotrexate, hydroxyurea, and vincristine: Combination chemotherapy in squamous carcinoma of the female genitalia

Abstract Concurrent multiple drug regimens have proved superior to single agent therapy in a number of malignancies. Currently available oncolytic agents when used alone have been largely ineffective in managing recurrent and disseminated squamous carcinoma of the female genitalia. Rationally designed combination drug therapy could produce improved objective and subjective benefits for these patients. The results obtained in 15 evaluable patients treated with systemic methotrexate, hydroxyurea, and vincristine are presented and discussed. Only one objective response was obtained. The problems of managing recurrent cervical carcinoma with drug therapy are reviewed.
Some consequences of the increasing number of female American dentists.

In addition to the changing realities for dental services caused by governmental legislative and agency pronouncements, consumer activists, and an assortment of other factors, the increasing percentage of women dental practitioners could have one of the more significant long-term effects on the manner in which the profession provides services.
Region specific expression of NMDA receptor NR1 subunit mRNA in hypothalamus and pons following chronic morphine treatment

The NMDA receptor has been implicated in opioid tolerance and physical dependence. Using in situ hybridization techniques, the effects of chronic morphine treatment on the expression of mRNAs encoding the NMDA receptor subunits NR1, NR2A, and NR2B were investigated. A significant increase in the level of the NR1 subunit mRNA was found in the locus coeruleus and the hypothalamic paraventricular nucleus following 3 days of intracerebroventricular (i.c.v.) morphine infusion (26 nmol μl−1 h−1) through osmotic minipumps. No changes were detected in expression of the NR1 mRNA in the frontal cortex, caudate–putamen, nucleus accumbens, amygdala, CA1, CA2, and the dentate gyrus of the hippocampus, and in the central grey after morphine treatment. The expression of NR2A and NR2B subunit mRNAs did not change after morphine treatment in any brain region. These results suggest that changes in gene expression of the NR1 subunit of the NMDA receptor are involved in the development of morphine tolerance and dependence.
Molecular Biology of Chronic Thromboembolic Pulmonary Hypertension

Recent efforts have seen major advances in elucidating the mechanisms underlying pulmonary arterial hypertension. However, chronic thromboembolic pulmonary hypertension (CTEPH) often has been excluded from these studies. Consequently, whereas the clinical, radiographic, and hemodynamic characteristics of CTEPH have been well described, there remains a deficit in our understanding of the cellular, molecular, and genetic mechanisms underlying CTEPH. Furthermore, although prior venous thromboembolism may act as the inciting event, it is still unclear what predisposes some patients to develop CTEPH. CTEPH has two major pathogenic components. The first is the primary obstruction of central pulmonary arteries by accumulation of thrombotic material. The second is characterized by severe pulmonary vascular remodeling, similar to that seen in idiopathic pulmonary arterial hypertension. Other articles in this series describe the pathological, surgical, and therapeutic aspects of CTEPH. Here, we review the potential molecular and cellular mechanisms that may contribute to the pathogenesis of CTEPH.
Calpain Regulates Actin Remodeling during Cell Spreading

Previous studies suggest that the Ca2+-dependent proteases, calpains, participate in remodeling of the actin cytoskeleton during wound healing and are active during cell migration. To directly test the role that calpains play in cell spreading, several NIH-3T3– derived clonal cell lines were isolated that overexpress the biological inhibitor of calpains, calpastatin. These cells stably overexpress calpastatin two- to eightfold relative to controls and differ from both parental and control cell lines in morphology, spreading, cytoskeletal structure, and biochemical characteristics. Morphologic characteristics of the mutant cells include failure to extend lamellipodia, as well as abnormal filopodia, extensions, and retractions. Whereas wild-type cells extend lamellae within 30 min after plating, all of the calpastatin-overexpressing cell lines fail to spread and assemble actin-rich processes. The cells genetically altered to overexpress calpastatin display decreased calpain activity as measured in situ or in vitro. The ERM protein ezrin, but not radixin or moesin, is markedly increased due to calpain inhibition. To confirm that inhibition of calpain activity is related to the defect in spreading, pharmacological inhibitors of calpain were also analyzed. The cell permeant inhibitors calpeptin and MDL 28, 170 cause immediate inhibition of spreading. Failure of the intimately related processes of filopodia formation and lamellar extension indicate that calpain is intimately involved in actin remodeling and cell spreading.
Nitrogen-containing compounds in two CR2 meteorites: 15N composition, molecular distribution and precursor molecules

Abstract Amino acids, amines and aldehydes were obtained from the water extracts of two CR2 carbonaceous chondrites from Antarctica and analyzed for their molecular and 15 N isotopic content. These compounds were found to differ significantly from those of CM chondrites in both overall abundances and molecular distribution. The amino acids suites comprise a preponderant abundance of linear, 2-H amino acids, show rapid non-linear decrease with the compounds’ increasing chain length and include protein amino acids never identified in meteorites before, such as threonine, tyrosine and phenylalanine. The presence of tertiary amines as well as a diverse, large abundance of aldehydes and ketones also distinguishes both CR2 organic suites. The δ 15 N values determined for CR2 amino acids have a distribution between molecular subgroups that is opposite to the one of their δD values, with 2-H amino acids having higher δ 15 N and lower δD values than 2-methyl amino acids, while the opposite is true for 2-methyl amino acids. Based on theoretical data, these isotopic findings would place the formation of the two amino acid groups or their direct precursors at different ISM stages of star formation.
Identification of GABAA/Benzodiazepine Receptors on Clathrin‐Coated Vesicles from Rat Brain

To investigate the subcellular compartments that are involved in the endocytosis and intracellular trafficking of GABAA/benzodiazepine receptors, we have studied the distribution and properties of clonazepam-displaceable binding of [3H]flunitrazepam to membrane fractions from rat brain. The microsomal fraction was subjected to density centrifugation and gel filtration to isolate clathrin-coated vesicles. Homogeneity of the coated-vesicle fraction was demonstrated by using electron microscopy and by analysis of clathrin subunits and clathrin light-chain kinase. Vesicles exhibiting specific binding of [3H]flunitrazepam eluted from the sieving gel as a separate peak, which was coincident with that for coated vesicles. Scatchard analysis of equilibrium binding of [3H]flunitrazepam to coated vesicles yielded a KD value of 21 +/- 4.7 nM and a Bmax value of 184 +/- 28 fmol/mg. The KD value for coated vesicles was 12-19-fold that found with microsomal or crude synaptic membranes. This low-affinity benzodiazepine receptor was not identified on any other subcellular fraction and thus appears to be a novel characteristic of coated vesicles. The Bmax value for coated vesicles, expressed per milligram of protein, corresponded to 16 and 115% of that found for crude synaptic and microsomal membrane fractions, respectively. Because the trafficking of neurotransmitter receptors via clathrin-coated vesicles is most likely to occur through endocytosis, the data suggest that an endocytotic pathway may be involved in the removal of GABAA/benzodiazepine receptors from the neuronal surfaces of the rat brain. This mechanism could play a role in receptor sequestration and down-regulation that is produced by exposure to GABA and benzodiazepine agonists.
Glucocorticoid Receptors and the Cell Cycle: Evidence that the Accumulation of Glucocorticoid Receptors during the S Phase of the Cell Cycle is Dependent on Ribonucleic Acid and Protein Synthesis

HeLa S3 cells contain high affinity, saturable protein receptor molecules which steriospecifically bind active glucocorticoids. The number of glucocorticoid receptors per cell changes as cells in culture proceed through the cell cycle (1). HeLa S3 cells brought to the GI/S boundary by the double thymidine block procedure undergo a rapid synchronous round of DNA synthesis when released into thymidine-free medium. Analysis of glucocorticoid receptor binding indicates a rapid rise in cellular receptor number when measurements are made in whole cells at either 3 C (cytoplasmic) or 37 C (nuclear). Cytoplasmic receptors are maintained at levels about 150% above late GI values throughout S and GII phases until mitosis occurs, whereas the nuclear binding of hormone is dramatically reduced during GII and remains low during mitosis and early GI. Similar cell cycle-dependent alterations in receptor number occur in synchronized cell populations obtained by unit gravity sedimentation. Sucrose density gradient analysis...
Origin of the late Paleozoic plutonic massifs in Morocco

Throughout northwestern Africa are small (less than 200 km 2 ) late Paleozoic massifs. These are shallowly emplaced into unmetamorphosed Paleozoic sediments and always produce a well-defined contact metamorphic aureole. The Tichka massif is the only well-exposed massif with over 2,000 m of vertical relief developed. In contrast, the other massifs have been barely unroofed. The Tichka massif contains basic rocks surrounding teardrop-shaped granitic pods. At the contact of the massif with the overlying sediments, large masses of granite occur. On the basis of field relationships, two models can be proposed: the rock types are related to a common parent, or the dioritic and granitic magmas are independent melts. A least-squares approximation test, using all available chemical data, is consistent with the latter model. The granitic massifs approximate a “minimum-temperature melt” composition, which suggests that these rocks originate by fractional fusion of the crustal rocks. The heat source is proposed to be caused by emplacement of mantle-derived gabbroic melts. In some massifs the granitic material was generated and emplaced without intermingling with the gabbroic melts, and it is these massifs that are associated with relatively large negative gravity anomalies (−40 mgal). The chemistry and mineralogy of these massifs are statistically identical. In contrast the Tichka and Midelt massifs are not associated with negative gravity anomalies, and the granitic rocks from these two massifs are statistically identical; but each is statistically different from the massifs with negative gravity anomalies. The Tichka massif contains abundant, possibly mantle-derived, basic rocks and it is inferred that the Midelt massif does also. There is no evidence that supports a subduction zone model for the origin of these late Paleozoic massifs. It is proposed that the massifs of Morocco may be a response of the continental crust to initial spreading and rifting of North America from Africa. The origin of the granitic rocks is suggested to be the result of fractional fusion of the lower crust, with the heat source caused by sporadic upwelling of mantle-derived gabbroic material associated with the initial extension and thinning of the lithosphere. On the basis of the ages of these massifs, the initial activity began about 320 m.y. B.P.
EXPERIMENTAL 0$sub 2$$sup +$ (2.12 MeV) $Yields$ 2$sub 1$$sup +$ (1.46 MeV) B(E2) STRENGTH AND PAIRING-VIBRATION CALCULATIONS IN $sup 40$Ar.

The lifetime of the 2.12-MeV ${0}_{2}^{+}$ state in $^{40}\mathrm{Ar}$ has been measured by a $p\ensuremath{-}\ensuremath{\gamma}$ delayed-coincidence technique. This state was populated by the ($p,{p}^{\ensuremath{'}}$) reaction with 5.3-MeV protons bombarding an Ar gas target. A mean lifetime of $\ensuremath{\tau}=150\ifmmode\pm\else\textpm\fi{}20$ psec was obtained for the ${0}_{2}^{+}$ state. This lifetime implies for the ${0}_{2}^{+}$ \ensuremath{\rightarrow} ${2}_{1}^{+}$ transition $B(E2)=42.9\ifmmode\pm\else\textpm\fi{}5.7$ ${\mathit{e}}^{2}$${\mathrm{F}}^{4}$. Pairing-vibration model calculations for $^{40}\mathrm{Ar}$ were made using experimental information regarding energies and $B(E2)$ strengths for the three lowest levels of both $^{42}\mathrm{Ca}$ and $^{38}\mathrm{Ar}$. Three kinds of interaction were considered: first, no interaction; second, a phenomenological quadrupole-quadrupole interaction; and third, the Kuo-Brown bare $G$ matrix elements. None of these calculations can accurately describe both the energy spectrum and the $E2$ transition strengths in $^{40}\mathrm{Ar}$. This result may be an indication of the inadequacy of the pairing-vibration model for $^{40}\mathrm{Ar}$.
Determinants of corporate growth opportunities of emerging firms

Abstract Recently, several questions have been raised about how the market capitalization of young technology firms is determined, even as they continue to generate negative earnings. In this paper we present an empirical analysis of a real options valuation model of intangible assets. Using a sample of 243 Internet and biotech firms, we examine the determinants of growth opportunities of emerging firms. We show that the speed of innovation is a critical determinant of a firm’s market value. We also establish a differential impact of volatility on real growth options. In particular, we find that the value of an at-the-money real growth option rises with higher volatility, whereas the value of a deep in-the-money real growth option is less sensitive to volatility changes.
Seasonal variation of terpenoid constituents in natural populations of juniperus pinchotii sudw

Abstract Foliage samples were taken from sixteen trees in eight natural populations of Juniperus pinchotii Sudw. in July and again in January to determine if seasonal variations occur in the volatile terpenoids and if the summer or winter collections would be more variable. Gas/liquid chromatographic analysis revealed that significant differences do occur from summer to winter in the relative composition of the terpenoids. The summer collections were more variable than the winter collections which indicates the desirability of winter sampling when practical.
A neural network for nonlinear Bayesian estimation in drug therapy

The feasibility of developing a neural network to perform nonlinear Bayesian estimation from sparse data is explored using an example from clinical pharmacology. The problem involves estimating parameters of a dynamic model describing the pharmacokinetics of the bronchodilator theophylline from limited plasma concentration measurements of the drug obtained in a patient. The estimation performance of a backpropagation trained network is compared to that of the maximum likelihood estimator as well as the maximum a posteriori probability estimator. In the example considered, the estimator prediction errors (model parameters and outputs) obtained from the trained neural network were similar to those obtained using the nonlinear Bayesian estimator.
Conceptual Spaces and Pronominal Reference in American Sign Language

American Sign Language uses spatial locations as an integral part of its systems of pronominal reference. Referents mentioned in an ASL discourse may be associated with points in the signing space (“referential loci”). Pronominal signs are directed to those loci, unambiguously indicating their referents. Referential loci are sometimes analyzed as overt phonological representations of the semantic indices associated with referents in the discourse. In this paper I show that referential loci do not function merely to index or identify referents, but rather that they carry a great deal of additional information pertaining to the conceptual location of referents in the discourse space. I examine contexts in which one referent is associated with two distinct loci in the signing space, and offer a preliminary formulation of principles governing locus selection in such contexts.
Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ) peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17–42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.