cssi/SciSciGPT-SciSciNet huggingface dataset:
Abstract 5461: The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The goal of precision medicine is to use patient-specific markers to design individualized treatment strategies. Promoter methylation of O6-methylguanine-DNA methyltransferase (MGMT), which encodes for the DNA repair protein MGMT, has been shown to predict glioblastoma patient survival after treatment with temozolomide. Unfortunately, there is no approved therapeutic alternative for patients whose tumors have an unmethylated MGMT promoter and are unlikely to respond to temozolomide treatment. Promoter methylation status of MGMT is used to predict expression levels of MGMT, despite some observed discordance between promoter methylation and protein levels. We hypothesized that incorporation of MGMT gene body cytosine modification levels in models of temozolomide response may lead to better prediction of MGMT expression levels and, more importantly, improved methods of prediction for glioblastoma patient response to temozolomide. Using 91 human glioblastoma samples from The Cancer Genome Atlas, we observed significant variation in MGMT expression levels in patients with an unmethylated promoter, with higher levels of gene body cytosine modification correlating with higher gene expression levels. Furthermore, inducing hypomethylation across the MGMT gene body with decitabine resulted in decreased levels of MGMT gene expression in lymphoblastoid and glioblastoma cell lines. These data indicate an important functional role for gene body cytosine modifications in maintaining gene expression levels. We reasoned that the decrease in MGMT expression induced by decitabine might render resistant glioblastoma cell lines more sensitive to temozolomide. Indeed, MGMT-expressing glioblastoma cell lines pre-treated with decitabine became significantly more sensitive to temozolomide-induced cytotoxicity. Overall, our results demonstrate a functional role for gene body cytosine modification in regulating gene expression of MGMT and suggest that patients with an unmethylated MGMT promoter could benefit from pre-treatment with decitabine to increase tumor sensitivity to temozolomide. Citation Format: Erika L. Moen, Amy L. Stark, Wei Zhang, M. Eileen Dolan, Lucy A. Godley. The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5461. doi:10.1158/1538-7445.AM2014-5461
Recognition of virally transformed cells by lymphocytes from patients with prostatic cancer

Abstract Data presented describe the first assay using human peripheral blood lymphocyte (PBL) against two unique virally transformed cell lines in vitro. Human cells transformed by a cytomegalovirus (CMV-Mj) isolated from normal human prostate tissue were used as target cells in microcytotoxicity assays with lymphocytes from 100 patients. Three target cell types were used: control human embryonic lung cells (HEL), transformed HEL cells (CMV-Mj-HEL-2), and transformed HEL cells retrieved from tumors induced in athymic nude mice (CMV-Mj-HEL-2, T-1) by injection of CMV-Mj-HEL-2 cells. PBL preparations from 84 per cent of all patients tested significantly killed CMV-Mj-HEL-2, T-1 cells. However, only PBL from patients with prostatic carcinoma were cytotoxic for CMV-Mj-HEL-2 cells significantly more often than for control HEL. The implications of this approach are discussed.
The Role of Adaptation in Archaeological Explanation

Adaptation, a venerable icon in archaeology, often is afforded the vacuous role of being an ex-post-facto argument used to "explain" the appearance and persistence of traits among prehistoric groups—a position that has seriously impeded development of a selectionist perspective in archaeology. Biological and philosophical definitions of adaptation—and by extension, definitions of adaptedness—vary considerably, but all are far removed from those usually employed in archaeology. The prevailing view in biology is that adaptations are features that were shaped by natural selection and that increase the adaptedness of an organism. Thus adaptations are separated from other features that may contribute to adaptedness but are products of other evolutionary processes. Analysis of adaptation comprises two stages: showing that a feature was under selection and how the feature functioned relative to the potential adaptedness of its bearers. The archaeological record contains a wealth of information pertinent to examining the adaptedness of prehistoric groups, but attempts to use it will prove successful only if a clear understanding exists of what adaptation is and is not.
Physical organic photochemistry

Physical organic photochemistry has been concerned with the systematic investigation of structure-reactivity relationships involved in the photophysics and photochemistry of organic molecules. The field relies heavily on the use of physical and computational methods to elucidate mechanistic pathways that allow an understanding of the molecular basis of observed or predicted structure-reactivity relationships. Determination of rate laws through kinetic analysis, syntheses of “tailor made” structures to test theories or mechanisms, and the use of product structure has been the dominant tool in physical organic chemistry and has shown similar validity in physical organic photochemistry. Reactive intermediates, which were postulated to explain observed products, have played an important role in the development of physical organic chemistry. In physical organic photochemistry these reactive intermediates have often been directly detected by time resolved spectroscopic methods. During the 1960s the methods of physical organic photochemistry typically involved steady state kinetics, product analysis and the assumption of triplets as ubiquitous intermediates. During the 1970s time resolved methods became available and traditional reactive intermediates (carbenes, ylides, radicals, biradicals etc.) became accessible to direct spectroscopic observation, characterization and investigation. In addition, singlet states, exciplexes and radical ions were added to the list of commonly occurring reactive intermediates. There was a shift in the theoretical framework for thinking about photochemical reactions from the state diagram level to the energy surface level. During the 1980s the use of sophisticated instrumentation and time resolution of the order of nanoseconds became more common. During this period the pervasive occurrence of electron transfer processes in organic photochemical reactions became apparent, and reactive intermediates such as contact ion pairs and solvent separated ion pairs became familiar in a variety of reactions. A major change occurred as photochemists began to investigate photoprocesses occurring in microheterogeneous systems such as micelles, cyclodextrins, polymers, and porous solids. It was discovered that weak magnetic fields can strongly modify photoprocesses which occur in microheterogeneous media if radical pairs or biradicals are involved . Since my last review in 1984, the basic paradigms for investigating organic photochemistry have not changed very much, but advances in instrumentation have continued to have a major impact on the field. For example
Phonon Focusing in Solids

In phonon-propagation studies using heat pulses it has been found that predominantly transverse phonons are observed for [100] propagation in LiF whereas mainly longitudinal phonons are observed for this direction in KCl. This result and similar effects previously reported on other crystals are explained in terms of a phonon-focusing effect that arises from elastic anisotropy.
Direct infrared measurements of phased-array antenna source distributions

A thermal imaging technique has been developed to measure electromagnetic (EM) fields. This technique is applied in this paper to measure the EM fields radiated by phased array antennas. This thermal technique is based on infrared (IR) measurements of the heat patterns produced in a thin, lossy detector screen placed near the antenna in the plane over which the field is to be measured. A low-loss, planar detector screen was made from a carbon loaded polyimide film to measure the intensity distribution of the electric field radiated from the antenna. The Joule (conductive) heating in the screen causes the temperature of the screen to rise in proportion to the intensity of the wave incident on the screen. The temperature distribution on the surface of the film is captured with an IR imaging camera. The magnitude of the radiated field at each location in the detector screen (on a pixel by pixel basis) is determined directly from the temperature distribution in the IR thermogram of the field. The temperature rise in the screen material (over the ambient background temperature of the screen) was measured at NIST/Boulder when the screen was irradiated by a plane wave of known intensity. A calibration table of measured temperature rise versus expected field intensity was obtained for the detector screen. This thermal imaging technique has the advantages of simplicity, speed, and portability over existing hard-wired probe methods and produces a 2D picture (a pseudo-color image) of the field. In general, these images can be used for field diagnostics of the antenna (near-field or far-field patterns) and/or to evaluate the aperture excitation of the array. In particular, the source distribution in the aperture plane of the antenna was measured. This distribution can be compared to a standard 'test pattern', e.g., full power, equal-phase, broadside illumination, to determine the operational state of each individual element of the array, which controls the radiation pattern of the antenna. Phase shifters and/or attenuators which produce incorrect element phase magnitudes or phase shifts can be identified with this technique. Faulty elements, once located, can be repaired.
Cu isotope fractionation during bornite dissolution: An in situ X-ray diffraction analysis

Abstract Low-temperature ore deposits exhibit a large variation in δ 65 Cu (~ 12‰), and this range has been attributed, in part, to isotope fractionation during weathering reactions of primary minerals such as chalcocite and chalcopyrite. Here, we examine the fractionation of Cu isotopes during dissolution of another important Cu ore mineral, bornite, using a novel approach that combines time-resolved X-ray diffraction (XRD) and isotope analysis of reaction products. During the initial stages of bornite oxidative dissolution by ferric sulfate ( 65 Cu) relative to the solid, with an average apparent isotope fractionation (Δ aq − min = δ 65 Cu aq − δ 65 Cu min 0 ) of 2.20 ± 0.25‰. When > 20 mol% Cu was leached from the solid, the difference between the Cu isotope composition of the aqueous and mineral phases approached zero, with ∆ aq − min 0 values ranging from − 0.21 ± 0.61‰ to 0.92 ± 0.25‰. XRD analysis allowed us to correlate changes in the atomic structure of bornite with the apparent isotope fractionation as the dissolution reaction progressed. These data revealed that the greatest degree of apparent fractionation is accompanied by a steep contraction in the unit-cell volume, which we identified as a transition from stoichiometric to non-stoichiometric bornite. We propose that the initially high ∆ aq − min values result from isotopically heavy Cu ( 65 Cu) concentrating within Cu 2+ during dissolution. The decrease in the apparent isotope fractionation as the reaction progresses occurs from the distillation of isotopically heavy Cu ( 65 Cu) during dissolution or kinetic isotope effects associated with the depletion of Cu from the surfaces of bornite particles.
GAD and GABA transporter (GAT-1) mRNA expression in the developing rat hippocampus

Synaptic inhibition in the mammalian central nervous system is mostly mediated by GABA (γ-aminobutyric acid). Inhibitory interneurons can be identified by staining for glutamate decarboxylase (GAD), the key enzyme which produces the transmitter. After release, GABA is removed from the extracellular space by specific transporters which are localized at the presynaptic endings of interneurons, in adjacent glial processes and, possibly, also in the postsynaptic target cell membranes. The GABAergic system undergoes profound functional and structural changes during the first 2 weeks of postnatal development, including migration of interneurons and changes in the level of expression and subcellular distribution of GABA transporters. We therefore analyzed the distribution of mRNA coding for GAD and GAT-1 (the main neuronal GABA transporter) in the developing rat hippocampus. Our data show that both transcripts are present in putative interneurons from the first postnatal day and exhibit a largely similar distribution throughout postnatal ontogenesis, with some specific differences in certain hippocampal subfields. Quantification of stained somata confirmed the postnatal redistribution of putative interneurons in the area dentata from dendritic layers towards the hilus. We also found a general staining of principal cell layers for both probes, which differs with postnatal age and between GAD and GAT-1 mRNA. Together, our data reveal a profound reorganization of the GABAergic system in the rat hippocampus during the first weeks of postnatal development.
Structural requirements of ceramide and sphingosine based inhibitors of mitochondrial ceramidase.

The effects of structural analogues of ceramide on rat brain mitochondrial ceramidase (mt-CDase) were investigated. Design of target compounds was mainly based on modifications of the key elements in ceramide and sphingosine, including stereochemistry, the primary and secondary hydroxyl groups, the trans double bond in the sphingosine backbone, and the amide bond. Mt-CDase was inhibited by (1) all stereoisomers of d-erythro-ceramide (d-e-Cer) with an IC50 of 0.11, 0.21, and 0.26 mol % for the l-threo, d-threo, and l-erythro isomers, respectively; (2) all stereoisomers of sphingosine with IC50 ranging from 0.04 to 0.14 mol %, N-methyl-d-erythro-sphingosine (N-Me-Sph, IC50 0.13 mol %); and (3) d-erythro-urea-C16-ceramide (C16-urea-Cer IC50 0.33 mol %). The enzyme was not inhibited by N-methyl ceramide (N-Me-C16-Cer), 1-O-methyl ceramide (1-O-Me-C16-Cer), 3-O-methyl ceramide (3-O-Me-C16-Cer), cis-d-erythro ceramide (cis-d-e-C16-Cer) and 3-O-methyl-d-erythro-sphingosine (3-O-Me-Sph). It was less potently inhi...
Aggression control in a bachelor herd of fringe-eared oryx (Oryx gazella callotis), with melengestrol acetate: Behavioral and endocrine observations

Aggression control is becoming an important component in the management of animals in captivity, but rigorous quantification of aggressive behavior has heretofore been lacking. This study was done to assess the ability of melengestrol acetate (MGA) given with feed (1.54 mg/kg) to control aggression in a bachelor group of fringe-eared oryx (Oryx gazella callotis). Systematic behavioral observations were conducted and fecal androgen content was measured for 42 and 90 days, respectively, before treatment, and during the 42 days of treatment. There was a significant reduction in concentrations of fecal androgen from 153 ± 6.0 to 95 ± 4.5 ng/g (T66 = 7, P < 0.0001). This reduction in androgen excretion was apparent after the first week of treatment. There was measurable MGA excreted in the feces during treatment. Although treatment did not arrest all aggressive behaviors among animals, the decline in androgens and increase in MGA was accompanied by a significant reduction in several measures of agonistic behavior. Posturing, aggressive contact, pursuit, and submission occurred significantly less frequently after treatment, and there was also a reduction in fighting-intention movements. Thus, both ritualized and nonritualized aspects of aggression were affected. Reductions in hormones and aggressive behaviors coincided temporally, suggestive of a potential causal relationship. Consistent with this hypothesis is a strong positive correlation between fecal androgen and total aggressive acts. This effect was not the result of a single behavioral element but occurred across several categories of agonistic behavior. Zoo Biol 20:375–388, 2001. © 2001 Wiley-Liss, Inc.
Integration of well posedness analysis in software engineering

This paper advocates the use of well posedness analysis as a tool to use in software engineering. Well posedness analysis as a problem solving tool has seen too little use, especially in computer science and software engineering. A problem is well posed if and only if: (1) at least one solution exists, (2) at most one solution exists, and (3) the solution is stable. Here well posedness analysis is described as an augmentation to software engineering as an approach to improving software quality.
Simple Methods for Generating and Detecting Locus- Specific Mutations Induced with TALENs in the Zebrafish Genome

The zebrafish is a powerful experimental system for uncovering gene function in vertebrate organisms. Nevertheless, studies in the zebrafish have been limited by the approaches available for eliminating gene function. Here we present simple and efficient methods for inducing, detecting, and recovering mutations at virtually any locus in the zebrafish. Briefly, double-strand DNA breaks are induced at a locus of interest by synthetic nucleases, called TALENs. Subsequent host repair of the DNA lesions leads to the generation of insertion and deletion mutations at the targeted locus. To detect the induced DNA sequence alterations at targeted loci, genomes are examined using High Resolution Melt Analysis, an efficient and sensitive method for detecting the presence of newly arising sequence polymorphisms. As the DNA binding specificity of a TALEN is determined by a custom designed array of DNA recognition modules, each of which interacts with a single target nucleotide, TALENs with very high target sequence specificities can be easily generated. Using freely accessible reagents and Web-based software, and a very simple cloning strategy, a TALEN that uniquely recognizes a specific pre-determined locus in the zebrafish genome can be generated within days. Here we develop and test the activity of four TALENs directed at different target genes. Using the experimental approach described here, every embryo injected with RNA encoding a TALEN will acquire targeted mutations. Multiple independently arising mutations are produced in each growing embryo, and up to 50% of the host genomes may acquire a targeted mutation. Upon reaching adulthood, approximately 90% of these animals transmit targeted mutations to their progeny. Results presented here indicate the TALENs are highly sequence-specific and produce minimal off-target effects. In all, it takes about two weeks to create a target-specific TALEN and generate growing embryos that harbor an array of germ line mutations at a pre-specified locus.
Reconstruction of the spring ligament using a peroneus longus autograft tendon transfer.

Background: The spring (calcaneonavicular) ligament provides one of the main static supports of the medial arch of the foot. The purpose of this study was to retrospectively assess the results of p...
The Scattering of X-rays from Paraffin, Aluminum, Copper, and Lead

The radiation from a tungsten-target x-ray tube operated at 80 kv was filtered through 0.244 cm of aluminum and the intensities of the scattered radiations from paraffin, aluminum, copper, and lead were observed by the ionization method. The scattered intensities at angles in the range of 30\ifmmode^\circ\else\textdegree\fi{} to 120\ifmmode^\circ\else\textdegree\fi{} with the forward direction of the primary beam were compared with the scattered intensities at 90\ifmmode^\circ\else\textdegree\fi{}. Values of the intensity at 90\ifmmode^\circ\else\textdegree\fi{} for paraffin were compared with the intensity at 90\ifmmode^\circ\else\textdegree\fi{} for the other materials. The scattering from paraffin and aluminum was at an effective wave-length of 0.32A; from copper 0.26A, and from lead 0.27A. The Dirac value of the scattering from paraffin at 90\ifmmode^\circ\else\textdegree\fi{} was used as the basis for calculating the absolute values of the scattering per gram and the scattering per electron.
Review on Phase-Field Modeling of Microstructure Evolutions: Application to Electron Beam Additive Manufacturing

Powder-bed electron beam additive manufacturing (EBAM) is a relatively new technology to produce metallic parts in a layer by layer fashion by melting and fusing metallic powders. EBAM is a rapid solidification process and the properties of the parts depend on the solidification behavior as well as the microstructure of the build material. Thus, the prediction of part microstructures during the process may be an important factor for process optimization. Nowadays, the increase in computational power allows for direct simulations of microstructures during materials processing for specific manufacturing conditions. Among different methods, phase-field modeling (PFM) has recently emerged as a powerful computational technique for simulating microstructure evolutions at the mesoscale during a rapid solidification process. PFM describes microstructures using a set of conserved and non-conserved field variables and the evolution of the field variables are governed by Cahn-Hilliard and Allen-Cahn equations. By using the thermodynamics and kinetic parameters as input parameters in the model, PFM is able to simulate the evolution of complex microstructures during materials processing. The objective of this study is to achieve a thorough review of PFM techniques used in various processes, attempted for an application to microstructure evolutions during EBAM. The concept of diffuse interfaces, phase field variables, thermodynamic driving forces for microstructure evolutions and the kinetic phase-field equations are described in this paper.© 2014 ASME
Tropomyosin from adult human skeletal muscle is partially phosphorylated

Alpha and beta tropomyosins were isolated from postmortem adult human psoas and pectoralis major muscles. 1. 1. 31P nuclear magnetic resonance and amino acid analysis were used to show that 10% of the major alpha tropomyosin component was phosphorylated. 2. 2. The 31P NMR spectra also suggested that human beta tropomyosin was phosphorylated, but to a lesser extent.
EFFECTS OF SOIL PROPERTIES ON OVERLAND FLOW AND INFILTRATION

Soil properties have profound effects on overland flows over porous media. These effects are investigated by using a surface-subsurface flow conjunctive simulation model which solves the Saint- Venant equations for the overland flow and Richards' equation for the two-dimensional unsaturated and saturated porous medium flow. Guided by a dimensional analysis, four soil properties are studied, namely, porosity, vertical and horizontal saturated hydraulic conductivities, and unsaturated soil hydraulic characteristics which is expressed in two pairs of parameters describing the relationships between the degree of saturation and suction pressure, and between the relative conductivity and suction pressure, respectively. The results confirm the common belief that overland flow increases for decreasing soil porosity or saturated conductivity while the infiltration into the soil decreases. The effect of the ratio between horizontal and vertical saturated conductivity is insignificant, indicating the soil anisotropi...
Comparison of simultaneous electrophysiologic and mechanical effects of verapamil and nifedipine in cultured chick embryo ventricular cells

In order to examine possible differences in mechanisms of action of nifedipine and verapamil, simultaneous recordings of membrane potential and cell motion were made during exposure of cultured chick embryo ventricular cells to these drugs. Both verapamil and nifedipine produced a rapid negative inotropic effect and excitation-contraction coupling delay presumably related to the ability of both agents to inhibit Ca2+ influx via the slow Ca channel, and thus decrease the [Ca2+]i transient. However, for an equivalent negative inotropic effect, verapamil produced relatively more membrane diastolic depolarization and slowing of repolarization than did nifedipine. Verapamil also produced a more marked decrease in +dV/dtmax. In ion flux studies, it was demonstrated that verapamil produced a significant inhibition of 24Na influx, relative to control, whereas nifedipine did not. Verapamil also produced a slight decrease in 42K efflux, of borderline significance. These findings support previous results which indicate there are differences in the mechanisms of action of these Ca2+-channel blocking drugs.
Anesthesia- and opioids-related malpractice claims following tonsillectomy in USA: LexisNexis claims database 1984–2012

Summary Background Although commonly performed, tonsillectomy is not necessarily a low-risk procedure for litigation. We have reviewed malpractice claims involving fatal and nonfatal injuries following tonsillectomy with an emphasis on anesthesia- and opioid-related claims and their characteristics. Methods Tonsillectomy-related malpractice claims and jury verdict reports from the United States (US) between 1984 and 2012 found in the LexisNexis MEGA™ Jury Verdicts and Settlements database were reviewed by two independent reviewers. LexisNexis database collects nationwide surgical, anesthesia, and other malpractice claims. Data including years of case and verdicts, surgical, anesthetic and postoperative opioid-related complications, details of injury, death, cause of death, litigation result, and judgment awarded were analyzed. When there were discrepancies between the two independent reviewers, a third reviewer (SS) was involved for resolution. Inflation adjusted monetary awards were based on 2013 US dollars. Results There were 242 tonsillectomy-related claim reports of which 98 were fatal claims (40.5%) and 144 nonfatal injury claims (59.5%). Verdict/settlement information was available in 72% of cases (n = 175). The median age group of patients was 8.5 years (range 9 months to 60 years). Primary causes for fatal claims were related to surgical factors (n = 39/98, 39.8%) followed by anesthesia-related (n = 36/98, 36.7%) and opioid-related factors (n = 16/98, 16.3%). Nonfatal injury claims were related to surgical (101/144, 70.1%), anesthesia (32/144, 22.2%)- and opioid-related factors (6/144, 4.2%). Sleep apnea was recorded in 17 fatal (17.4%) and 15 nonfatal claims (10.4%). Opioid-related claims had the largest median monetary awards for both fatal ($1 625 892) and nonfatal injury ($3 484 278) claims. Conclusions Tonsillectomy carries a high risk from a medical malpractice standpoint for the anesthesiologists and otolaryngologists. Although surgery-related claims were more common, opioids- and anesthetic-related claims were associated with larger median monetary verdicts, especially those associated with anoxic, nonfatal injuries. Caution is necessary when opioids are prescribed post-tonsillectomy, especially in patients with sleep apnea.
Epitaxial YBa2Cu3O7 on Biaxially Textured Nickel (001): An Approach to Superconducting Tapes with High Critical Current Density

In-plane—aligned, c axis—oriented YBa2Cu3O7 (YBCO) films with superconducting critical current densities Jc as high as 700,000 amperes per square centimeter at 77 kelvin have been grown on thermomechanically rolled-textured nickel (001) tapes by pulsed-laser deposition. Epitaxial growth of oxide buffer layers directly on biaxially textured nickel, formed by recrystallization of cold-rolled pure nickel, made possible the growth of YBCO films 1.5 micrometers thick with superconducting properties that are comparable to those observed for epitaxial films on single-crystal oxide substrates. This result represents a viable approach for the production of long superconducting tapes for high-current, high-field applications at 77 kelvin.
Product Pipelines and Pharmaceutical Risk Management in the New Era of Strict Regulatory Scrutiny

The value of a pharmaceutical company may be defined as its pipeline or portfolio of products and their potential value in the marketplace. One strategy to help mitigate the multitude of risks in pharmaceutical product development is to balance a portfolio across therapeutic areas, levels of risk and potential for returns. Risks include unexpected toxicities, therapeutic failure and inappropriate risk-benefit for the patient, as well as technical, financial, regulatory, political or social failure. Strategic reviews of a company’s portfolio will help ensure its product line-up is balanced appropriately to meet corporate goals and that product risks have been considered. Following the withdrawal of VioxxTM from the marketplace, a higher level of scrutiny has been focused on the safety of new pharmaceutical products. There is preliminary evidence that the overall number of approvals for new molecular entities decreased in 2005 relative to 2004. Certainly, all approvals of new COX-2 inhibitors have been suspended, leaving lumiracoxib and etoricoxib with an uncertain fate. Accusations have been voiced that the VioxxTM withdrawal was a result of shortened regulatory review times in the US, promulgated by the Prescription Drug User Fee Act. However, analysis by the Tufts Center for the Study of Drug Development has shown drug withdrawals, pre- and post-Act, are the same — withdrawn drugs did not have shorter review times than drugs remaining on the market. Options are being sought by the industry and regulators to find better ways to uncover unexpected toxicities early in development and monitor evolving toxicity profiles during a product’s marketing phase. Most agree, it is undesirable to delay the approval of new products, as this would stifle innovation and leave patients without needed therapies.
Depositional and pedogenic influences on the environmental geology of Holocene Mississippi River floodplain deposits near Ferriday, Louisiana

Abstract Core descriptions and the mineralogy of Holocene Mississippi River floodplain deposits in Louisiana provide insights on fluid migration pathways and the origin of iron-rich ground waters in the Mississippi River Alluvial Aquifer (MRAA). Vertical changes in the sedimentologic and pedologic characteristics of floodplain deposits near Ferriday, Louisiana, provide evidence for two stages of floodplain development and suggest that depositional processes and drainage conditions changed substantially during the Holocene. Depositional and pedogenic processes produced complex fluid migration pathways in the MRAA confining unit and also contributed to the formation of iron-rich ground waters. Lower Holocene deposits in the study area are older than ∼5000 yrs BP and show evidence of crevassing, lacustrine delta building, and multi-channel stream deposition. These processes deposited thin and narrow sheet sands, which represent fluid migration pathways in the MRAA confining unit. Poor drainage conditions during this initial stage of floodplain development also favored the precipitation of authigenic siderite and pyrite in poorly-drained swamps and shallow lakes. The pyrite and siderite probably represent the source of iron-rich ground waters in the MRAA. Upper Holocene floodplain deposits are younger than ∼ 5000 yrs BP and represent the transition to the present-day meandering regime of the Mississippi River near Ferriday. This second stage of floodplain development was accompanied by pedogenesis, which produced slickensides in clayey backswamp soils. The abundance of slickensides and the presence of the thin and narrow sheet sands indicates that fluid migration in the MRAA confining unit near Ferriday is greater than generally recognized. Seasonal water table fluctuations and the mixing of oxygenated meteoric and reduced ground waters cause iron oxide reduction and pyrite oxidation in backswamp settings, which releases iron into solution. The presence of high (up to 16 mg/l) dissolved iron concentrations in water wells that are screened beneath pyrite- and siderite-rich, muddy backswamp deposits near Ferriday, suggests that the distribution of fine-grained alluvium is a primary control on the presence of iron-rich waters in the MRAA. In contrast, water wells that are screened in sandy meander belt deposits, which lack abundant iron-bearing minerals, have low (less than 1 mg/l) concentrations of total dissolved iron. Studies of large floodplains such as the Mississippi River, highlight the importance of floodplain histories for evaluating geologic influences on water quality, developing proper floodplain land use strategies, and for improving our understanding of the environmental geology of floodplain systems.
NADPH oxidase and reactive oxygen species as signaling molecules in carcinogenesis

Reactive oxygen species (ROS) are small molecule metabolites of oxygen that are prone to participate in redox reactions via their high reactivity. Intracellular ROS could be generated in reduced nicotinamide-adenine dinucleotidephosphate (NADPH) oxidase-dependent and/or NADPH oxidase-independent manners. Physiologically, ROS are involved in many signaling cascades that contribute to normal processes. One classical example is that ROS derived from the NADPH oxidase and released in neurotrophils are able to digest invading bacteria. Excessive ROS, however, contribute to pathogenesis of various human diseases including cancer, aging, dimentia and hypertension. As signaling messengers, ROS are able to oxidize many targets such as DNA, proteins and lipids, which may be linked with tumor growth, invasion or metastasis. The present review summarizes recent advances in our comprehensive understanding of ROSlinked signaling pathways in regulation of tumor growth, invasion and metastasis, and focuses on the role of the NADPH oxidase-derived ROS in cancer pathogenesis.
Media consumption and girls who want to have fun

This essay explores the nature and function of listening to music from the perspective of semiotic phenomenology. Listening to music is a form of media consumption, a habitual practice that inscribes social meanings and organizes pleasure. The analysis of listening to music occurs in the three stages of description, definition, and interpretation. The description specifies the lived reality of listening to music in a postmodern world. The definition reduces this description to the structures of affect that locate audiences and interpretive positions on music. The interpretation elucidates the potential for co‐optation in pop music.
Health-Related Quality of Life Among Cancer Survivors Attending Support Groups

There is limited research on the relationship between Health-related quality of life (HRQoL) and socioeconomic status (SES) among long-term cancer survivors. The goal of this study was to assess Global HRQoL among 102 adult cancer survivors attending support groups in San Diego County and to examine differences by SES and acculturation. Community-based participatory research methods were followed to recruit a purposive sample of English and Spanish-speaking adult cancer survivors attending cancer support groups. Self-report questionnaires assessing age, acculturation (i.e., language), SES (i.e., income and education), cancer history, and Global HRQoL measured by the FACT-G were administered. Multivariate regression examined the relationship between SES and acculturation with HRQoL, adjusting for covariates. Participants were 58.8 years on average (SD = 10.06) and varied in terms of SES. Most participants (91.5 %) were women, 51.7 % were non-Hispanic white, and 48.3 % were Hispanic/Latino. Global HRQoL scores in the study sample were lower compared to previously reported studies. After adjusting for covariates, SES and acculturation were not significantly related to HRQoL. Stage at diagnosis was significantly related to HRQoL measures in adjusted analyses. HRQoL did not vary by SES or acculturation. There is a need to increase access to linguistically and culturally appropriate cancer care and supportive care services. Future studies may find existing support group settings useful for targeting psychosocial issues for more advanced stage cancer survivors.
Optical nonlinearities and ultrafast carrier dynamics in semiconductor doped glasses

The linear and nonlinear optical properties of commercially available CdSxSe1m x doped glasses are reviewed and the origin, magnitude, and temporal response of the nonlinearities are discussed. The room-temperature carrier dynamics are analysed using femtosecond interband pump-probe measurements. Our experimental results show the evolution of the carriers into a hot, quasi-thermal plasma distribution via electron-electron and electron-phonon scattering. The quasi-thermal distribution cools to the lattice temperature in about 750 fs filling the states just above the band-edge. This band-filling nonlinearity is seen as the bleaching of the absorption above the bandedge. The carrier recombination lifetime is measured to be ; 10 ps at higher carrier densities.
Spatial autocorrelation, phylogenetic constraints, and the causes of sexual dimorphism in primates

Cheverud et al. (1985) apply the important and relatively new methodology of spatial autocorrelation to the quantification of phylogenetic constraints on adaptation and illustrate the use of these methods in an allometric study of sexual dimorphism in body size among extant nonhuman primates. Though of potentially broad applicability, the technique was completely overlooked in a recent review of methods to control for the effects of common descent in comparative studies (Bell, 1989). Their approach therefore deserves a wider recognition. However, their specific conclusion, that phytogeny is the primary determinant of patterns of sexual dimorphism among primates, has been uncritically accepted. We present four main methodological problems with their approach that should temper the interpretation of their analysis: biased phylogenetic relatedness scores, biased sample selection, size dependence in sex dimorphism measurement, and deficiencies in selection of a structural path model. We conclude that, even in terms of the analysis by Cheverud and co-workers (1985), phylogenetic inertia is not the primary reason for body size dimorphism.
Genomics of Heart Failure

Cardiovascular disease is the leading cause of death in men and women, and heart failure (HF) is associated with high rates of morbidity and mortality. Most common forms of HF are non-mendelian and the evidence for heritability is modest. Study of the genetic susceptibility to HF has been limited to patients with rare familial forms of HF and candidate gene association studies in patients with distinct subtypes of HF. However, with the completion of the human genome project and the development of the HapMap template, new large-scale genome-wide association studies are possible. This article reviews the status of these and other important developments in genomics, in particular genome-wide sequencing, and other "omics".
Design knowledge acquisition for DFM methodologies

Design for Manufacturability (DFM) is a philosophy that encourages the communication of manufacturing information at the earliest stages of design in order to design parts and products that can be produced with greater ease and economy. This paper discusses the extensive experience gathered during the development of several DFM models in order to draw some conclusions and express some concerns that should be of interest to all those who develop or use manufacturing models that rely on design knowledge acquisition of knowledge from domain experts and/or industrial sites.
Enhanced thermal stability of electrooptic polymer Modulators using the diels-alder crosslinkable polymer

A thermally stable modulator using a novel Diels-Alder crosslinkable electrooptic (EO) polymer was fabricated. This new material system presents a smartly controlled process to overcome the EO coefficient-thermal stability tradeoff of conventional thermosetting EO polymers and obtains poling efficiency and thermal stability simultaneously. The modulator showed long-term stability at 85/spl deg/C, which shows potential for industrial applications.
Calcium and magnesium movements through sarcoplasmic reticulum, endoplasmic reticulum, and mitochondria.

Free cytoplasmic [Ca2+] is normally maintained at or below micromolar levels by actively transporting cell membranes and organelles, and by binding to high affinity, Ca-binding proteins. Until recently, the structural identity of the organelles that normally regulate cytoplasmic Ca2+ has been the subject of considerable debate (A.P. Somlyo, 1984). The primary role, in skeletal muscles, of the well-organized sarcoplasmic reticulum (SR) is generally accepted (Ebashi and Endo, 1968; Martonosi and Beeler, 1983) but, because of the smaller volume of SR in smooth muscle (A.V. Somlyo, 1980; A.P. Somlyo, 1985a) and in cardiac muscle (Sommer and Johnson, 1979), its dominant role in regulating cytoplasmic Ca2+ was not as readily recognized. It had been suggested, erroneously in retrospect, that in these muscles and in nonmuscle cells, mitochondria play a major role in Ca2+ regulation. This conclusion was based largely on studies of isolated organelles and on compartmental analysis of 45Ca fluxes, but the question whether the mitochondria or the endoplasmic reticulum (ER) regulate cytoplasmic Ca2+ could be conclusively resolved only by direct measurements of their calcium content in situ. This became possible with electron probe X-ray microanalysis (EPMA) (reviewed in A.P. Somlyo, 1985b) of rapdily frozen tissues. The results of these studies, that we summarize here, have shown that the ER, not mitochondria, are primarily responsible for physiological Ca2+ regulation and also revealed unexpected, and possibly physiologically significant, changes in mitochondrial magnesium.
Use of Autonomic Maneuvers to Probe Phenotype/Genotype Discordance in Congenital Long QT Syndrome

Patients with congenital long QT syndrome due to potassium channel mutations (LQT1 and LQT2) may elude diagnosis due to normal electrocardiographic findings at rest, yet remain at risk of sudden death during bradycardia or sympathetic stimulation. To test the hypothesis that autonomic maneuvers can unmask long QT syndrome in genetically abnormal subjects with a normal phenotype (QTc ≤450 ms), we exposed 13 controls (33 ± 9 years; 5 men), 5 patients with LQT1 (32 ± 12 years; 3 men), and 5 patients with LQT2 (30 ± 11 years; 5 men) to phenylephrine bolus, exercise, and epinephrine infusion. The QT interval was measured at baseline and after each intervention. A substantial overlap was found in QTc among the groups at baseline and after phenylephrine. In contrast, QTc was significantly and consistently longer in subjects with LQT1 compared with controls during and after exercise (492 ± 40 vs 407 ± 14 ms, p
Germination and seedling growth of cotton: salinity‐calcium interactions

Abstract. The effects of NaCl salinity on germination and early seedling growth of cotton were studied. Germination was both delayed and reduced by 200 mol m−3 NaCl in the presence of a complete nutrient medium. Seedlings, 7–9 d old, were greatly reduced in fresh weight by salinity. The addition of supplemental Ca2+ (10 mol m−3 as SO42− or Cl−) to the medium did not improve germination but, to a large degree, offset the reduction in root growth caused by NaCl. Roots growing in the high salt medium without supplemental Ca2+ appeared infected by microbes. The cation specificity of the beneficial Ca2+ effect on growth was ascertained by testing additions of MgSO4 or KCl to the NaCl treatments. The contents of K4 and Ca2+ were reduced in both roots and shoots by the NaCl treatments. Supplemental Ca2+ partially offset this effect for K4 in the roots and for Ca2+ in both roots and shoots. Sodium contents were not affected by the supplemental Ca2+. It is concluded that the beneficial effect of high Ca2+ concentrations on root growth of cotton seedlings in a saline environment may be due to maintenance of K/Na-selectivity and adequate Ca status in the root.
Fascioliasis: Case Reports and Review

Fasciola hepatica, a zoonotic liver fluke, can cause disease in humans. Fascioliasis, while common in some tropical and developing countries, is uncommon in the United States. We report two cases of fascioliasis that illustrate both the hepatic and biliary stages of the disease. Clinical features and diagnostic aspects including serologic, radiographic, and histopathologic studies are emphasized. Praziquantel was ineffective in treatment of both patients. Bithionol appears to be an effective treatment for fascioliasis
Introduction: Why Study Statistics?

We live in a world that relies increasingly on numerical information. Day after day, newspapers and magazines, radio and TV inundate us with quantitative statements: People who smoke are almost twice as likely to have automobile accidents and three times as likely to have heart attacks than people who do not smoke. Eighteen million families tuned in to a particular TV program. By eating 35 grams of oat bran daily, a person can lower her/his cholesterol level by three percent. Two out of three doctors prefer product P. By attending a coaching school, high school students can increase their SAT scores by several hundred points. In 1988, Americans gambled to the tune of nearly one thousand dollars for every man, woman or child.
FAP related periampullary adenocarcinoma

INTRODUCTION The risk of periampullary neoplasia in patients with familial adenomatous polyposis (FAP) is significantly increased compared to the general population.
Effects of Timber Harvesting on Southern Appalachian Salamanders

We compared the species richness and abundance of salamanders on six recent clearcuts ( 50 years old) in southern Appalachian forests in western North Carolina, U.S.A. Catches of salamanders from plots in mature forest stands were about five times higher than those on recent clearcuts. Almost all species and major taxonomic groups of salamanders were adversely affected by timber removal. Mean number of species collected per plot was about twice as great in mature forest stands as in clearcuts. Analyses of stand age versus salamander catch for 47 plots indicate that 50–70 years are required for populations to return to predisturbance levels following cutting. We conservatively estimate that clearcutting in U.S. national forests in western North Carolina results in a loss of nearly 14 millton salamanders annually. It also is chronically reducing regional populations by more than a quarter of a billion salamanders (9%) below that which could be sustained if mature forests were not cut. Nosotros comparamos la riqueza de especies y abundancia de las salamandras en seis recientes cortas totales de bosque ( 50 anos) en los bosques del sur de los Apalaches, en el oeste de Carolina del Norte, Estados Unidos. La captura de salamandras por plot en bosques de rodales maduros fue aproximadamente cinco veces mayor que en aquellos cortados recientemente. Casi todas las especies y los mayores grupos taxonomicos de salamandras fueron adversamente afectados por la tala. La media del numero de especies capturada por plot fue aproximadamente dos veces mayor en los rodales de bosques maduros que en los cortados recientemente. Los analisis de edad del rodal versus captura de salamandras para 47 plots indican que entre 50–70 anos son necesarios para que las poblaciones retornen a los niveles previos a la perturbacion ocasionada por la tala del bosque. Nosotros estimamos en una forma conservadora que la tala de los Bosques Nacionales en el oeste de Carolina del Norte trae como consecuencia una perdida de alrededor de 14 millones de salamandras anualmente. La tala tambien esta reduciendo cronicamente las poblaciones a nivel regional en mas de un cuarto de billones de salamandras (9%) por debajo del nivel que podria ser sostenido por los bosques maduros si no hubieran sido cortados.