cssi/SciSciGPT-SciSciNet huggingface dataset:
Association of Maternal Age and Parity with Birth Weight, Sex Ratio, Stillbirths and Multiple Births

Body size at birth and factors believed to influence it have been the subject of investigation in several geographic regions to a lesser extent also in Africa for a good number of years. In Ethiopia it is only recently that information on birth weight has become available. In 1962 Hofvander reported a mean weight of 2.95 kg for 554 newborns delivered at a maternity center in Addis Ababa. Five years later Young published a mean birth weight of 3.12 kg and a low birth weight rate of 9.4% for 500 consecutive live single births. Findings by the same author in another smaller city were 3.05 kg and 13.4% respectively. In connection with an ongoing study in Addis Ababa on the impact of nutrition on reproduction it seemed desirable to obtain further data on relevant attributes of the newborn. For this purpose the records of a maternity hospital in Addis Ababa were searched for information on birth weights. The availability of good records on age and parity of mother the sex of the infant stillbirths and multiple births made it also possible to look at these variables and their association with the size at birth of this newborn. (excerpt)
Smad3 Mediates Transforming Growth Factor-β–Induced α-Smooth Muscle Actin Expression

Transforming growth factor-beta (TGF-beta)-induced alpha-smooth muscle actin (ASMA) expression is a key indicator of myofibroblast differentiation from fibroblasts. Recent studies suggest that a TGF-beta control element is important in the regulation of the ASMA gene promoter by TGF-beta. In this study, the role of Smad3, a key component of the Smad pathway that mediates TGF-beta signaling in regulation of ASMA gene expression, is investigated. All members of the Smad family were expressed in rat lung fibroblasts, and Smad3 expression was elevated upon TGF-beta 1 treatment. Transfection with a Smad3-expressing plasmid markedly increased Smad3 and ASMA protein expression, whereas transfection with an antisense Smad3 plasmid suppressed Smad3 and ASMA expression. Similar effects were noted when the cloned rat ASMA promoter-luciferase reporter gene construct was used to monitor transcriptional activation of the ASMA gene. Electrophoretic mobility shift assays and DNA affinity precipitation indicated Smad3 binding to at least two regions of the promoter containing CAGA motifs, termed Smad3-binding elements (SBEs). Mutation of one of the SBEs decreased promoter activity significantly, indicative of a functional role for this SBE. Taken together, these findings suggest a role for Smad3 in TGF-beta regulation of ASMA gene expression in myofibroblast differentiation.
Laboratory study of intraspecific and interspecific competition within and between two sympatric bark beetle species, Ips pini and I. paraconfusus1

Ips paraconfusus and I. pini were forced to construct galleries and oviposit within a limited resource. Other sources of mortality were restricted and both attack density and number of females per male were maintained in single species and mixed species bolts to enhance competition. Interspecific competition effects were not greater than intraspecific effects if attack density and parent sex ratios were held lower than what is normally seen under natural conditions. However, interspecific competition had a much greater effect than intraspecific competition when natural conditions were approximated. These competition effects may have provided the ecological pressure to explain the evolution of mutually inhibitory pheromone communication between these sympatric species. Zusammenfassung Laborversuche zur intraspezifischen und interspezifischen Konkurrenz in und zwischen zwei sympatrischen Borkenkafern, Ips pini und I. paraconfusus Ips pini und I. paraconfusus wurden auf begrenztem Brutmaterial zur Anlage ihrer Frasgange und zur Eiablage gebracht. Andere Mortalitatsursachen wurden eingeschrankt und sowohl Angriffsdichte wie Zahl der Weibchen pro Mannchen variiert pro Art und in Stammabschnitten mit beiden Borkenkaferarten gemeinsam, um die Konkurrenz zu erhohen. Wenn Angriffsdichte und Geschlechtsverhaltnis der Elternkafer niedriger waren als unter Normalbedingungen im Freiland, lagen die Auswirkungen der interspezifischen Konkurrenz nicht uber denen der intraspezifischen Konkurrenz. Entsprachen dagegen die Aufzuchtbedingungen den Normalverhaltnissen im Freiland, so hatte die interspezifische Konkurrenz einen viel groseren Einflus als intraspezifische Konkurrenz. Solche Konkurrenzphanomene waren moglicherweise der Ausloser fur die Evolution von Pheromon-Systemen, mit denen sich diese sympatrischen Borkenkaferarten gegenseitig ablenken konnen.
Quinoprotein methanol dehydrogenase: a molecular dynamics study and comparison with crystal structure

Abstract One of the mechanisms proposed for methanol oxidation by methanol dehydrogenase (MDH) involves a hydride transfer to the quinone carbonyl carbon C5 of 2,7,9-tricarboxy-1H-pyrrolo[2,3-f]-quinoline-4,5-dione (PQQ), initiated by abstraction of a proton from the substrate methanol by a general base. Molecular dynamics studies are performed on MDH-bound to the C5 reduced intermediate (C5RI) of PQQ, for 3 ns. The structural features of the MD and X-ray structures are compared. An interesting feature observed during simulations is the strong hydrogen bond between oxyanion O5 of C5RI and Asp297–CO 2 H in the active site. Asp297–CO 2 − is suggested to be the general-base catalyst for removing the hydroxyl proton of methanol in concert with the hydride ion transfer from the putative methoxide to C5 carbonyl of PQQ. The formed Asp297–CO 2 H acts as the required proton source for the immediate product. Anticorreleated motions observed in the MD structure are not across the active site to influence the reaction mechanism of MDH.
Land markets and public policy: A conceptual framework☆

Abstract This paper presented a conceptual framework to analyse the nature and effectiveness of land policies in a broad context of national policy-making. Special attention was given to the way in which explicit and implicit land-use policies affect land-use decisions. A classification system of land-use policies was developed and the concepts of dominance and consistency were presented. The system and concepts can be usefully applied for empirical investigations.
Oxidation of perfluoroaromatics

Abstract 3,4,5,6-Tetrafluoro-2-nitroaniline (I), 2,3,5,6-tetrafluoro-4-nitroaniline (IV) and 2,5,6-trifluoro-4-nitro-1,3-phenylenediamine (VI) react with nitrous acid to give 3,4,5-trifluoro-6-nitro-1,2-diazo-oxide (III), 3,5,6-trifluoro-4-nitro-1,2-diazo-oxide and (V) 5-fluoro-6-nitro-bis-1,2:3,4-diazo-oxide (VII), respectively. Reduction of the diazo-oxide (III) with hypophosphorous acid gives 4,5,6-trifluoro-3-nitrophenol (VIII). Treatment of 2,3,4,6-tetrafluoroacetanilide with nitric acid affords trifluoro- p -benzoquinone (X), the reduction of which gives trifluorohydroquinone (XI). Proton and fluorine chemical shifts and coupling constants of the new compounds are reported.
Influence of Microbial Stimulation on Hypergammaglobulinemia and Autoantibody Production in Pristane-Induced Lupus

Pristane induces a lupus-like syndrome characterized by autoantibody production and glomerulonephritis in nonautoimmune strains of mice. Although it has been suggested that this syndrome results from nonspecific immune activation, there is little evidence so far that B cells are activated nonspecifically by pristane or that this promotes autoimmunity. In this study, we examined whether polyclonal hypergammaglobulinemia occurs in pristane-induced lupus, and its relationship to the production of anti-DNA, nRNP/Sm, and Su autoantibodies. In conventionally housed mice, there was a marked increase in total IgM and IgG3 2 weeks after ip pristane injection, followed by increased IgG1, IgG2a, and IgG2b levels. IgM levels were higher in pristane-treated specific pathogen-free (SPF) mice than in conventionally housed mice, whereas IgG and IgA levels were reduced. Pristane induced anti-nRNP/Sm and Su autoantibodies in SPF mice, but their onset was delayed and levels were lower than those in conventionally housed mice. There was no consistent relationship between total IgG1, 2a, and 2b hypergammaglobulinemia and production of anti-nRNP/Sm and Su autoantibodies. Moreover, the total Ig levels were similar in the anti-nRNP/Sm-positive and -negative groups. In contrast, production of IgM anti-ssDNA antibodies paralleled IgM hypergammaglobulinemia in some, but not all, mice. These studies indicate that pristane-induced lupus is associated with marked hypergammaglobulinemia, the magnitude of which is influenced by the microbial environment. However, anti-nRNP/Sm and Su autoantibody production is at least partly independent of polyclonal B cell activation. The data strongly suggest that pristane-induced lupus is not exclusively the consequence of nonspecific immune stimulation. They also point to the importance of microbial stimulation in the development of hypergammaglobulinemia in this inducible lupus model.
Globalization of Pediatric Research: Analysis of Clinical Trials Completed for Pediatric Exclusivity

OBJECTIVE: We evaluated the setting of published studies conducted under the US Pediatric Exclusivity Provision, which provides economic incentives to pharmaceutical companies to conduct drug studies with children. METHODS: Published studies containing the main results of trials conducted in 1998–2007 under the Pediatric Exclusivity Provision were included. Data were extracted from each study and described, including the therapeutic area of drug studied, number of patients enrolled, number of sites, and location where the study was conducted, if reported. RESULTS: Overall, 174 trials were included (sample size: 8–27 065 patients); 9% did not report any information regarding the location or number of sites where the study was conducted. Of trials that did report such information, 65% were conducted in ≥1 country outside the United States, and 11% did not include any sites in the United States. Fifty-four countries were represented, and 38% of trials enrolled patients in ≥1 site located in a developing/transition country, including more than one-third of infectious disease, cardiovascular, and allergy/immunology trials. CONCLUSIONS: The majority of published pediatric trials conducted under the Pediatric Exclusivity Provision included sites outside the United States, and more than one-third of trials enrolled patients in developing/transition countries.
Micro-injection of Lygus salivary gland proteins to simulate feeding damage in alfalfa and cotton flowers.

Alfalfa and cotton flowers were pierced with small glass capillaries of an overall size and shape similar to that of Lygus stylets, and injected with small quantities (6 to 100 nL) of solutions that contained Lygus salivary enzymes. Crude and partially purified protein solutions from Lygus heads and isolated salivary glands showed substantial polygalacturonase (PG) activity, as has been previously reported. Following injection with both crude and partially purified protein solutions, as well as with pure fungal and bacterial PGs, flowers of both alfalfa and cotton exhibited damage similar to that caused by Lygus feeding. Injection with the same volume of a buffer control as well as a buffer control containing BSA at a comparable protein concentration (approximately 6 µg/mL) showed no symptoms. These results are consistent with a previously suggested hypothesis that the extensive tissue damage caused by Lygus feeding is primarily due to the action of the PG enzyme on the host tissue, rather than to mechanical damage caused by the insect stylet. Substantial genotypic variation for a PG inhibiting protein (PGIP) exists in alfalfa and cotton. We, therefore, suggest that breeding and selection for increased native PGIP levels, or transformation with genes encoding PGIP from other plant species, may be of value in obtaining alfalfa and cotton varieties that are more resistant to Lygus feeding damage. Arch. Insect Biochem. Physiol. 58:69–83, 2005. © 2005 Wiley-Liss, Inc.
Thickness and other effects on oxide and interface damage by plasma processing

The authors point out that plasma induced oxide charging occurs mainly during the overetch time. There is no measurable additional damage during the moment of plasma turn-on and turn-off. Plasma acts more like a current source than a voltage source. This is fortunate for future thinner oxides. There is a latent interface damage remaining after the forming gas anneal. A discrepancy between the defect densities measured in test structures and in circuits is explained. >
Sustainable energy technologies and distributed generation

Changes are imminent in the energy sector for a sustainable future. The word sustainability itself has been broadly defined to cover both economic and social goals and the business case for energy sustainability in this larger context has been made. Some of the promising technologies are briefly outlined in this paper. A brief overview which follows is by no means exhaustive, and represents just examples of the technology-related issues.
EFFECTS OF INTERTRIAL REINFORCERS ON SELF-CONTROL CHOICE

In three experiments, pigeons chose between a small amount of food delivered after a short delay and a larger amount delivered after a longer delay. A discrete-trial adjusting-delay procedure was used to estimate indifference points--pairs of delay-amount combinations that were chosen about equally often. In Experiment 1, when additional reinforcers were available during intertrial intervals on a variable-interval schedule, preference for the smaller, more immediate reinforcer increased. Experiment 2 found that this shift in preference occurred partly because the variable-interval schedule started sooner after the smaller, more immediate reinforcer, but there was still a small shift in preference when the durations and temporal locations of the variable-interval schedules were identical for both alternatives. Experiment 3 found greater increases in preference for the smaller, more immediate reinforcer with a variable-interval 15-s schedule than with a variable-interval 90-s schedule. The results were generally consistent with a model that states that the impact of any event that follows a choice response declines according to a hyperbolic function with increasing time since the moment of choice.
Cell-Specific Metabolism and Pathogenesis of Transmembrane Prion Protein

The C-transmembrane form of prion protein ((Ctm)PrP) has been implicated in prion disease pathogenesis, but the factors underlying its biogenesis and cyotoxic potential remain unclear. Here we show that (Ctm)PrP interferes with cytokinesis in cell lines where it is transported to the plasma membrane. These cells fail to separate following cell division, assume a variety of shapes and sizes, and contain multiple nuclei, some of which are pyknotic. Furthermore, the synthesis and transport of (Ctm)PrP to the plasma membrane are modulated through a complex interaction between cis- and trans-acting factors and the endoplasmic reticulum translocation machinery. Thus, insertion of eight amino acids before or within the N region of the N signal peptide (N-SP) of PrP results in the exclusive synthesis of (Ctm)PrP regardless of the charge conferred to the N region. Subsequent processing and transport of (Ctm)PrP are modulated by specific amino acids in the N region of the N-SP and by the cell line of expression. Although the trigger for (Ctm)PrP upregulation in naturally occurring prion disorders remains elusive, these data highlight the underlying mechanisms of (Ctm)PrP biogenesis and neurotoxicity and reinforce the idea that (Ctm)PrP may serve as the proximate cause of neuronal death in certain prion disorders.
Factor structure of the Henderson Environmental Learning Process Scale.

Summary.-The Henderson Environmental Learning Process Scale (HELPS) was administered to the primary caregivers of 185 elementary school children enrolled in self-contained classes for the learning handicapped. Scores on four annual administrations of the instrument were aggregated, and the data were subjected to a principal-factor analysis. The resulting six factorsReinforcement, Community Involvement, Intellectual Guidance, Role Playing, Expectations, and Literacy--did not correspond closely to those found by Henderson, Bergan, and Hunt in a previous study. The pioneering research of Dave (1963) and Wolf (1964) led directly to a number of efforts to identify variables in the home environment that are related to children's intelligence and academic achievement (Hanson, 1975; Mosychuk, 1966; Radin, 1969). The Henderson Environmental Learning Process Scale (HELPS) (Henderson, Bergan, & Hunt, 1972) is one product of these efforts. In its original form, it was a 55-item questionnairedesigned to elicit responses bearing on environmental stimulation, parental guidance, models, reinforcement, and level of aspiration. Henderson, et al. (1972) administered the HELPS to the mothers of 126 first graders and selected the 25 items that were most highly correlated with the total score for further study. Raw scores on these items were adjusted to control for response bias (Bergan, 1968), and the data were subjected to a principal-component analysis. The resulting five factors-Extended Interests and Community Involvement, Valuing Language and School Related Behavior, Intellectual Guidance, Providing a Supportive Environment for School Learning, and AttentionAid not generally correspond to the factors hypothesized. The purpose of the present study was to reexamine the factor structure of the HELPS. For this purpose, we elected to return to the original item pool but eliminated four items that depended upon the presence of a father or father surrogate in the home. We also chose to use raw scores rather than adjusting them to control for response bias. Our sample consisted of 185 primary caregivers, almost all of them the mothers, of elementary school children enrolled in self-contained classes for the learning handicapped (educable mentally retarded and educationally handicapped) in four Southern California counties.
Generation of Trypanosoma cruzi-Specific CD8+ T-Cell Immunity Is Unaffected by the Absence of Type I Interferon Signaling

Trypanosoma cruzi is a protozoan parasite that causes human Chagas’ disease, a leading source of congestive heart failure in Central and South America. CD8+ T cells are critical for control of T. cruzi infection, and CD8+ T cells recognizing the immunodominant trans-sialidase gene-encoded peptide TSKB20 (ANYKFTLV) account for approximately 30% of the total CD8+ T-cell population at the peak of infection in C57BL/6 mice. Type I interferons (IFN-I) are pleiotropic cytokines that play a critical role in both innate and adaptive immunity against a variety of infections, but their induction and their role in infection are dictated by the infectious agent. Because type I IFNs and IFN-responsive genes are evident early after T. cruzi infection of host cells, we examined the influence of IFN-I on the development of CD8+ T-cell responses during this infection. Mice lacking the receptor for IFN-I (IFNARKO) and their wild-type counterparts both developed chronic infections and generated similar frequencies of immunodominant TSKB20- and subdominant TSKB18-specific CD8+ T cells following T. cruzi infection. In contrast, peak TSKB20-specific CD8+ T-cell responses generated during infection with vaccinia virus engineered to express TSKB20 were approximately 2.5-fold lower in IFNARKO mice than B6 mice, although after viral clearance, the frequencies of TSKB20-specific CD8+ T cells stabilized at similar levels. Together, these data suggest that IFN-I induction and biology are dependent upon the microbial context and emphasize the need to investigate various infection models for a full understanding of CD8+ T-cell development.
Re-inventing intratumoral immunotherapy for melanoma

Immunotherapeutics have been applied intratumorally to manage accessible lesions and to induce systemic immunity in malignant melanoma. Intratumoral bacillus Calmette-Guerin (BCG) has been used for 40 years, and intratumoral BCG, IL-2, IFN-α and imiquimod are recommended as treatment options for patients with in-transit melanoma metastases. Regression of cutaneous metastases can be achieved. Subcutaneous metastases are more refractory, and regression of uninjected, visceral metastases is infrequent. Other microbial products, cytokines, chemicals, immune cells, antibody and viral and plasmid vectors expressing immunologically active molecules have been tested. Antitumor activity has not been demonstrated to be superior to that of intratumoral BCG. There are few controlled trials, and whether survival is impacted with any approach has not yet been established. The immunotherapeutics applied and the intratumoral administration procedure itself can activate responses that are immune inhibitory. More rigorous ...
A Physiologically Based Pharmacokinetic Model for Inhalation and Intravenous Administration of Naphthalene in Rats and Mice

A diffusion limited physiologically based pharmacokinetic model for rats and mice was developed to characterize the absorption, distribution, metabolism, and elimination of naphthalene after inhalation exposure. This model includes compartments for arterial and venous blood, lung, liver, kidney, fat, and other organs. Primary sites for naphthalene metabolism to naphthalene oxide are the lung and the liver. The data used to create this model were generated from National Toxicology Program inhalation and iv studies on naphthalene and consisted of blood time-course data of the parent compound in both rats and mice. To examine the basis for possible interspecies differences in response to naphthalene, the model was extended to describe the distribution and metabolism of naphthalene oxide and the depletion and resynthesis of glutathione. After testing several alternative models, the one presented in this paper shows the best fit to the data with the fewest assumptions possible. The model indicates that tissue dosimetry of the parent compound alone does not explain why this chemical was carcinogenic to the female mouse lung but not to the rat lung. The species difference may be due to a combination of higher levels of naphthalene oxide in the mouse lung and a greater susceptibility of the mouse lung to epoxide-induced carcinogenesis. However, conclusions regarding which metabolite(s) may be responsible for the lung toxicity could not be reached.
THE ROLE OF FLOODS IN PARTICULATE ORGANIC MATTER DYNAMICS OF A SOUTHERN APPALACHIAN RIVER/FLOODPLAIN ECOSYSTEM

We investigated the effect of a flood on particulate organic matter (POM) dynamics in the floodplain and active channel of the Little Tennessee River in western North Carolina. We mea- sured litterfall, leaf breakdown, and floodplain litter (before and after the flood) at 12 sites. Annual litterfall (256-562 g m22 y21) was typical of a temperate deciduous forest but lower than lowland floodplain forests in the eastern US. Leaf breakdown rates of 4 tree species (Acer rubrum, Carpinus caroliniana, Juglans nigra ,a ndPlatanus occidentalis) ranged from 0.001 to 0.010/d. We separated the 12 sites into 2 groups (inundated and non-inundated) based on the degree of flooding after a flood on 8 January 1998 and determined POM exchange between the active channel and floodplain. Significant transport of leaves from the floodplain to the river occurred at inundated sites, but transport of herbaceous or woody material did not occur. The flood increased leaf breakdown rates of all 4 tree species. Our measurements of litterfall, leaf breakdown, and floodplain litter standing crop suggest that leaves entrained from the floodplain of Little Tennessee River during floods are a source of POM to the active channel. However, flood input of leaves to the river were a small source of POM com- pared to direct leaffall.
Interaction Effects of Emotional Status and Sexual Abuse on Adult Sexuality

This study examined the additive, interaction effects of emotional status with sexual abuse on adult sexual functioning and sexual responsibility. The Golombok Rust Inventory of Sexual Satisfaction (GRISS; Rust & Golombok, 1986), the Personality Assessment Inventory (PAI; Morey, 1991), and a questionnaire regarding sexual experiences, number of unwanted pregnancies, number of unsafe sexual partners, and sexual abuse history, were administered to 200 psychology students. One hundred and forty-three participants were retained in the study. Two-way multivariate analyses of variance (MANOVA) were conducted for the sexual functioning variables (as measured by the GRISS), while two-way analyses of variance (ANOVA) were conducted for the sexual irresponsibility variables (as measured by the sexual experiences questionnaire). It was found that women who have high anxiety scores on the PAI and have a history of sexual abuse reported higher numbers of unwanted pregnancies, while sexual abuse history was not associated with numbers of unwanted pregnancies for women with lower levels of anxiety. Results were not significant, however, for the sexual functioning variables. In addition, depression and alcoholism did not have interacting effect on the association between sexual abuse history and any of the sexuality variables. These results may suggest that the effects of sexual abuse on adult sexuality may not be as pervasive as was once thought.
Soil–pile interaction during the passage of rayleigh waves: An analytical solution

A simple analytical solution is presented to calculate the single-pile response when excited by the passage of Rayleigh seismic waves. Closed-form expressions for the horizontal and vertical displacement distributions are presented for piles with finite or infinite length. The analytical results for both free-head and fixed-head piles are obtained through a dynamic Winkler model, with realistic frequency-dependent ‘springs’ and ‘dashpots’. The results of the presented method are in excellent agreement with results of a rigorous solution. It is shown that in vertical motion, the differences between pile and soil displacements are far more significant than in horizontal motion, and therefore, further work is needed to investigate the importance of pile-soil-pile interaction (group effects), because of the vertical component of Rayleigh seismic waves.
Febrile Ulceronecrotic Mucha-Habermann Disease in a 34-Month-Old Boy: A Case Report and Review of the Literature

We report a case of febrile ulceronecrotic Mucha-Habermann disease (FUMHD) in a 34-month-old boy. Our patient had a history of biopsy-proven pityriasis lichenoides et varioliformis acuta (PLEVA) since age 2. At 34 months, his skin lesions rapidly progressed to ulceration and necrosis in the setting of high fever. Skin biopsy revealed an intense lichenoid infiltrate with parakeratosis at the edges of areas of epidermal necrosis consistent with FUMHD, which is the severe variant of PLEVA. Despite initial treatment with prednisolone, his disease progressed to involve more than 50% of his body surface area. In addition to corticosteroids, he was treated with intravenous immunoglobulin, dapsone, and acyclovir, without complete resolution of disease. Methotrexate successfully cleared his skin disease and systemic symptoms. This patient highlights the exceptional response of FUMHD to methotrexate. Based on our review of the literature, this also represents the youngest reported case of FUMHD.
Rapid restoration of critical infrastructures: an all-hazards paradigm for fusion centres

This paper takes a holistic approach to rapid restoration of critical infrastructures and key resources (CIKR) in the USA. In the wake of Hurricane Katrina, the all-hazards paradigm remains vital to the homeland security mission. A proposal is presented to overhaul state and local fusion centre guidelines to build on existing counterterrorism functions through the incorporation of compulsory all-hazards analytic capabilities with a core focus on CIKR support. In this role, fusion centres will be able to work with public and private sector partners in a unified preparation and mitigation effort, subsequently acting as force multipliers for community stakeholder-driven rapid restoration of CIKR following any type of emergency.
The 13C4 Monoclonal Antibody That Neutralizes Shiga Toxin Type 1 (Stx1) Recognizes Three Regions on the Stx1 B Subunit and Prevents Stx1 from Binding to Its Eukaryotic Receptor Globotriaosylceramide

The 13C4 monoclonal antibody (MAb) recognizes the B subunit of Stx1 (StxB1) and neutralizes the cytotoxic and lethal activities of Stx1. However, this MAb does not bind to the B polypeptide of Stx2, despite the 73% amino acid sequence similarity between StxB1 and StxB2. When we compared the amino acid sequences of StxB1 and StxB2, we noted three regions of dissimilarity (amino acids 1 to 6, 25 to 32, and 54 to 61) located near each other on the crystal structure of StxB1. To identify the 13C4 epitope, we generated seven Stx1/Stx2 B chimeric polypeptides that contained one, two, or three of the dissimilar StxB1 regions. The 13C4 MAb reacted strongly with StxB1 and the triple-chimeric B subunit but not with the other chimeras. Mice immunized with the triple-chimeric B subunit survived a lethal challenge with Stx1 but not Stx2, substantiating the identified regions as the 13C4 MAb epitope and suggesting that the incorporation of this epitope into StxB2 altered sites necessary for anti-Stx2-neutralizing Ab production. Next, single amino acid substitutions were made in StxB1 to mimic Stx1d, a variant not recognized by the 13C4 MAb. The 13C4 MAb reacted strongly to StxB1 with the T1A or G25A mutations but not with the N55T change. Finally, we found that the 13C4 MAb blocked the binding of Stx1 to its receptor, globotriaosyl ceramide. Taken together, these results indicate that the 13C4 MAb prevents the interaction of Stx1 with its receptor by binding three nonlinear regions of the molecule that span receptor recognition sites on StxB1, one of which includes the essential residue 55N.
Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors

G protein-coupled receptors (GPCRs) are an evolutionarily conserved family of signaling molecules comprising approximately 2% of the human genome; this receptor family remains a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of drug action at GPCRs over the past decade have revealed existing and novel ligands that exhibit polypharmacology-that is, drugs with activity at more than one receptor target for which they were designed. These "off-target" drug actions can be a liability that causes adverse side effects; however, in several cases, drugs with less selectivity demonstrate better clinical efficacy. Here we review physical screening and cheminformatic approaches that define drug activity at the GPCR receptorome. In many cases, such profiling has revealed unexpected targets that explain therapeutic actions as well as off-targets underlying drug side effects. Such drug-receptor profiling has also provided new insights into mechanisms of action of existing drugs and has suggested directions for future drug development.
Precision resistors: a review of material characteristics, resistor design, and construction practices

An understanding of the properties of resistance materials and of the effects on resistor characteristics of construction practice is necessary to assure optimum application. Reviewed are some of the characteristics of moderate-precision film resistors, the nature of the principal high performance resistance alloys and the design and construction of high-precision resistors. The effects of resistor termination and terminals are also reviewed with emphasis on the requirements necessary to produce four-terminal and series-parallel connections.
Using flow geometry for drifter deployment in Lagrangian data assimilation

Methods of Lagrangian data assimilation (LaDA) require carefully chosen sites for optimal drifter deployments. In this work, we investigate a directed drifter deployment strategy with a recently developed LaDA method employing an augmented state vector formulation for an Ensemble Kalman filter. We test our directed drifter deployment strategy by targeting Lagrangian coherent flow structures of an unsteady double gyre flow to analyse how different release sites influence the performance of the method. We consider four different launch methods; a uniform launch, a saddle launch in which hyperbolic trajectories are targeted, a vortex centre launch, and a mixed launch targeting both saddles and centres. We show that global errors in the flow field require good dispersion of the drifters which can be realized with the saddle launch. Local errors on the other hand are effectively reduced by targeting specific flow features. In general, we conclude that it is best to target the strongest hyperbolic trajectories for shorter forecasts although vortex centres can produce good drifter dispersion upon bifurcating on longer time-scales.
Nonlinear Fredholm Integral Equations

It was stated in Chapter 4 that Fredholm integral equations arise in many scientific applications. It was also shown that Fredholm integral equations can be derived from boundary value problems. Erik Ivar Fredholm (1866–1927) is best remembered for his work on integral equations and spectral theory. Fredholm was a Swedish mathematician who established the theory of integral equations and his 1903 paper in Acta Mathematica played a major role in the establishment of operator theory. The linear Fredholm integral equations and the linear Fredholm integro-differential equations were presented in Chapters 4 and 6 respectively. It is our goal in this chapter to study the nonlinear Fredholm integral equations of the second kind and systems of nonlinear Fredholm integral equations of the second kind.
Alteration of Trabecular Aqueous Flow After Cataract Extraction

Two human eyes that had undergone intracapsular cataract extraction were perfused with cationized ferritin. In both eyes segmental areas of trabecular meshwork collapse were demonstrated superiorly, adjacent to the cataract incision. Electron-microscopic study of these regions disclosed no labeling of the trabecular beams and trabecular spaces, suggesting impermeability to aqueous flow. In other regions, a diffuse labeling with cationized ferritin was demonstrated throughout the trabecular spaces, indicating aqueous flowthrough. Use of corneoscleral sutures may cause trabecular collapse and impermeability. When the collapse is extensive, subsequent increase in intraocular pressure may follow.
Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2.

Protein tyrosine phosphatases (PTPs) have been the subject of considerable pharmaceutical-design efforts because of the ubiquitous connections between misregulation of PTP activity and human disease. PTP-inhibitor discovery has been hampered, however, by the difficulty in identifying cell-permeable compounds that can selectively target PTP active sites, and no PTP inhibitors have progressed to the clinic. The identification of allosteric sites on target PTPs therefore represents a potentially attractive solution to the druggability problem of PTPs. Here we report that the oncogenic PTP Shp2 contains an allosteric-inhibition site that renders the enzyme sensitive to potent and selective inhibition by cell-permeable biarsenical compounds. Because Shp2 contains no canonical tetracysteine biarsenical-binding motif, the enzyme’s inhibitor-binding site is not readily predictable from its primary or three-dimensional structure. Intriguingly, however, Shp2’s PTP domain does contain a cysteine residue (C333) at a position that is removed from the active site and is occupied by proline in other classical PTPs. We show that Shp2’s unusual cysteine residue constitutes part of a Shp2-specific allosteric-inhibition site, and that Shp2’s sensitivity to biarsenicals is dependent on the presence of the naturally occurring C333. The determinative role of this residue in conferring inhibitor sensitivity is surprising because C333’s side chain is inaccessible to solvent in Shp2 crystal structures. The discovery of this cryptic Shp2 allosteric site may provide a means for targeting Shp2 activity with high specificity and suggests that buried-yet-targetable allosteric sites could be similarly uncovered in other protein families.
Abstract 3149: MicroRNA-141 inhibits proliferation and invasion by suppressing the Wnt signaling pathway in renal cell carcinoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL MicroRNAs (miRNAs) are highly conserved, single stranded, non-coding RNAs of approximately 22 nucleotides that regulate gene expression by posttranscriptional silencing of specific target mRNAs, by repressing translation or cleaving RNA transcripts. miRNAs regulate diverse cellular processes such as cell-cycle progression, proliferation, apoptosis and development. miRNAs have been shown to function as oncogenes or tumor suppressor genes. MicroRNA-141 has recently been reported to play a role in the epithelial to mesenchymal transition (EMT) process and the expression of miR-141 is inversely correlated with tumorigenicity and invasiveness in several human cancers. The function of miR-141 in renal cell carcinoma has not been studied, therefore we studied the functional effects of miR-141 on renal cell carcinoma. We found that miR-141 was down regulated in human kidney cancer tissues compared with adjacent normal tissues. We also found that miR-141 was down regulated in renal cell carcinoma human cell lines, 769P, 786-O and ACHN compared with normal kidney cell line, HK-2. Transfection of miR-141 into renal cell carcinoma cells promoted apoptosis, inhibited in vitro cell proliferation and inhibited cell invasion. We found that miR-141 has a binding site in 3′UTR of the TCF7L2 (Transcription factor 7-like 2) gene which can activate the canonical Wnt pathway. miR-141 was found to down regulate expression of TCF7L2 by targeting its 3′ UTR as shown by luciferase reporter assays in renal cell carcinoma. Luciferase assays using T cell factor (TCF) reporter plasmids also showed that miR-141 represses TCF/LEF transcriptional activity, indicating that miR-141 suppresses the canonical Wnt pathway in renal cell carcinoma. Our results demonstrate that miR-141 suppresses malignancy by targeting TCF7L2 and inhibiting the Wnt signaling pathway in renal cell carcinoma. Source of Funding: Grants R01CA138642, VA Research Enhancement Award Program (REAP), and VA Merit Review grants Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3149. doi:1538-7445.AM2012-3149
Retroperitoneal Lymphadenectomy for Clinical Stage a Testis Cancer (1965 to 1989): Modifications of Technique and Impact on Ejaculation

Results with primary retroperitoneal lymphadenectomy in 464 patients with clinical stage A nonseminomatous germ cell testis cancer (1965 to 1989) were reviewed. The false-negative staging error by clinical methods remains at 30%. The relapse rate in pathological stage A cancer patients was 11% (37 of 323), with 2 deaths. For pathological stage B disease 64% of the patients were cured by retroperitoneal lymphadenectomy alone. With modern adjuvant chemotherapy no stage B tumor relapsed since 1979 and the survival rate was 100%. For all 25 years (464 patients) the relapse rate was 14% and the survival rate was 98.9% (3 cancer and 2 noncancer deaths). Because these results are based on preoperative clinical staging, they are directly comparable with series using radiotherapy or surveillance.
Unrelated donors are associated with improved relapse-free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem cell transplantation.

Reduced intensity allogeneic stem cell transplantation (RI alloSCT) is a potentially curative treatment approach for patients with myelodysplastic syndrome (MDS). It is currently unclear if older related donors are better than younger unrelated donors for patients with MDS undergoing RI alloSCT. We retrospectively studied 53 consecutive MDS patients who underwent RI alloSCT between April 2007 and June 2014 and evaluated associations between donor type and outcomes with adjustment for significant covariates. 34 patients (median age: 64 years) and 19 patients (median age: 60 years) received allografts from unrelated and related donors, respectively. Unrelated donors were younger than related donors (median age: 32 vs. 60 years, P < 0.0001). There were no significant differences in baseline disease characteristics of patients receiving allografts from related or unrelated donors. Patients who received allografts from unrelated donors had a lower relapse risk (adjusted hazard ratio [aHR] = 0.35, P = 0.012) and improved relapse-free survival (aHR = 0.47, P = 0.018). HLA mismatched unrelated donors were associated with a higher risk of grade 2-4 acute graft versus host disease (GVHD) (HR = 4.64, P = 0.002) without an accompanying increase in the risk of non-relapse mortality (P = 0.56). Unrelated donors provided a higher mean CD8 cell dose (P = 0.014) and were associated with higher median donor T cell chimerism at day 60 (P = 0.003) and day 100 (P = 0.03). In conclusion, patients with MDS who received allografts from unrelated donors had a lower risk of relapse and improved relapse-free survival when compared to patients who received allografts from related donors. These findings should be confirmed in a prospective study. Am. J. Hematol. 91:883-887, 2016. © 2016 Wiley Periodicals, Inc.
Correlation of Behavioral Interviewing Performance With Obstetrics and Gynecology Residency Applicant Characteristics

Objective To determine which individual residency applicant characteristics were associated with improved performance on standardized behavioral interviews. Behavioral interviewing has become a common technique for assessing resident applicants. Few data exist on factors that predict success during the behavioral interview component of the residency application process. Design Interviewers were trained in behavioral interviewing techniques before each application season. Standardized questions were used. Behavioral interview scores and Electronic Residency Application Service data from residency applicants was collected prospectively for 3 years. Setting It included the Accreditation Council for Graduate Medical Education–accredited obstetrics-gynecology residency program at a Midwestern academic medical center. Participants Medical students applying to a single obstetrics-gynecology residency program from 2012 to 2014 participated in the study. Results Data were collected from 104 applicants during 3 successive interview seasons. Applicant’s age was associated with higher overall scores on questions about leadership, coping, and conflict management (for applicants aged ≤25, 26-27, or ≥28 y, mean scores were 15.2, 16.0, and 17.2, respectively; p = 0.03), as was a history of employment before medical school (16.8 vs 15.5; p = 0.03). Applicants who participated in collegiate team sports scored lower on questions asking influence/persuasion, initiative, and relationship management compared with those who did not (mean, 15.5 vs 17.1; p = 0.02). Conclusions Advanced applicant age and history of work experience before medical school may improve skills in dealing with difficult situations and offer opportunities in leadership. In the behavioral interview format, having relevant examples from life experience to share during the interviews may improve the quality of the applicant’s responses. Increased awareness of the factors predicting interview performance helps inform the selection process and allows program directors to prioritize the most appropriate candidates for the match.
Friends in Low Places

It has become common, and almost boring, to hear that poetry has died or is undergoing a slow, silently wailing death. Every few years a manifesto will appear that announces again the demise of what some see as an antiquated form of expression that no one reads and that only a few people pretend to enjoy.
Artifacts on Craniocervical CT Angiography

With the advent in the late 1990s of multichannel, multidetector (also called “multislice”) technology for CT, and its subsequent implementation, the performance of CT angiography (CTA) has been augmented in terms of coverage, speed, and dose efficiency. Overall, perhaps more than 95 % of examinations are interpretable and have adequate contrast attenuation (>150 HU), and more than 85 % have adequate difference in contrast density (>50 HU) between arteries and veins for the purpose of CTA. However, there are a number of artifacts that can limit CTA evaluation and potentially lead to false interpretation. Kim et al. describe these artifacts in detail, but for the purposes of discussion here, these are the most common: Streak artifact from dense contrast material in adjacent veins, such as within a subclavian vein or brachiocephalic vein that may obscure visualization of an adjacent common carotid artery or vertebral artery Streak artifact or decreased attenuation horizontally due to the shoulders Streak or beam-hardening artifact from metal such as dental amalgam Contrast reflux into neck veins Flow-related artifacts due to the high speed of multislice CT acquisition Motion artifacts
Experimental evidence that ooid size reflects a dynamic equilibrium between rapid precipitation and abrasion rates

Ooids are enigmatic concentrically coated carbonate sand grains that reflect a fundamental mode of carbonate sedimentation and inorganic product of the carbon cycle—trends in their composition and size are thought to record changes in seawater chemistry over Earth history. Substantial debate persists concerning the roles of physical, chemical, and microbial processes in their growth, including whether carbonate precipitation on ooid surfaces is driven by seawater chemistry or microbial activity, and what role—if any—sediment transport and abrasion play. To test these ideas, we developed an approach to study ooids in the laboratory employing sediment transport stages and seawater chemistry similar to natural environments. Ooid abrasion and precipitation rates in the experiments were four orders of magnitude faster than radiocarbon net growth rates of natural ooids, implying that ooids approach a stable size representing a dynamic equilibrium between precipitation and abrasion. Results demonstrate that the physical environment is as important as seawater chemistry in controlling ooid growth and, more generally, that sediment transport plays a significant role in chemical sedimentary systems.