cssi/SciSciGPT-SciSciNet huggingface dataset:
Effective and Specific Inhibition of the CD40-CD154 Costimulatory Interaction by a Naphthalenesulphonic Acid Derivative

Costimulatory interactions are important regulators of T-cell activation and, hence, promising therapeutic targets in autoimmune diseases as well as in transplant recipients. Following our recent identification of the first small-molecule inhibitors of the CD40-CD154 costimulatory protein-protein interaction (J Mol Med 87, 2009, 1133), we continued our search within the chemical space of organic dyes, and we now report the identification of the naphthalenesulphonic acid derivative mordant brown 1 as a more active, more effective, and more specific inhibitor. Flow cytometry experiments confirmed its ability to concentration-dependently inhibit the CD154(CD40L)-induced cellular responses in human THP-1 cells at concentrations well below cytotoxic levels. Binding experiments showed that it not only inhibits the CD40-CD154 interaction with sub-micromolar activity, but it also has considerably more than 100-fold selectivity toward this interaction even when compared to other members of the tumor necrosis factor superfamily pairs such as TNF-R1-TNF-α, BAFF-R(CD268)-BAFF(CD257/BLys), OX40(CD134)-OX40L(CD252), RANK(CD265)-RANKL(CD254/TRANCE), or 4-1BB(CD137)-4-1BBL. There is now sufficient structure-activity relationship information to serve as the basis of a drug discovery initiative targeting this important costimulatory interaction.
Potential new drug therapies in advanced renal cell carcinoma - an investigation of different combinatory drug regimens on the proliferation of cultured human renal cell carcinoma cells.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5550 Renal cell carcinoma accounts for approximately 2–3% of all malignancies. Contrary to localized disease, which often can be cured by surgery, there is no effective treatment for metastatic renal cell cancer. Due to the lack of clinically relevant antiproliferative drugs, we investigated several combinatory regimens of recently developed drugs. Using UMRC3 cells as a model for metastatic renal cell cancer, we studied the effect of monotherapy compared to that of a combination of Imatinib, 2-Methoxyestradiol (2ME2) and/or 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) on cell proliferation. Due to the different mechanisms of action of these drugs - Imatinib, a receptor tyrosine kinase inhibitor, is known to inhibit the bcr-abl fusion protein, stem-cell factor receptor c-Kit, and platelet derived growth factor receptor (PDGFR) signaling; 2ME2, an estrogen metabolite, inhibits hypoxia-inducible factor-1, a key angiogenic transcription factor and stabilizes microtubules while YC-1 known as an inhibitor of platelet aggregation blocks HIF-1 - we evaluated whether an additive or even synergistic antiproliferative effect could be achieved. We identified doses for which cell proliferation is inhibited by 25%. Using these doses, we found additive inhibitory effects using a combination of Imatinib and YC-1 as well as 2ME2 and YC-1. Synergistic antiproliferative effects could be demonstrated by combining Imatinibwith 2ME2 and all three drugs. Our data indicate a greater efficacy of renal cell cancer inhibition by using combinatory drug therapies compared to a single drug application. Due to the low dosage of each drug, a lower toxicity profile could be assumed. We are currently examining the mechanism of these additive and synergistic activities in vitro and in vivo.
Oyster Utilization and Host Variation of the Oyster Pea Crab (Zaops ostreum)

ABSTRACT The oyster pea crab Zaops ostreum (Say, 1817), is a parasite of the eastern oyster Crassostrea virginica Gmelin (1791). This study examined the frequency of occurrence and impact of pea crabs on adult (50–70 mm shell height [SH]) oysters from natural intertidal reefs in Hewletts Creek, Wilmington, NC and artificially created intertidal reefs from Jones Island, NC. The reefs at Hewletts Creek and Jones Island were also sampled in the fall of 2012 to quantify the presence of pea crabs in two cooccurring bivalve species, the scorched mussel Brachidontes exustus (Linneaus, 1758), and the ribbed mussel Geukensia demissa (Dillwyn, 1817). To evaluate the impact of pea crabs on juvenile oysters (mean SH 11.07 ± 0.16 mm), oysters were deployed in Hewletts Creek at three densities during July 2013 and then retrieved in October 2013. The percent occurrence of pea crabs in adult oysters was low on the natural reefs (1%–3.7%), greater on the created reefs (10%), whereas the percent occurrence in the deployed ...
Considerations in multidimensional filter bank design

The authors exploit a number of issues in multidimensional (MD) filter bank design, including the choice of permissible passband supports, the cyclic property of decimation matrices required for filter bank design using transformations, etc. A class of useful tree-structure filter banks is proposed. These filter banks apply to the commonly-used hexagonal decimation. >
A combinatorial proof of Andrews' partition functions related to Schur's partition theorem

We construct an involution to show equality between partition functions related to Schur's second partition theorem.
GM-CSF and Flt-3 ligand counteract a deficient capacity for respiratory virus-induced IFN-γ production

Abstract Rationale After Sendai virus-induced bronchiolitis as weanlings, BN, unlike F344, rats develop a postbronchiolitis asthma-like phenotype, which is prevented by IFN-γ therapy. Innate mechanisms of Sendai virus-induced IFN-γ production, which are dependent on NK cells and the production of IFN-γ-inducing cytokines (IL-12 and IL-18), are markedly attenuated in BN, compared with F344, weanlings. GM-CSF and Flt-3 ligand may enhance innate immunity by augmenting dendritic cell or dendritic and NK cell development, respectively. We hypothesized that treatment with GM-CSF and Flt-3 ligand would counteract the reduced capacity of BN weanlings to secrete IFN-γ and IFN-γ-inducing cytokines in response to virus. Methods Splenocytes from uninfected weanlings were preincubated for 16 h with or without GM-CSF or Flt-3 ligand and then for 24 h with or without Sendai virus. IFN-γ, IL-12, and IL-18 were measured in supernates by ELISA. Results GM-CSF and Flt-3 ligand triggered 12- and 8-fold increases, respectively, in virus-induced IFN-γ production by BN splenocytes ( p Conclusions GM-CSF-mediated enhancement of virus-induced IFN-γ production from BN splenocytes appeared to result from increases in IL-12 secretion, suggesting that GM-CSF augmented deficient dendritic cell activity. Flt-3 ligand-mediated, IL-12-independent increases in virus-induced IFN-γ production may arise from enhancement of deficient NK cell responses. These results suggest a basis for attenuated innate anti-viral responses in BN weanlings.
Numerical simulation study of a hydrazine/nitrogen dioxide diffusion flame in a Burke-Schumann burner

The conservation equations in the boundary layer form have been solved for co-axial flowing streams of hydrazine and nitrogen dioxide. Detailed chemical kinetics and transport were used in the simulation which included 22 species (plus diluent) and 151 reactions. The solution is compared with the classic Burke-Schumann solution, and individual elements of the Shvab-Zeldovich approximations pertaining to the latter are examined. The numerical solution with detailed chemistry shows good qualitative agreement with the classic Burke-Schumann solution for general flame shape and major species profiles. Quantitative discrepancies arise from the use of the flame sheet approximation and to changes of pD with temperature and composition. Additional discrepancies arise from the use of detailed chemistry which allows for the consumption of reactants by intermediate, species and by unimolecular processes.
COMPETITIVE AND COLLABORATIVE RESPONSES TO NEGATIVE FEEDBACK

This study examined the impact of interpersonal and intrapersonal factors upon the use of competitive and collaborative conflict resolution strategies in response to negative feedback Male and female college students were asked to recall instances of interpersonal conflicts where they received negative feedback from peers. Different factors predicted competition and collaboration. Greater negative affect led to more competition, while feedback on more important topics within closer relationships led to more collaboration. Gender had indirect effects on both of these assertive strategies, with women being more likely to both compete and collaborate. Several implications for further research are discussed.
Agreement probabilities for some CPIT—neyman smooth tests

The CPIT transformations do not, in general, give the same set of transformed values for different orderings of the observations in a sample. When these transformations are followed by a test of uniformity to give an overall goodness—of—fit test, it is possible to obtain different results for different orderings of a sample. We consider here the probability that two goodness—of—fit tests based on randomly selected permutations of the same sample and a Neyman smooth uniformity test will agree in their conclusions. We observe for the cases considered in a simulation study that the probability of agreement is generally large and tends to one with increasing n, under alternative hypotheses.
NSMAP: a method for spliced isoforms identification and quantification from RNA-Seq.

The development of techniques for sequencing the messenger RNA (RNA-Seq) enables it to study the biological mechanisms such as alternative splicing and gene expression regulation more deeply and accurately. Most existing methods employ RNA-Seq to quantify the expression levels of already annotated isoforms from the reference genome. However, the current reference genome is very incomplete due to the complexity of the transcriptome which hiders the comprehensive investigation of transcriptome using RNA-Seq. Novel study on isoform inference and estimation purely from RNA-Seq without annotation information is desirable. A N onnegativity and S parsity constrained M aximum A P osteriori (NSMAP) model has been proposed to estimate the expression levels of isoforms from RNA-Seq data without the annotation information. In contrast to previous methods, NSMAP performs identification of the structures of expressed isoforms and estimation of the expression levels of those expressed isoforms simultaneously, which enables better identification of isoforms. In the simulations parameterized by two real RNA-Seq data sets, more than 77% expressed isoforms are correctly identified and quantified. Then, we apply NSMAP on two RNA-Seq data sets of myelodysplastic syndromes (MDS) samples and one normal sample in order to identify differentially expressed known and novel isoforms in MDS disease. NSMAP provides a good strategy to identify and quantify novel isoforms without the knowledge of annotated reference genome which can further realize the potential of RNA-Seq technique in transcriptome analysis. NSMAP package is freely available at https://sites.google.com/site/nsmapforrnaseq .
Curvilinear areas in the perinephric fat seen on MR images

Abstract AIM: On magnetic resonance (MR) images, strands correspond to curvilinear areas running in the perinephric fat, and haloes to those lying on the renal surface. Our aim was to examine the diagnostic significance and histopathological basis of these areas. PATIENTS AND METHODS: MR images obtained in 46 patients without renal disease and 96 patients with renal disease were assessed for the signal intensity and extent of strands and haloes, and their degree of right-left asymmetry. RESULTS: Strands usually revealed low signal intensity on Tl-weighted MR images and high signal intensity on fat-suppressed T2-weighted images and contrast-enhanced fat-suppressed T1-weighted images. Haloes revealed high signal intensity on fat-suppressed T2-weighted images, but most of haloes were not clearly depicted on Tl-weighted images or contrast-enhanced fat-suppressed T1-weighted images. Strands and haloes were common and usually symmetrical or only mildly asymmetrical in both patient groups. However, in 11 of the 96 patients with renal disease, prominent strands and/or haloes appeared with remarkable asymmetry and likely represented definite changes in the perinephric fat. At histopathology, vascular loose fibrous tissue was found at the sites of strands and haloes. CONCLUSION: Strands and haloes usually represent normal anatomical variations. However, the presence of prominent strands or haloes with remarkable right-left asymmetry implies abnormality and may provide additional information in the evaluation of renal disease.
Gene expression changes in postmortem tissue from the rostral pons of multiple system atrophy patients

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by various degrees of Parkinsonism, cerebellar ataxia, and autonomic dysfunction. In this report, Affymetrix DNA microarrays were used to measure changes in gene expression in the rostral pons, an area that undergoes extensive damage in MSA, but not other synucleinopathies. Significant changes in expression of 254 genes (180 downregulated and 74 upregulated) occurred in pons tissue from MSA patients when compared with control patients. The downregulated genes were primarily associated with biological functions known to be impaired in Parkinson's disease (PD) and other neurological diseases; for example, downregulation occurred in genes associated with mitochondrial function, ubiquitin-proteasome function, protein modification, glycolysis/metabolism, and ion transport. On the other hand, upregulated genes were associated with transcription/RNA modification, inflammation, immune system function, and oligodendrocyte maintenance and function. Immunocytochemistry, in conjunction with quantitative image analysis, was carried out to characterize α-synuclein protein expression as glial cytoplasmic inclusions in the pontocerebellar tract in rostral pons tissue and to determine the relationship between the amount of aggregated α-synuclein protein and changes in specific gene expression. Of the regulated genes, 86 were associated with the amount of observed aggregated α-synuclein protein in the rostral pons tissue. These data indicate that cells in the pons of MSA patients show changes in gene expression previously associated with the substantia nigra of PD patients and/or other neurological diseases, with additional changes, for example related to oligodendrocyte function unique to MSA. © 2007 Movement Disorder Society
Domestic cases of hemorrhagic fever with renal syndrome in the United States.

Although serologic studies have identified hantaviral infection in the United States, acute disease has not been recognized. This study describes 3 cases of domestically acquired hemorrhagic fever with renal syndrome (HFRS) in the United States. Infection was due to a local strain of Seoul virus (Baltimore rat virus). A review of the clinical features indicated a mild illness characterized by nausea, vomiting, renal and liver failure similar to HFRS described elsewhere for rat-borne viruses. Follow-up of 2 patients identified persitent hypertension and renal disease providing further evidence of an association between past hantaviral infection and hypertensive renal disease.
Propofol Disrupts Functional Interactions between Sensory and High-Order Processing of Auditory Verbal Memory

Current theories suggest that disrupting cortical information integration may account for the mechanism of general anesthesia in suppressing consciousness. Human cognitive operations take place in hierarchically structured neural organizations in the brain. The process of low-order neural representation of sensory stimuli becoming integrated in high-order cortices is also known as cognitive binding. Combining neuroimaging, cognitive neuroscience, and anesthetic manipulation, we examined how cognitive networks involved in auditory verbal memory are maintained in wakefulness, disrupted in propofol-induced deep sedation, and re-established in recovery. Inspired by the notion of cognitive binding, an functional magnetic resonance imaging-guided connectivity analysis was utilized to assess the integrity of functional interactions within and between different levels of the task-defined brain regions. Task-related responses persisted in the primary auditory cortex (PAC), but vanished in the inferior frontal gyrus (IFG) and premotor areas in deep sedation. For connectivity analysis, seed regions representing sensory and high-order processing of the memory task were identified in the PAC and IFG. Propofol disrupted connections from the PAC seed to the frontal regions and thalamus, but not the connections from the IFG seed to a set of widely distributed brain regions in the temporal, frontal, and parietal lobes (with exception of the PAC). These later regions have been implicated in mediating verbal comprehension and memory. These results suggest that propofol disrupts cognition by blocking the projection of sensory information to high-order processing networks and thus preventing information integration. Such findings contribute to our understanding of anesthetic mechanisms as related to information and integration in the brain.
Hilgenreiner measurements of the hip roentgenograms in 247 normal infants 6 and 7 months of age

Summary The Hilgenreiner measurements of roentgenograms of the hips were determined for a group of infants 6 and 7 months of age. Also, data on the presence or absence of the capital epiphysis were obtained, and follow-up studies of those infants whose measurements deviated from the “average” were made. It is suggested that Hilgenreiner measurements be used for interpretative purposes in relation to two standard deviations from the mean.
Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow

This study was undertaken to characterize the adhesion of LS174T colon adenocarcinoma cells to 4-h TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) under flow in the presence and ab...
An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care.

We introduce the first implantable drug delivery system based on MEMS (Micro-Electro-Mechanical-Systems) technology specifically designed as a platform for treatment in ambulatory emergency care. The device is named IRD 3 (implantable rapid drug delivery device) and allows rapid delivery of drugs. Vasopressin was used as a model drug for in vitro tests as it is a commonly used drug for cardiac resuscitation. Experimental results reveal that the IRD 3 provides an effective method for rapid delivery without significant drug degradation. Several medical uses and delivery modalities for IRD 3 are proposed.
Cell-Type Specific Expression of a Dominant Negative PKA Mutation in Mice

We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology.
IFN‐γ‐Mediated Inhibition of COX‐2 Expression in the Placenta from Term and Preterm Labor Pregnancies

Problem The inflammatory-anti-inflammatory cytokine network is thought to play a critical role in regulated progression and termination of pregnancy. The aim of this study was to evaluate the effects of interferon (IFN)-gamma on the expression of Cyclooxygenase (COX)-2 and production of prostaglandin E(2) (PGE(2)) in the human placenta from term and preterm labor deliveries. Method of study Placental explant culture system was used. COX-2 expression was determined by complementary techniques of immunohistochemistry and Western blotting. Released IFN-gamma and PGE(2) by placental explants were measured by enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 1 (STAT1) phosphorylation was evaluated by Western blotting using a specific antibody. Results IFN-gamma was poorly detected in the placenta but was significantly expressed in decidual tissues from both term and preterm pregnancies as detected by immunohistochemistry. IFN-gamma significantly inhibited COX-2 expression and PGE(2) release in cultured placental explants from term and preterm labor deliveries. This effect most likely occurred in a STAT1-dependent manner as this regulatory protein was phosphorylated in response to IFN-gamma. IFN-gamma receptor (IFN-gammaR) was expressed in normal early pregnancy placental samples. However, its expression was significantly reduced in placental samples from term and preterm deliveries. Of interest, IFN-gammaR was expressed in placentas from term and preterm labor deliveries after 24 hr in culture. Conclusions Our data suggest that the human placenta is an important site for IFN-gamma-mediated repression of COX-2 expression and PGE2 production, implying that functional withdrawal of IFN-gamma may be involved in the onset of term or preterm labor.
Chemical modification of enzymes: Critical evaluation of the graphical correlation between residual enzyme activity and number of groups modified

In the study of chemical modification of enzymes and other biologically active proteins, plots of fractional residual activity as a function of number of groups modified per enzyme molecule are often used to establish a correlation between the chemical modification and enzyme inactivation reactions and to determine the stoichiometry of the modification reaction. This paper presents a critical examination of the underlying theoretical framework of such graphs. Whereas these plots are usually presented as linear functions, it is shown here that the general equation describing the relationship between inactivation and modification contains an exponential term; therefore, in the general case, the plot is actually a curve. It is suggested that caution be exercised in the interpretation of such plots and that equations such as those derived in the text be used to fit theoretical curves to the data, in order to maximize the information gained from chemical modification experiments.
Efficient Implementation Algorithms for Homogenized Energy Models

The homogenized energy framework quantifying ferroelectric and ferromagnetic hysteresis is increasingly used for comprehensive material characterization and model-based control design. For operating regimes in which thermal relaxation mechanisms and stress-dependencies are negligible, existing algorithms are sufficiently efficient to permit device optimization and the potential for real-time control implementation. In this paper, we develop algorithms employing lookup tables which permit the high speed implementation of formulations which incorporate relaxation mechanisms and electromechanical coupling. Aspects of the algorithms are illustrated through comparison with experimental data.
Ignition of Fabrics Under Radiative Heating

Abstract Experiments have been performed to develop test methods for the purpose of assessing fabric ignition characteristics with respect to the fabric burn injury potential. Thermophysical fabric properties relevant to the description of the ignition process are presented. Fabric ignition or melting times have been measured and are presented in non-dimensional form for radiative heating of desiccated fabrics. The significant fabric properties required to describe the ignition process and the probability of ignition under given exposure conditions are listed.
A new control architecture with enhanced ARP, burst-based transmission, and hop-based wavelength allocation for ethernet-supported IP-over-WDM MANs

This paper focuses on the control architecture and the enabling technologies for the Ethernet-supported Internet protocol-over-wavelength-division-multiplexing metropolitan area networks. We present the general architecture of an access node of such networks and propose solutions to facilitate the essential system functionalities. The aim is to render the flexible and high-capacity metropolitan network, which provides service provisioning improvement and resource utilization efficiency for the packet-dominated data traffic. Specifically, an enhanced address resolution protocol is proposed to reduce the call setup latency and the signaling overhead associated with the address probing procedure, a burst-based transmission mechanism is adopted to improve the network throughput and resource utilization efficiency, and a wavelength allocation algorithm is investigated to provide flexible bandwidth multiplexing with fairness and high scalability. Theoretical analysis and simulations are conducted to evaluate the performance of our algorithms, demonstrating that the proposed architecture and technologies deliver substantial transport performance improvement with efficient network resource utilization.
Morphology of seahorse head hydrodynamically aids in capture of evasive prey

Seahorses are very slow swimmers, yet they are specialized hunters of fast and evasive prey. Here the authors show that seahorse head morphology functions to create a zone of minimum hydrodynamic disturbance, which allows the seahorse to slowly approach the prey, and to position itself within capture range.
MODELS OF LONG-PERIOD SUPERSTRUCTURES

The cause of the stability of long-period superstructures is still something of a mystery. Typically, two very different models have been proposed: according to model I, the period of the superstructure (or modulation) is determined by lowering of the electronic energy resulting from the formation of a new Brillouin zone. According to model II, competing short-range interactions tend to produce long-period structures, the wavelength of which is determined by configurational entropy considerations. Model I is exemplified by the Sato and Toth theory, apparently applicable to long-period superstructures in Cu-Au, for example. Model II is exemplified by the Axial Next Nearest Neighbor Ising Model, for which a low-temperature free energy expansion has recently been given by Fisher and Selke. The latter model appears to apply to long-period superstructures in Ag/sub 3/Mg.
Evaluation of fasciotomy and vasodilator for treatment of frostbite in the dog.

Abstract Severe freezing injury was produced in the hind foot of 26 mongrel dogs. All dogs were given daily whirlpool treatment and protective bandaging for 14 days following injury. In addition, certain dogs received a vasodilator, fasciotomy, or both vasodilator and fasciotomy following injury. Deep foot temperatures, foot volumes, tissue pressures, and 14 day tissue loss-salvage scores were compared. Significant differences between fasciotomy and nonfasciotomy dogs were seen in foot temperature, volume, and tissue pressure immediately following fasciotomy. Though there was no significant difference in 14 day tissue loss, there was clinically apparent prolongation of integrity of the local vascular system for 2 to 5 days following fasciotomy, and total foot salvage in several dogs receiving fasciotomy.
Schistosoma mansoni: Adult worm chemoattraction, with and without barriers

Abstract Heterosexual and homosexual chemoattraction studies were done with 8- to 12-week-old Schistosoma mansoni adults in linear chambers containing Earle's saline, in the absence and presence of both perforated and unperforated dialysis sac chimney barriers. In the absence of barriers attraction was seen in all heterosexual and homosexual combinations. After 90 min of observation at 37 C, organisms maintained at 4 or 37 C for at least 1 hr prior to the assay showed heterosexual attraction similar to those used immediately after perfusion. There was significantly more heterosexual attraction between worms from same than different pairs. In the presence of perforated barriers the greatest attraction was heterosexual, with males moving toward females; heterosexual attraction with females moving toward males was approximately equal to homosexual female attraction, and male homosexual attraction was not seen. In the presence of unperforated barriers the greatest attraction of females toward males occurred during the first 0.5 hr; within 3 to 4 hr females were no longer significantly attracted to males. However, after 0.5 hr males were more significantly attracted to females in unperforated than perforated chimneys. These studies demonstrate that adult schistosomes attract each other in vitro , and that there is a chemical basis for this attraction.
Sharp-line electronic spectra and metal-ligand geometry

The narrow intraconfigurational lines in the electronic spectra of transition metal complexes can, unlike broad bands, be assigned to single electronic transitions. The positions of, and especially the splittings within, these lines are strongly influenced by the angular positions and orientations of the ligands. The angular overlap model (AOM) is well suited to treat the exact geometry as part of the ligand field potential. It is possible in some instances to deduce particular bond angles by analysis of the electronic spectrum. It is suggested that when AOM parameters are deduced from spectral data, the ligand geometry be explicitly included, either directly from an X-ray crystal structure, if available, or from an approximate method, such as a molecular mechanics calculation. This ought to insure the maximum transferability of parameters for a particular ligand in different complexes, and for a particular coordinating group in different ligands.
The dose effect of continuous passive motion in postoperative rehabilitation of the first metatarsophalangeal joint

Continuous passive motion (CPM) has been utilized in postoperative rehabilitation of many joints of the body. Little has been published regarding its applications in the first metatarsal phalangeal joint or other joints of the foot. A review of the basic science and clinical studies regarding the dose effects on the healing of articular cartilage defects and periarticular tissues has led to possible correlations in treating disorders of the first metatarsal phalangeal joint. Proposed protocols are being presented which may be helpful in future clinical studies to confirm the benefits of CPM in this joint of the foot.
Use and employer costs of a pharmacotherapy smoking-cessation treatment benefit.

Background Employers cite a lack of information on the cost of insurance coverage for smoking-cessation treatment as a barrier to its provision. This study describes the use of a new insurance benefit for smoking-cessation pharmacotherapy, and its pharmaceutical costs to a large public employer between 2001 and 2003. Methods Annual enrollment and pharmaceutical claims data were collected from the health plans that contracted with the Wisconsin Department of Employee Trust Funds (ETF). State employees, retirees, and adult dependents who obtained health insurance through the ETF constituted our sample, approximately 150,000/year. Pharmacotherapy benefit use was defined as a paid claim for one of four U.S. Food and Drug Administration–approved smoking-cessation medications. Pharmaceutical cost was defined as the ingredient cost (+) dispensing fee (−) member copayment. Analyses included estimation of the proportion of smokers who used the benefit each year and across 3 years, the average annual cost per user, and the per member per month (PMPM) pharmaceutical cost to the employer. Data were collected from 2001 to 2004 and analyzed in 2005–2006. Results Annual benefit use among smokers ranged from 6% to 7% with a 3-year rate of approximately 17%. The PMPM cost of the covered pharmacotherapy was approximately $0.13. Conclusions The cost to employers of providing insurance coverage for smoking-cessation pharmacotherapy to their employees is low. By informing insurance purchasing decisions, these results may facilitate the adoption of such coverage, with the goal of ultimately reducing the proportion of employees who smoke.
Octamer Binding Factors and Their Coactivator Can Activate the Murine PU.1 (spi-1) Promoter

PU.1 (spi-1), a member of the Ets transcription factor family, is predominantly expressed in myeloid and B cells, activates many B cell and myeloid genes, and is critical for development of both of these lineages. Our previous studies (Chen, H. M., Ray-Gallet, D., Zhang, P., Hetherington, C. J., Gonzalez, D. A., Zhang, D.-E., Moreau-Gachelin, F., and Tenen, D. G. (1995) Oncogene 11, 1549-1560) demonstrate that the PU.1 promoter directs cell type-specific reporter gene expression in myeloid cell lines, and that PU.1 activates its own promoter in an autoregulatory loop. Here we show that the murine PU.1 promoter is also specifically and highly functional in B cell lines as well. Oct-1 and Oct-2 can bind specifically to a site at base pair -55 in vitro, and this site is specifically protected in B cells in vivo. We also demonstrate that two other sites contribute to promoter activity in B cells; an Sp1 binding site adjacent to the octamer site, and the PU.1 autoregulatory site. Finally, we show that the B cell coactivator OBF-1/Bob1/OCA-B is only expressed in B cells and not in myeloid cells, and that OBF-1/Bob1/OCA-B can transactivate the PU.1 promoter in HeLa and myeloid cells. This B cell restricted coactivator may be responsible for the B cell specific expression of PU.1 mediated by the octamer site.
PERFORMANCE AUDITING OF AN IN VITRO AIR POLLUTION EXPOSURE SYSTEM

Databases derived from human health effects research play a vital role in setting environmental standards. An underlying assumption in using these databases for standard setting purposes is that they are of adequate quality. The performance auditing program described provides novel methods for determining data quality for one form of human health effects research, in vitro exposure to air pollutants. This article presents the development and implementation of a performance auditing program for an in vitro system used by U.S. Environmental Protection Agency researchers to expose human cells to air pollution. Audit procedures for determining the accuracy of critical operating parameters of the system are described. The results of initial audits of the system's ability to control and measure temperature, humidity, and pollutant gas concentration and distribution within the exposure chambers of the system are listed. The utility of the performance auditing program in assisting health effects researchers to de...
CGRPα-expressing sensory neurons respond to stimuli that evoke sensations of pain and itch

Calcitonin gene-related peptide (CGRPα, encoded by Calca) is a classic marker of nociceptive dorsal root ganglia (DRG) neurons. Despite years of research, it is unclear what stimuli these neurons detect in vitro or in vivo. To facilitate functional studies of these neurons, we genetically targeted an axonal tracer (farnesylated enhanced green fluorescent protein; GFP) and a LoxP-stopped cell ablation construct (human diphtheria toxin receptor; DTR) to the Calca locus. In culture, 10–50% (depending on ligand) of all CGRPα-GFP-positive (+) neurons responded to capsaicin, mustard oil, menthol, acidic pH, ATP, and pruritogens (histamine and chloroquine), suggesting a role for peptidergic neurons in detecting noxious stimuli and itch. In contrast, few (2.2±1.3%) CGRPα-GFP+ neurons responded to the TRPM8-selective cooling agent icilin. In adult mice, CGRPα-GFP+ cell bodies were located in the DRG, spinal cord (motor neurons and dorsal horn neurons), brain and thyroid—reproducibly marking all cell types known to express Calca. Half of all CGRPα-GFP+ DRG neurons expressed TRPV1, ∼25% expressed neurofilament-200, <10% contained nonpeptidergic markers (IB4 and Prostatic acid phosphatase) and almost none (<1%) expressed TRPM8. CGRPα-GFP+ neurons innervated the dorsal spinal cord and innervated cutaneous and visceral tissues. This included nerve endings in the epidermis and on guard hairs. Our study provides direct evidence that CGRPα+ DRG neurons respond to agonists that evoke pain and itch and constitute a sensory circuit that is largely distinct from nonpeptidergic circuits and TRPM8+/cool temperature circuits. In future studies, it should be possible to conditionally ablate CGRPα-expressing neurons to evaluate sensory and non-sensory functions for these neurons.
Redox Signaling and the Innate Immune System in Alcoholic Liver Disease

Abstract The development of alcoholic liver disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the liver. Although the mechanisms for ALD are not completely understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor...
The role of calcineurin/NFAT in SFRP2 induced angiogenesis--a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus.

Tacrolimus (FK506) is an immunosuppressive drug that binds to the immunophilin FKBPB12. The FK506-FKBP12 complex associates with calcineurin and inhibits its phosphatase activity, resulting in inhibition of nuclear translocation of nuclear factor of activated T-cells (NFAT). There is increasing data supporting a critical role of NFAT in mediating angiogenic responses stimulated by both vascular endothelial growth factor (VEGF) and a novel angiogenesis factor, secreted frizzled-related protein 2 (SFRP2). Since both VEGF and SFRP2 are expressed in breast carcinomas, we hypothesized that tacrolimus would inhibit breast carcinoma growth. Using IHC (IHC) with antibodies to FKBP12 on breast carcinomas we found that FKBP12 localizes to breast tumor vasculature. Treatment of MMTV-neu transgenic mice with tacrolimus (3 mg/kg i.p. daily) (n = 19) resulted in a 73% reduction in the growth rate for tacrolimus treated mice compared to control (n = 15), p = 0.003; which was associated with an 82% reduction in tumor microvascular density (p<0.001) by IHC. Tacrolimus (1 µM) inhibited SFRP2 induced endothelial tube formation by 71% (p = 0.005) and inhibited VEGF induced endothelial tube formation by 67% (p = 0.004). To show that NFATc3 is required for SFRP2 stimulated angiogenesis, NFATc3 was silenced with shRNA in endothelial cells. Sham transfected cells responded to SFRP2 stimulation in a tube formation assay with an increase in the number of branch points (p<0.003), however, cells transfected with shRNA to NFATc3 showed no increase in tube formation in response to SFRP2. This demonstrates that NFATc3 is required for SFRP2 induced tube formation, and tacrolimus inhibits angiogenesis in vitro and breast carcinoma growth in vivo. This provides a rationale for examining the therapeutic potential of tacrolimus at inhibiting breast carcinoma growth in humans.
Systolic algorithms for solving a sparse system of linear equations in circuit simulation

Abstract Systolic algorithms providing near ideal speedups have been developed for solving a dense system of linear equations. However, in applications like circuit simulation, the resulting matrix equation is quite sparse ( > 99% zeros) which makes the dense matrix solution approach inefficient. Although sparse matrix solvers for circuit simulation have been devised for parallel shared memory machines and vector processors, their performance in terms of speedup has been limited due to tightly coupled and unstructured sparse equations. This paper first develops a systolic sparse matrix algorithm by modifying an existing partitionable dense matrix solution algorithm. The sparse algorithm is then further improved to include parallel execution by multiple systolic processor modules. Reordering schemes based on a modified Markowitz algorithm are also developed that minimize the fill-in-during the matrix solution by our sparse algorithms thereby improving the execution time. Results on several randomly generated sparse matrices and those generated from ISCAS benchmark circuits are presented to show the efficiency of our sparse algorithm and its excellent speedup as the number of processors in the systolic array is increased.
Quantum versus semiclassical description of self-trapping: Anharmonic effects

Self-trapping has been traditionally studied on the assumption that quasiparticles interact with harmonic phonons and that this interaction is linear in the displacement of the phonon. To complement recent semiclassical studies of anharmonicity and nonlinearity in this context, we present below a fully quantum-mechanical analysis of a two-site system, where the oscillator is described by a tunably anharmonic potential, with a square well with infinite walls and the harmonic potential as its extreme limits, and wherein the interaction is nonlinear in the oscillator displacement. We find that even highly anharmonic polarons behave similar to their harmonic counterparts in that self-trapping is preserved for long times in the limit of strong coupling, and that the polaronic tunneling time scale depends exponentially on the polaron binding energy. Further, in agreement, with earlier results related to harmonic polarons, the semiclassical approximation agrees with the full quantum result in the massive oscillator limit of small oscillator frequency and strong quasiparticle-oscillator coupling. {copyright} {ital 1999} {ital The American Physical Society}
Cellular membrane potentials and contractility of normal rat atrium and the effects of temperature, tension and stimulus frequency.

Simultaneous recording of membrane potentials and contractility in isolated rat atria by means of intracellular micro-electrodes and a sensitive strain gage has been used to establish the normal characteristics of the tissue as well as effects of temperature, stimulus frequency and initial tension on muscle. Preliminary correlations between duration of the action potential and the degree of contraction indicate that the rate of repolarization is of major importance in determination of the contractile response.
Cell-free co-production of an orthogonal transfer RNA activates efficient site-specific non-natural amino acid incorporation

We describe a new cell-free protein synthesis (CFPS) method for site-specific incorporation of non-natural amino acids (nnAAs) into proteins in which the orthogonal tRNA (o-tRNA) and the modified protein (i.e. the protein containing the nnAA) are produced simultaneously. Using this method, 0.9-1.7 mg/ml of modified soluble super-folder green fluorescent protein (sfGFP) containing either p-azido-l-phenylalanine (pAzF) or p-propargyloxy-l-phenylalanine (pPaF) accumulated in the CFPS solutions; these yields correspond to 50-88% suppression efficiency. The o-tRNA can be transcribed either from a linearized plasmid or from a crude PCR product. Comparison of two different o-tRNAs suggests that the new platform is not limited by Ef-Tu recognition of the acylated o-tRNA at sufficiently high o-tRNA template concentrations. Analysis of nnAA incorporation across 12 different sites in sfGFP suggests that modified protein yields and suppression efficiencies (i.e. the position effect) do not correlate with any of the reported trends. Sites that were ineffectively suppressed with the original o-tRNA were better suppressed with an optimized o-tRNA (o-tRNA(opt)) that was evolved to be better recognized by Ef-Tu. This new platform can also be used to screen scissile ribozymes for improved catalysis.
Nanodiamond Lateral Field Emission Devices: Fabrication, Emission Current Scaling, Temperature- and Radiation-Tolerance

A field emission device in lateral configuration is a favourable construct for electron emission due to versatility for electrode geometry design, precise control of anode-cathode spacing, and low capacitance. The development of micropatterning nanodiamond (ND) films using reactive ion etching has been critical to the utilization of ND as an electron emitter. We have fabricated lateral devices with high aspect ratio, finger-like ND emitters with sharp apexes and investigated how the number of emitters scales with respect to the forward emission current derived from the ND lateral device. We also report total dose (15 Mrad(SiO2)) and high temperature (> 200 °C) tests on these devices. No measurable change in the device performance is observed under adverse operating conditions.
Empirical mathematical models and artificial neural networks for the determination of alum doses for treatment of southern Australian surface waters

The potential for predicting alum doses for surface waters from southern Australia based on physico-chemical parameters of the raw waters was studied. These parameters included dissolved organic carbon (DOC), absorbance at 254 nm, turbidity and alkalinity. Procedures used for assessing the predictability of alum dosing were empirical mathematical models and artificial neural networks. Alum doses determined by jar tests were selected on the basis of target values for settled and filtered turbidities, colour and residual aluminium. Regression equations which incorporated the parameters of DOC, UV absorbance (254 nm/cm), turbidity, alkalinity and pH gave correlation coefficients of greater than 0.9. These equations gave a high frequency of prediction within ±10 mg/L alum of actual doses. Similarly, 86% of alum doses predicted by artificial neural networks were within 10 mg/L of the actual doses. Although a good prediction of coagulant dosing was achieved, it is likely that the models generated are specific for the types of waters studied and the criteria for alum dose selection.
Ribosomal RNA sequence conservation and gene number in the larval brine shrimp

Abstract The haploid genome size of Artemia is determined to be about 0.9·10 12 , as evidenced both by Feulgen microspectrophotometry of individual diploid class nuclei, which are but one of five polyploid classes present within the larvae, and by analysis of the reassociation kinetics of the isolated single copy DNA component. Polysomes isolated from 24-h incubation stage larvae contain an average of 10 ribosomes per messenger RNA molecule. Their rRNAs are found to have sedimentation coefficients of 18 S and 26 S, corresponding to molecular weights of 0.70·10 6 and 1.40·10 6 , respectively, as determined by polyacrylamide electrophoresis and also by sucrose density centrifugation. Denaturation in glyoxal followed by agarose gel electrophoresis shows that unlike deuterostome rRNAs, Artemia 26 S rRNA contains a cryptic nick about midway in the molecule, which is not found in the 18 S molecule. Isolated rRNAs were labelled in vitro with 125 I and hybridized with filter-immobilized DNA to saturation, which occurred at 0.051% for Xenopus , and at 0.074% for Artemia . From these results, it is calculated that in the haploid Artemia genome there are about 320 copies of the (18 S + 26 S) ribosomal RNA genes. Reciprocal heterologous hybridizations between these two species show that they share about 30% homology between their rDNA coding sequences.