cssi/SciSciGPT-SciSciNet huggingface dataset:
Mutant bacteriophage T7 RNA polymerases with altered termination properties

We have identified mutants of bacteriophage T7 RNA polymerase (RNAP) that are altered in their ability to pause or terminate at a variety of signals. These signals include a terminator found fortuitously in the human preproparathyroid hormone (PTH) gene, a pause site found in the concatamer junction (CJ) of replicating T7 DNA, and termination signals that are also utilized by Escherichia coli RNAP (e.g. rrnB T1 and T2). Whereas the mutant enzymes terminate normally at the late terminator in T7 DNA (T(phi)) and rrnB T2, they fail to terminate at one of the termination sites of rrnB T1, and also fail to recognize the PTH and CJ signals. The mutant enzymes exhibit normal processivity on linear templates, but show a slightly reduced processivity on supercoiled templates and terminate more efficiently when synthesizing poly(U) tracts. The mutant enzymes also show a decreased tendency to produce aberrant transcription products from DNA templates having protruding 3' ends. T7 lysozyme (an inhibitor of T7 RNAP) has been shown to exert its action by preventing the transition of the RNAP from an unstable initiation complex (IC) to a stable elongation complex (EC). We have found that T7 lysozyme enhances recognition of CJ by wild-type T7 RNAP, and that mutant T7 RNAPs that show increased sensitivity to lysozyme show enhanced recognition of this signal, even in the absence of lysozyme. These results, together with the observation that the mutations that result in the termination-deficient phenotype affect a region of the RNAP that has been implicated in RNA binding and upstream promoter contacts, support the hypothesis that, in some cases, termination represents a reversal of the events that occur during initiation.
Molecular coevolution of the vertebrate cytochrome c 1 and Rieske Iron Sulphur Protein in the cytochrome bc 1 complex

Cytochrome c1 (cyt-c1) and the Rieske Iron Sulphur Protein (ISP) are subunits of the cytochrome bc1 complex located in the mitochondria functioning both as a proton pump and an electron transporter. Vertebrate model organism phylogenies were used in conjunction with existing 3D protein structures to evaluate the biochemical evolution of cyt-c1 and ISP in terms of selection on amino acid properties. We found selection acting on the exterior surfaces of both proteins and specifically the core region of cyt-c1. There is evidence supporting coevolution of these proteins relative to alpha helical tendencies, compressibility and equilibrium constant.
Optimal Design for Multinomial Choice Experiments

Abstract The author derives D-optimal designs for main-effects, multinomial choice experiments using attribute levels as design parameters. The design solutions are similar to standard main-effects designs except that one attribute is used to manipulate response probabilities. The manipulator is key to implementing optimal designs in practice.
Broadband Microwave Frequency Characterization of 3-D Printed Materials

3-D printing allows increased design flexibility in the fabrication of microwave circuits and devices and is reaching a level of maturity that allows for functional parts. Little is known about the RF and microwave properties of the standard materials that have been developed for 3-D printing. This paper measures a wide variety of materials over a broad spectrum of frequencies from 1 MHz to 10 GHz using a variety of well-established measurement methods.
On driven, dissipative, energy-conserving magnetohydrodynamic equilibria

A cylindrically symmetric, electrically driven, dissipative, energy-conserving magnetohydrodynamic equilibrium model is considered. The high-magnetic-field Braginskii electron electrical resistivity η parallel to a constant axial magnetic field B and ion thermal conductivity ĸ perpendicular to B are included in an energy equation and in Ohm's law. The expressions for η and ĸ depend on number density and temperature, which are functions of radius that are obtained as part of the equilibrium solution. The model has plasma-confining solutions, by which are meant solutions characterized by the separation of the plasma into two regions separated by a relatively thin transition region that is an internal boundary layer across which temperature and current density vary rapidly. The inner region has a temperature, pressure and current density that are much larger than in the outer region. The number density and thermal conductivity attain their minimum values in the transition region. The model has an intrinsic value of β, about 6.6%, which must be exceeded in order that a plasma-confining solution exist. The model has an intrinsic length scale, which, for plasma-confining solutions, is a measure of the thickness of the transition region separating the inner and outer regions of plasma. A larger class of transport coefficients is modelled by artificially changing η and ĸ by changing the constant coefficients η O and ĸ O that occur in their expressions. Increasing ĸ O transforms a state that does not exhibit confinement into one that does, improves the confinement in a state that already exhibits it, and leads to an increase in ĸ in the confined region of plasma. The improvement in confinement consists in a decrease in the thickness of the transition region. Decreasing η O subject to certain constraints, also transforms a state that does not exhibit confinement into one that does, improves the confinement in a state that already exhibits it, and leads to a decrease in η in the confined region of plasma. Increasing η O up to a critical point increases the current, temperature, and volume of the confined region of plasma, and causes the thickness of the transition region to increase. If η O is increased beyond the critical point, a plasma-confining state cannot exist. In all cases it is found that an increase in ĸ and a decrease in η in the confined region of plasma are associated with an improvement in the confinement properties of the equilibrium state. If the pressure and temperature are given on the cylinder wall, the equilibrium bifurcates when the electric field decreases below a critical value. The equilibrium can bifurcate into a state that exhibits confinement and a state that does not.
In mice with type 2 diabetes, a vascular endothelial growth factor (VEGF)-activating transcription factor modulates VEGF signaling and induces therapeutic angiogenesis after hindlimb ischemia

Peripheral arterial disease is a major complication of diabetes. The ability to promote therapeutic angiogenesis may be limited in diabetes. Type 2 diabetes was induced by high-fat feeding C57BL/6 mice (n = 60). Normal chow-fed mice (n = 20) had no diabetes. Mice underwent unilateral femoral artery ligation and excision. A plasmid DNA encoded an engineered transcription factor designed to increase vascular endothelial growth factor expression (ZFP-VEGF). On day 10 after the operation, the ischemic limbs received 125 microg ZFP-VEGF plasmid or control. Mice were killed 3, 10, or 20 days after injection (n = 10/group, at each time point). Limb blood flow was measured by laser Doppler perfusion imaging. VEGF mRNA expression was examined by real-time PCR. VEGF, Akt, and phospho-Akt protein were measured by enzyme-linked immunosorbent assay. Capillary density, proliferation, and apoptosis were assessed histologically. Compared with normal mice, mice with diabetes had greater VEGF protein, reduced phospho-Akt-to-Akt ratio before ligation, and an impaired perfusion recovery after ligation. At 3 and 10 days after injection, in mice with diabetes, gene transfer increased VEGF expression and signaling. At later time points, gene transfer resulted in better perfusion recovery. Gene transfer with ZFP-VEGF was able to promote therapeutic angiogenesis mice with type 2 diabetes.
On the measure of the set of factorizable polynomial bispectra

In a recent work (1989), the authors have shown that factorization of bispectrum is not always possible. In the present work, they show that the subset of factorizable bispectra has Lebesgue measure zero in the set of polynomial bispectra, i.e. those that are obtained from finite-support bicumulants. Hence, a polynomial bispectrum cannot almost always be exactly realized as that of the output of a linear model driven by a third-order white input. This result can be generalized to multidimensional polynomial bispectra. Although it follows that a linear model driven by a third-order white input cannot almost always realize a given bispectrum or a bicumulant sequence, the use of a linear model as an approximation in certain applications can be justified if the computed bispectrum has an index value close to unity. >
Food label use by older Americans: data from the Continuing Survey of Food Intakes by Individuals and the Diet and Health Knowledge Survey 1994-96.

Abstract This study examined older Americans' use of food labels as a tool to moderate dietary risk factors for heart disease. Data from the USDA's Continuing Survey of Food Intakes by Individual (CSFII) 1994-96 and the Diet and Health Knowledge Survey (DHKS) from 2,846 respondents aged 51 years and older was used. Indices were constructed to measure and correlate dietary intake, label use and understanding, and health status data. Understanding and use of food labels was lower among older age groups, while heart-related health problems increased. Use of food labels and percent energy intake from fat were inversely related (P< 0.01). Older Americans would benefit from education on food label use and interpretation to decrease their dietary risk factors for heart disease.
Choosing Carbon Mitigation Strategies Using Ethical Deliberation

Anthropogenic greenhouse gas emissions change earth’s climate by altering the planet’s radiative balance. An important first step in mitigation of climate change is to reduce annual increases in these emissions. However, the many suggested means of limiting emissions rates have led to few actual changes in policy or behavior. This disconnection can be attributed in part to the difficulty of convening groups of stakeholders with diverse values, the polarizing nature of current political systems, poor communication across disciplines, and a lack of clear, usable information about emission mitigation strategies. Here, electronically facilitated ethical deliberation, a method of determining courses of action on common goals by collaborative discussion, is used to evaluate Pacala and Socolow’s climate change stabilization strategies based on economic, technological, social, and ecological impacts across a wide range of spatial and temporal scales. Few previous analyses of climate mitigation strategies include all of these factors; rather, short-term technological feasibility studies and economic cost‐benefit analyses predominate. After accounting for tradeoffs among disparate criteria, strategies involving end-user efficiency (e.g., efficient buildings and vehicles), wind, and solar power rank highest, while carbon capture and storage, hydrogen fuel cells, and biofuels options rank lowest. This electronically facilitated deliberation method offers an alternative to oppositional debate or cost‐benefit analysis for assessing strategies where both quantitative and qualitative factors are important, information from disparate disciplines is relevant, and stakeholders are geographically dispersed.
Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.

Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1–M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1–M4 IC50 >30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
God Talk: Confusion between Science and Religion Posthumous Essay

Controversies concerning the religious implications of science have grown increasingly strained in recent years. Creation scientists have deployed new strategies to eliminate the teaching of evolution in public schools; right-to-life groups have obstructed fetal tissue research; and clerical groups have criticized genomics and genetic testing. Meanwhile, the Templeton Foundation has begun promoting the idea that there is no conflict between science and religion. In this paper, I explore emerging efforts to reconcile religion and science. I focus particularly on the use of religious imagery and metaphor by scientists as they seek to convince the public of the power of genes or to allay concerns about new technologies. I suggest that their use of Godtalk may reflect both its wider prevalence in political rhetoric in the United States and its instrumental utility in light of the religious implications of contemporary biology.
Carbon nanomaterials as metal-free catalysts in next generation fuel cells

A new class of carbon nanomaterials has been discovered as metal-free catalysts to dramatically reduce the cost and increase the efficiency of fuel cells. This article highlights recent progresses in this emerging research area. & 2012 Published by Elsevier Ltd.
Videofluororadiographic Descriptors of Swallowing Physiology in Typical Rett Syndrome: Post-Regression Stabilization During Early Childhood

Typical or classic Rett syndrome (RTT) is the only pervasive neurodevelopmental disorder with a known chromosomal abnormality. Despite differences in clinical phenotype of girls with RTT who share ...
Optimization of the weck-Cel collection method for quantitation of cytokines in mucosal secretions.

Measurement of immune components in mucosal secretions is important for the evaluation of local immunity at the mucosal surfaces. The Weck-Cel ophthalmic sponge provides a method for the collection of these secretions. The sponge absorbs a relatively large volume of material, therefore allowing for quantitation of multiple immune components. Additionally, it provides a method in which the same device may be used to collect specimens from different mucosal sites, such as the genital tract and oral cavity. This sampling technique has successfully been applied for collection and measurement of antibody in oral and genital tract secretions. The purpose of this work was to optimize the extraction of protein from the sponge matrix. Of particular interest was the recovery of cytokines from the sponge. Satisfactory recovery of the cytokines interleukin 1β (IL-1β), IL-2, IL-5, IL-12, IL-6, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor was obtained. However, IL-4 and gamma interferon recovery rates remained low. Using an alteration of the published extraction method, cytokine concentrations were measured in cervical secretions from women using oral contraceptives. The data revealed detectable concentrations of IL-6, IL-10, IL-8, and IL-12 on cycle days 9 and 20. The proposed technique provides an easy, practical, and consistent method for collection of nonconventional body fluids, such as cervicovaginal fluids and saliva, for the assay of immunoglobulins and several cytokines.
Approximate Controllability and Stabilizability of Time Delay Systems: Functional Analytic and Algebraic Results

Approximate versions of controllability, reachability, and null controllability for linear functional-differential systems of retarded type are considered in relation to spectral controllability and stabilizability in general function spaces not necessarily genrating a C o - semigroup in the state space. It is shown that spectral controllability is necessary for approximate coollability and reachability in a large variety of state spaces. Spectral controllability is also necessary for approximate null controllability on a fixed time interval. On the other hand, if the space of control functions is closed under right shifts, uniform approximate controllabiity implies spectral controllability. Also, open loop stabilizability is necessary for approximate null controllability. We show that three large families of concrete function spaces, C(k), Mp, and w(k,p), satisfy all our geneal assumptions. We generalize the notions of a dual transposed system and dual observability concepts, developed in [1], corresponding to approximate controllability concepts. This enables completion of our general results by proving that spectral controllability is sufficient for approximate null controllability and by deriving testable criteria from the dual problems. Such criteria assume an especially simple form when the final time T is greater than nh and also in case of discrete delays where connections to controllability over the ring of polynomials in a delay operator are established
Consistent placement of macro-blocks using floorplanning and standard-cell placement

While a number of recent works address large-scale standard-cellplacement, they typically assume that all macros are fixed.Floorplanning techniques are very good at handling macros, but donot scale to hundreds of thousands of placeable objects. Thereforewe combine floorplanning techniques with placement techniques in adesign flow that solves the more general placement problem. Ourwork shows how to place macros consistently with large numbers ofsmall standard cells. Our techniques can also be used to guidecircuit designers who prefer to place macros by hand.The proposed flow relies on an arbitrary black-box standard-cellplacer to obtain an initial placement and then removes possibleoverlaps using a fixed-outline floorplanner. This results in validplacements for macros, which are considered fixed. Remainingstandard cells are then placed by another call to the standard-cellplacer. Empirical evaluation on ibm benchmarks shows, in mostcases, wirelength improvements of 10%-50% compared to CadenceQPlace, as well as runtime improvements.
Role of Asphaltenes in Inhibiting Corrosion and Altering the Wettability of the Steel Surface

Abstract Asphaltenes (heptane insolubles) from a variety of crude oils have been identified previously as contributors to inhibition of internal corrosion of mild steel pipelines. However, the mech...
THE ROLE OF TIMING IN THE BRAIN STEM AUDITORY NUCLEI OF VERTEBRATES

Vertebrate animals gain biologically important information from environmental sounds. Localization of sound sources enables animals to detect and respond appropriately to danger, and it allows predators to detect and localize prey. In many species, rapidly fluctuating sounds are also the basis of communication between conspecifics. This information is not provided directly by the output of the ear but requires processing of the temporal pattern of firing in the tonotopic array of auditory nerve fibers. The auditory nerve feeds information through several parallel ascending pathways. Anatomical and electrophysiological specializations for conveying precise timing, including calyceal synaptic terminals and matching axonal conduction times, are evident in several of the major ascending auditory pathways through the ventral cochlear nucleus and its nonmammalian homologues. One pathway that is shared by all higher vertebrates makes an ongoing comparison of interaural phase for the localization of sound in the azimuth. Another pathway is specifically associated with higher frequency hearing in mammals and is thought to make use of interaural intensity differences for localizing high-frequency sounds. Balancing excitation from one ear with inhibition from the other in rapidly fluctuating signals requires that the timing of these synaptic inputs be matched and constant for widely varying sound stimuli in this pathway. The monaural nuclei of the lateral lemniscus, whose roles are not understood (although they are ubiquitous in higher vertebrates), receive input from multiple pathways that encode timing with precision, some through calyceal endings.
Experimental Vibration Control of a Two-Degree of Freedom, State-Switched Absorber System

A State-Switched Absorber (SSA) is a device capable of instantaneously changing its stiffness, thus it can switch between resonance frequencies, increasing its effective bandwidth as compared to classical tuned vibration absorbers for vibration control. Previous theoretical simulations show that for a system subjected to a multi-harmonic disturbance, using an appropriate logic for switching states, the SSA reduces vibration more effectively than classical tuned vibration absorbers (TVA). This paper considers the experimental performance of the SSA for vibration suppression of an elastically mounted lumped mass base. State switching is achieved using magneto-rheological fluid to connect or disconnect a coil spring in parallel with other coil springs. The stiffness state is controlled by applying or removing a magnetic field across of the MR fluid. Experiments were performed over a range of forcing and tuning frequencies. The SSA system, optimally tuned, outperformed the optimal classical TVA system for all combinations of forcing frequencies.Copyright © 2002 by ASME
Spelunking in the archives: Or how I learned to love the art of the unexpected

EDITOR'S SUMMARY Drawing on her archival research skills, the author took the opportunity to dig into the American Society for Information Science records (1939–1990), a special collection housed at the University of Michigan. The exploration was prompted by ASIS&T's 75th anniversary and Special Interest Group/History and Foundations of Information Science (SIG/HFIS). The archives represent the evolution of the society, starting as the American Documentation Institute. The material retrieved on the author's first visit did not correspond to the online finding aid, but subsequent inquiry found a new finding aid, which was not online, describing the collection, including expanded holdings. The ASIS&T historical records collection is open for additional deposits, including documents, personal papers, presentations, oral histories and images, with the goal of placing all materials online. It is hoped this adventure will prompt ASIS&T to become an example for implementing best practices in organizational records preservation and management.
Selective Methylation of Nucleosides1

Abstract Phenylalanine tRNA from Ehrlich ascites cells and Novikoff hepatoma has been found to contain 1-methyl-guanosine (5a) 2. The tRNA methyl transferases of e.g., normal liver tissue do not produce this N-methylated nucleoside. Indeed the urine of various human cancer patients has recently been found to contain unusually large amounts of certain partially methylated nucleosides and in amounts sufficient to serve as markers for evaluating disease progression.3 In general, a variety of methylated nucleosides4 have been discovered in animal RNA especially in tRNA and mRNA, and syntheses of these modified nuclesodies has been attempted using such reagents as methyl iodide,5 diazomethane,6 dimethyl sulfate,7 and trimethyl phosphate.8
Association Between Testosterone and Estradiol and Age-Related Decline in Physical Function in a Diverse Sample of Men

OBJECTIVES: To examine the association between aging and physical function in men by testing a theoretically based model of aging, hormones, body composition, strength, and physical function with data obtained from men enrolled in the Boston Area Community Health/Bone (BACH/Bone) Survey. DESIGN: Cross-sectional, observational survey. SETTING: Population-based. PARTICIPANTS: Eight hundred ten black, Hispanic, and white randomly selected men from the Boston area aged 30 to 79. MEASUREMENTS: Testosterone, estradiol, sex hormone–binding globulin, lean and fat mass, grip strength, and summated index of physical function (derived from walk and chair stand tests). RESULTS: Measures of grip strength and physical function declined strongly with age. For instance, 10 years of aging was associated with a 0.49-point difference (scale 0–7) in physical function. Age differences in total testosterone and estradiol concentrations were smaller than age differences in their free fractions. Weak or nonsignificant age-adjusted correlations were observed between hormones and measures of physical function, although path analysis revealed a positive association between testosterone and appendicular lean mass and a strong negative association between testosterone and total fat mass. Lean and fat mass, in turn, were strongly associated with grip strength and physical function, indicating the possibility that testosterone influences physical function via indirect associations with body composition. CONCLUSION: The age-related decline in serum testosterone concentration in men has a weak association with physical strength and functional outcomes through its associations with lean and fat mass.
Can long passwords be secure and usable

To encourage strong passwords, system administrators employ password-composition policies, such as a traditional policy requiring that passwords have at least 8 characters from 4 character classes and pass a dictionary check. Recent research has suggested, however, that policies requiring longer passwords with fewer additional requirements can be more usable and in some cases more secure than this traditional policy. To explore long passwords in more detail, we conducted an online experiment with 8,143 participants. Using a cracking algorithm modified for longer passwords, we evaluate eight policies across a variety of metrics for strength and usability. Among the longer policies, we discover new evidence for a security/usability tradeoff, with none being strictly better than another on both dimensions. However, several policies are both more usable and more secure that the traditional policy we tested. Our analyses additionally reveal common patterns and strings found in cracked passwords. We discuss how system administrators can use these results to improve password-composition policies.
Law and Society: Project and Practice

This review analyzes four decades of law-and-society scholarship by examining and contrasting the first and last 13 years of the Law & Society Review (LSR). It compares the programmatic statements of Law and Society Association presidents and LSR editors with the scholarship published, offering explanations for and critiques of project and practice.
Focus on Phosphodiesterase Inhibitors for the Treatment of Erectile Dysfunction in Older Men

Abstract Background Phosphodiesterase type 5 inhibitors (PDEIs) are the drugs of choice for the medical management of erectile dysfunction independent of the etiology of the disorder. Objective This review focuses on specific aspects of clinical use of PDEIs in older men with erectile dysfunction. Methods An electronic search of MEDLINE was conducted for articles published between January 1990 and January 2011 using the terms erectile dysfunction and PDEIs and limited to articles in English, humans, and males aged ≥45 years. The search was also conducted in EMBASE using the same search criteria for literature indexed between 1990 and 2010. Results A total of 1341 articles were identified. Of these, ∼91 were selected for this review. Sildenafil, vardenafil, and tadalafil are considered equally effective for erectile dysfunction, but they differ in some ways. Tadalafil's 36-hour duration of action allows for repeated sexual intercourse without the need to take additional medication in some patients, which is distinctly different from the shorter-acting sildenafil and vardenafil. Unlike tadalafil, the rate and extent of oral absorption of sildenafil and vardenafil are reduced by consumption of high-fat meals. Although headache, flushing, and rhinitis occur with all 3 PDEIs, cyanopsia is more common with sildenafil and vardenafil, and back pain is more common with tadalafil. Approximately 40% to 50% of patients who initially fail to respond to PDEIs can be salvaged with education and up-titration of dosing. PDEIs can be used in addition to antihypertensive medications in patients with well-controlled essential hypertension without producing clinically significant hypotension. Use of PDEIs in patients with cardiovascular disease is guided by the recommendations of the Second Princeton Consensus Conference. For the management of lower urinary tract symptoms due to benign prostatic hyperplasia, PDEIs may reduce obstructive voiding symptoms, but they do not increase urinary flow rate. Conclusion PDEIs are effective for erectile dysfunction and well tolerated in older men.
Estimating Statistical Eigen-Beamforming Gains Using Spatial Channel Correlation

Statistical eigen-beamforming (EBF) is a widely used multiple antenna transmission technique in which one antenna weight is used over potentially a large bandwidth (e.g., all subcarriers in OFDM). With N transmit antennas, the maximum gain for EBF at a receiver is 20 log N decibels over a single antenna transmission (assuming a power unfair comparison where each transmit antenna has a fixed power so the addition of new antennas brings a beamforming gain as well as a total transmit power increase). Based on statistical analysis of field data and observations, this gain is nearly achievable with line-of-sight transmissions. While useful for characterizing the benefits of EBF, the statistical analysis does not indicate the realizable gain for a particular location. This paper presents a relationship between the EBF gain, spatial correlation of the channel, and the number of transmit antennas. The conjectured gain is compared to the expected gain based on an analysis of field data. The results of this comparison show that the spatial correlation as defined in this paper can be used to predict the EBF gain accurately for a variety of antenna spacings and polarizations.
Selective Deletion of Pten in Pancreatic β Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing β cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of β-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total β-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in β cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for β-cell protection and regeneration therapies.
Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Abstract Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine9s entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.
Chemotherapy Plus Local Treatment in the Management of Intraocular Retinoblastoma

Objective: To describe platinum-based chemotherapy combined with local treatment modalities as an alternative to external beam radiotherapy for intraocular retinoblastoma. Design: Platinum levels were measured by atomic absorption analysis in the tumors of 2 patients with retinoblastoma given carboplatin 5 or 2.5 hours before enucleation. Platinum levels in heated vs nonheated Greene melanoma tumors in rabbits were compared. A retrospective review of 172 affected eyes in 136 consecutive patients treated for retinoblastoma between January 1990 and December 1995 was performed. From 1990 to 1992, all treatable eyes initially received systemic carboplatin, 560 mg/m 2 , followed by 15 to 30 minutes of continuous diode laser hyperthermia (thermochemotherapy). Since 1992, larger tumors were treated initially with 3 monthly cycles of carboplatin, etoposide, and vincristine sulfate to reduce tumor volume (chemoreduction) followed by sequential aggressive local therapy (SALT) during examinations under anesthesia every 2 to 3 weeks. Outcome Measure: Treatment success was defined as eradication of tumor without enucleation or external beam radiotherapy. Results: Significant therapeutic platinum levels were measured in the human tumors 2.5 and 5 hours after carboplatin administration. Increasing the temperature by 9°C for 15 minutes doubled platinum levels in the rabbit model. Of the 38 eyes with Reese-Ellsworth group 1 through 5b tumors that were treated primarily with thermochemotherapy, all 24 eyes with group 1 and 2 tumors were treated successfully and two of the 4 eyes with group 3 tumors and all 10 eyes with group 5b tumors were treated unsuccessfully. Chemoreduction plus SALT was the primary treatment in 35 eyes and was successful in all 10 eyes with group 1 through 4 tumors and unsuccessful in all 7 eyes with extensive subretinal seeding and all 18 eyes with group 5b tumors with vitreous seeding. Seventy patients received carboplatin or carboplatin, vincristine, and etoposide, with myelosuppression, occasionally associated with bacteremia, being the main side effect. Transfusions were required in 15% of patients. Radiation retinopathy occurred in all 6 eyes treated with iodine 125 plaques. Conclusions: Thermochemotherapy is successful primary treatment for Reese-Ellsworth group 1 and 2 retinoblastomas. For larger tumors in the absence of vitreous or extensive subretinal seeding, 3 cycles of chemoreduction followed by SALT eradicates residual viable tumor. Chemoreduction plus SALT was not successful in eyes with diffuse vitreous or extensive subretinal seeding. Prior chemotherapy increases the risk for radiation retinopathy following 125 I plaque therapy. External beam radiotherapy can safely be avoided in the primary treatment of Reese-Ellsworth groups 1 through 4 nondispersed retinoblastoma.
PATERNAL LOSS (PAL): A MEIOTIC MUTANT IN DROSOPHILA MELANOGASTER CAUSING LOSS OF PATERNAL CHROMOSOMES

The effects of a male-specific meiotic mutant, paternal loss (pal), in D. melanogaster have been examined genetically. The results indicate the following. (1) When homozygous in males, pal can cause loss, but not nondisjunction, of any chromosome pair. The pal-induced chromosome loss produces exceptional progeny that apparently failed to receive one, or more, paternal chromosomes and, in addition, mosaic progeny during whose early mitotic divisions one or more paternal chromosomes were lost. (2) Only paternally derived chromosomes are lost. (3) Mitotic chromosome loss can occur in homozygous pal+ progeny of pal males. (4) Chromosomes differ in their susceptibility to pal-induced loss. The site responsible for the insensitivity vs. sensitivity of the X chromosome to pal mapped to the basal region of the X chromosome at, or near, the centromere. From these results, it is suggested that pal+ acts in male gonia to specify a product that is a component of, or interacts with, the centromeric region of chromosomes and is necessary for the normal segregation of paternal chromosomes. In the presence of pal, defective chromosomes are produced and these chromosomes tend to get lost during the early cleavage divisions of the zygote. (5) The loss of heterologous chromosome pairs is not independent; there are more cases of simultaneous loss of two chromosomes than expected from independence. Moreover, an examination of cases of simultaneous somatic loss of two heterologs reveals an asymmetry in the early mitotic divisions of the zygote such that when two heterologs are lost at a somatic cleavage division, almost invariably one daughter nucleus fails to get either, and the other daughter nucleus receives its normal chromosome complement. It is suggested that this asymmetry is not a property of pal but is rather a normal process that is being revealed by the mutant. (6) The somatic loss of chromosomes in the progeny of pal males allows the construction of fate maps of the blastoderm. Similar fate maps are obtained using data from gynandromorphs and from marked Y chromosome (nonsexually dimorphic) mosaics.
Performance-Based Turnover on Corporate Boards

We examine the threat of turnover as an incentive to align the interests of corporate directors with shareholders. Our results suggest an economically significant relation between director turnover and past firm performance. This relation only manifests in idiosyncratic stock returns; consistent with the monitoring of actions attributable to corporate boards. The director turnover-performance sensitivity increases over time as well as post-SOX and contemporaneous listing standards. This sensitivity also varies with numerous governance characteristics, most notably with the presence of an active external blockholder. In sum, the threat of replacement in the context of poor firm performance represents an economically significant incentive for directors.
Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression

Aims Previously we have demonstrated altered microglia P2X4R expression in response to alcohol and pharmacological blockade with a selective P2X4R antagonist can reverse the action, suggesting that P2X4R play a role in mediating alcohol-induced effects on microglia. In the present study, we investigated the underlying signaling mediators, which may play a role in modulating P2X4R expression in microglia cells in response to alcohol. Methods Embryonic stem cell-derived microglia (ESdM) cells were used to investigate the potential mechanisms involved in the regulation of P2X4R in response to alcohol. Selective P2X4R antagonist and kinase inhibitors were used to further corroborate the signal transduction pathway through which alcohol modulates P2X4R expression in microglia. Results Alcohol (100 mM) suppressed phosphorylated AKT and ERK cascades in native ESdM cells. This alcohol-induced suppression was confirmed to be P2X4R-dependent through the use of a selective P2X4R antagonist and knockdown of P2XR4 by siRNA. Alcohol increased transcriptional activity of CREB. P2X4R antagonist blocked alcohol-induced effects on CREB, suggesting a P2X4R-mediated effect. Conclusion These findings provide important clues to the underlying mechanism of purinoceptors in alcohol-induced microglia immune suppression.
Nonlinear multivariate modeling of strand mechanical properties with near-infrared spectroscopy

The purpose of this research was to determine if nonlinear calibrations of near-infrared spectra could improve the prediction of strand mechanical properties. Strands similar in dimension to strands utilized in an oriented strand board composite process were prepared and tested for mechanical properties in three-point bending and then calibrated to near-infrared reflectance spectroscopy. It was found that an additional 7% to 16% of the variation in mechanical properties could be accounted for when second- and third-order terms were applied. Interpretation of models identified the magnitude of importance that various wood polymers play on mechanical properties and this interpretation was validated through wet chemistry. This work is significant because it demonstrates the potential of using near-infrared spectroscopy to monitor shifts in strand mechanical properties prior to wood composite manufacture and it helps to provide the fundamental relationship between near-infrared models, wood chemistry, and the...
The association between serum calcium levels and Chvostek sign: A population-based study

Abstract Background: The Chvostek sign—a contraction of ipsilateral facial muscles subsequent to percussion over the facial nerve—is considered a clinical indicator of hypocalcemia. I sought to evaluate the association between Chvostek sign and serum calcium levels. Methods: I performed a cross-sectional analysis of data gathered from a nationwide probability sample of 3,434 individuals, aged 25–74 years, in the First National Health and Nutrition Examination Survey, conducted from 1971 to 1975. Results: Increasing serum calcium levels were associated with an increased odds for a positive Chvostek sign. When compared to calcium levels in the lowest quartile (5.47–9.4 mg/dL), individuals with serum calcium levels of 9.4–9.6 mg/dL, 9.6–9.9 mg/dL, and 9.9–11.9 mg/dL had a 195% (95% confidence interval [CI] 23.3%–604%), 124% (95% CI −0.8% to 407%), and 159% (95% CI 33.8%–401%) increased odds—as opposed to the expected decreased odds—for a positive Chvostek sign. When adjusting for age, sex, and race, these increased odds were 220% (95% CI 32%–679%), 125% (95% 0.00%–409%), and 172% (35%–448%), respectively. For every 1 g/dL increase in serum calcium level, the odds for a positive Chvostek sign increased by 4% (95% CI 0.00%–8%). Conclusions: A positive Chvostek sign is informative of normal to increased serum calcium levels rather than hypocalcemia.
Crack Propagation in Polycrystalline Ceramics

In this chapter, the strength and shock resistance of ceramic materials will be related to microstructural details and the energy necessary to form fracture surfaces. The influence of grain size, grain orientation, crystal anisotropy, and residual stresses on crack propagation will be discussed. It will be argued that the strength of ceramic materials is closely related to the grain boundary or single-crystal fracture surface energy, while shock resistance is related to the surface energy required to propagate large cracks through polycrystalline materials. The use of fracture surface energies as a research technique and as a design parameter will be discussed.
Psychiatric care of lung cancer patients.

The best management of distress in a lung cancer patient involves aggressive physical symptom control, attention to concerns about death, and psychosocial support for the patient and his or her caregivers, as well as management of more typical psychiatric symptoms.
Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.
{CP} Nonconservation With Four Generations

A detailed and updated study of CP-nonconservation with four generations by using KL → μ+μ− and ϵ as input is carried out. The quark mixing and t′ quark mass are constrained. The t′ quark mass is between 100 GeV-250 GeV. The analysis also shows that the flavor-flip KM-matrix can be a solution for quark mixing. The top-quark lifetime can be lengthened by a factor of 100 or more. Mixing and CP-nonconservation in D0−D0, B0−B0 and BS0− BS0 can be large and ϵ′/ϵ can be smaller than 10−4.
Microstructures and Mechanical Properties of Sputtered Cu/Cr Multilayers

The microstructures and mechanical properties of Cu/Cr multilayers prepared by sputtering onto {l_brace}100{r_brace} Si substrates at room temperature are presented. The films exhibit columnar grain microstructures with nanoscale grain sizes. The interfaces are planar and abrupt with no intermixing, as expected from the phase diagram. The multilayers tend to adopt a Kurdjumov-Sachs (KS) orientation relationship: {l_brace}110{r_brace}Cr // {l_brace}111{r_brace}Cu, Cr // Cu. The hardness of the multilayered structures, as measured by nanoindentation, increase with decreasing layer thickness for layer thicknesses ranging from 200 nm to 50 nm, whereas for lower thicknesses the hardness of the multilayers is independent of the layer thickness. Dislocation-based models are used to interpret the variation of hardness with layer periodicity. The possible effects of factors such as grain size within the layers, density and composition of films and residual stress in the multilayers are highlighted. Comparisons are made to the mechanical properties of sputtered polycrystalline Cu/Nb multilayers which, like Cu/Cr, exhibit sharp fcc/bcc interfaces with no intermixing and a KS orientation relationship, but have a small shear modulus mismatch.
QUESTIONS AND ANSWERS—INEQUALITY IN MORTALITY OVER THE LIFE COURSE: WHY THINGS ARE NOT AS BAD AS YOU THINK

Inequality in mortality over the life course: Why things are not as bad as you think. (JEL D63, I18, I38, J1, J3, J18)