cssi/SciSciGPT-SciSciNet huggingface dataset:
Abstract 1650: Targeting of compensatory signaling pathways identified in a synthetic lethal screen leads to synergistic growth inhibition in bladder cancer cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Despite promising preclinical results, monotherapies that target deregulated signal transduction pathways often are insufficient to slow or shrink tumors in human patients. We hypothesize that multiple pathways within the cellular signaling network are altered in cancer cells, and that these pathways are acting in a redundant or compensatory manner to provide resistance against drugs targeting a single protein. A treatment plan consisting of multiple small molecules that inhibit these compensatory and redundant pathways should overcome this resistance. To discover pathways that act in a redundant or compensatory manner, we performed a screen that allows us to examine the cellular effects of blocking pathways both individually and in combination. We found that the combination of the epidermal growth factor receptor (EGFR) inhibitor lapatinib in combination with the phosphoinositol-3-kinase (PI3K) inhibitor LY294002 produced synergistic growth inhibition in UMUC-6 bladder cancer cells. In order to confirm that this effect was due to inhibition of the putative targets of these compounds, we substituted structurally distinct EGFR and PI3K inhibitors for lapatinib and LY294002 and obtained similar results. Cell cycle analysis of cells treated with this combination revealed an arrest in the G1 phase, which could explain the synergistic inhibition observed in the screen. In order to find a molecular mechanism for this synergistic effect, we performed Western blotting analysis of the cells treated with each drug individually and in combination. We found that treatment with LY294002 caused an increase in levels of phosphorylated SHC, and ERK, indicating that receptor tyrosine kinase signaling, and possibly EGFR signaling is activated to compensate for PI3K pathway inhibition. Inhibition of ERK activity with PD325901 produced the same effect as EGFR inhibition, confirming the role of ERK as a compensatory signaling molecule for PI3K inhibition. Parallel RNAi experiments against SHC are currently ongoing. These data suggest that synthetic lethal screening with a library of targeted inhibitors of signaling proteins can be used to search for combinatorial effects and functionally identify compensatory and redundant relationships between different signaling components. This work paves the way for the development of rational combinatorial therapies for the effective treatment of bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1650.
Clinical Trial Report: Is It Safe to Continue Anticoagulation Therapy in Patients with Infective Endocarditis?

Staphylococcus aureus is now the leading cause of infective endocarditis (IE), especially among patients who have previous exposure to medical care. Current guidelines indicate that anticoagulation is contraindicated in patients being treated for endocarditis because of the potential risk of cerebral hemorrhage. However, it may be desirable to continue anticoagulation therapy to reduce the risk of thromboembolic events, especially in patients with prosthetic heart valves. Indeed, many such patients are taking warfarin or heparin at the time endocarditis is diagnosed, creating a dilemma for clinicians faced with such patients. Aims
Fungal associations in the terrestrial paleoecosystern.

Despite a long geological history, information about the role of fungi in the paleoecosystem is only now beginning to emerge. Not only does the fossil record contain direct evidence of fungal diversity through time, it also provides information about interactions between fungi and plants, animals and the physical environment. This review summarizes some of the recent activities in paleomycology.
Pulsed laser deposition growth of ZnSe, MnSe, and ZnSe/MnSe epilayers

Abstract Epitaxial layers of ZnSe and MnSe as well as heterostructures of ZnSe/MnSe were grown on GaAs(100) substrates by pulsed-laser deposition (PLD). The X-ray diffraction patterns for different layers are presented as well as the low temperature magnetization for ultrathin MnSe/ZnSe structures.
Interrupting the Professional Schism That Allows Less Successful Educational Practices With ELLs to Persist

Different worldviews, different histories of induction into teaching, presumed differences in responsibilities, and different emphases in preservice and in-service preparation have all long contributed to enduring schisms that keep general education (or mainstream) teachers and English language support faculty from coordinating and finding common cause in their efforts. This division has been at the cost of impeding many English language learners' (ELLs) academic success. So, given that ELLs consecutively or concurrently negotiate these too-often separate schooling subworlds, it is imperative to overcome historical divisions and to conceptualize all teachers as needing (a) to be willing to see ELLs as part of their charge, and (b) to build the skills and capabilities to serve such students well.
Theoretical and experimental studies of propagation of beams through a finite sample of a cubically nonlinear material

Propagation of an externally focused or defocused Gaussian beam in a cubically nonlinear material is studied analytically and experimentally. The theoretical analysis is applied to determine the sign and magnitude of n2 for a material by means of a single-beam experiment with a finite nonlinear sample within which propagational diffraction cannot be neglected. Experimental results for a solution of chlorophyll in ethanol are reported. Based on available theory, an average n2 can be defined for a nonlinearity of thermal origin, and this value is found to be in good agreement with experimental results. Finally, the theoretical analysis and the experimental results of a double-beam experiment performed to determine the sign and magnitude of n2 are also presented.
The Whittier Narrows, California Earthquake of October 1, 1987—Response of Lifelines and Their Effect on Emergency Response:

Abstract The response of lifeline systems was good, but there were component failures. Communication inadequacies did have a significant impact on the emergency response system. The dysfunction of lifelines, primarily power, communication, and natural gas systems put an added burden on the emergency response system and was the source of most fires. Damage and dysfunction included the frequently observed failure of ceramic elements on high voltage substation equipment, damage to large liquid storage tanks, and the saturation of the telephone system, including emergency response networks, with inappropriate calls. These hold the potential for compounding impacts after larger, more damaging earthquakes. The need to change operating procedures of some lifelines and to update emergency response public information is indicated.
Genetic organization and transposition properties of IS511

IS511 is an endogenous insertion sequence (IS) of the bacterium Caulobactercrescentus strain CB15 and it is the first Caulobacter IS to be characterized at the molecular level. We determined the 1266-bp nucleotide sequence of IS511 and investigated its genetic organization, relationship to other ISs, and transposition properties. IS511 belongs to a distinct branch of the IS3 family that includes ISRI, IS476, and IS1222, based on nucleotide sequence similarity. The nucleotide sequence of IS511 encodes open reading frames (orfs) designated here as orfA and orfB, and their relative organization and amino acid sequences of the predicted protein products are very similar to those of orfAs and orfBs of other IS3 family members. Nuclease S1 protection assays identified an IS511 RNA, and its 5′ end maps approximately 16 nucleotides upstream of orfA and about six nucleotides downstream of a sequence that is similar to the consensus sequence of C. crescentus housekeeping promoters. Evidence is presented that IS511 is capable of precise excision from the chromosome, and transposition from the chromosome to a plasmid. Transpositional insertions of IS511 occurred within sequences with a relatively high G + C content, and they were usually, but not always, flanked by a 4-bp direct repeat that matches a sequence at the site of insertion. We also determined the nucleotide sequence flanking the four endogenous IS511 elements that reside in the chromosome of C. crescentus. Our findings demonstrate that IS511 is a transposable IS that belongs to a branch of the IS3 family.
Mechanistic Insights into the Factors Determining Exo−Endo Selectivity in the Lewis Acid-Catalyzed Diels−Alder Reaction of 1,3-Dienes with 2-Cycloalkenones

We adduce evidence that the asynchronous, Lewis acid-catalyzed Diels−Alder reaction of 2-cycloalkenones with nonsimple α,β-enones can proceed via transition states in which the 1,3-diene subunit is skewed, i.e., nonplanar, with profound effects on the ratio of exo and endo addition products.
‘How do I do it if I don’t like writing?’: Adolescents’ stances toward writing across disciplines

This research embedded in the National Study of Writing Instruction examines higher- and lower-achieving adolescents’ stances toward content-area writing through a qualitative discourse analysis of interviews with 40 students in California, Kentucky, New York, and Texas secondary schools. The study asked: (1) How do students’ stances toward writing compare in general and across disciplines? (2) How do stances compare among middle and high school students and among students with different achievement histories? Results suggest that adolescents generally hold positive attitudes toward writing that allows for the expression of subjective stances, which they report is more commonly assigned in English language arts classrooms. Implications for the adoption of new US standards for disciplinary writing are discussed.
Rat pup social motivation: A critical component of early psychological development

Examining the role of the offspring in early social dynamics is especially difficult. Human developmental psychology has found infant behavior to be a vital part of the early environmental setting. In the rodent model, the different ways that a rodent neonate or pup can influence social dynamics are not well known. Typically, litters of neonates or pups offer complex social interactions dominated by behavior seemingly initiated and maintained by the primary caregiver (e.g., the dam). Despite this strong role for the caregiver, the young most likely influence the litter dynamics in many powerful ways including communication signals, discrimination abilities and early approach behavior. Nelson and Panksepp (1996) developed a preference task to examine early rodent pup social motivation. We have used the same task to examine how variations in maternal care or different environmental perturbations could alter the rat pup preferences for social-related stimuli. Rat pups receiving low levels of maternal licking and grooming were impaired in maternal odor cue learning and emitted lower levels of 22 kHz ultrasounds compared to pups from the high licking and grooming cohort. Prenatal stress or early exposure to a toxicant (polychlorinated biphenyl) altered early social preferences in the rat pup in different ways indicating that diverse strategies are expressed and specific to the type of perturbation exposure. A greater focus on the offspring motivation following early ‘stressors’ will allow for more complete understanding of the dynamics in behavior during early social development.
Effect of dietary histidine on olfaction, and rat brain and muscle concentration of histidine-containing dipeptides.

— Young adult male rats were fed three diets; one was devoid of histidine (HF), the second supplied the maintenance requirement (M, 3.7% protein, 0.07% histidine), and the third provided an optimal amount of histidine for growth (G, 10.0% protein, 0.21% histidine). The M diet was pair-fed with the HF diet. After an 11 weeks experimental period, some HF animals were given the M diet for an 11 day repletion period. On the HF diet carnosine in the olfactory bulb and pectoral muscle, homocarnosine in whole brain and hemoglobin were sharply and significantly reduced in concentration below the levels found in the M and G groups. During the 11 day repletion period all concentrations except for hemoglobin returned to normal. Comparison of olfactory ability between M and HF rats showed no significant difference indicating that if carnosine is involved in olfaction, the amount required must be very small. Restricted food intake had no apparent effect on the concentration of histidine-containing dipeptides but did influence hemoglobin concentration. The HF rats appeared to exhibit an altered state of emotionality compared to either of the other two treatment groups.
Visual Tracking of Active and Passive Movements of the Hand

Two experiments were performed to evaluate the influence of movement frequency and predictability on visual tracking of the actively and the passively moved hand. Four measures of tracking precision were employed: (a) saccades/cycle, (b) percent of pursuit movement, (c) eye amplitude/arm amplitude, (d) asynchrony of eye and hand at reversal. Active and passive limb movements were tracked with nearly identical accuracy and were always vastly superior to tracking an external visual target undergoing comparable motion. Proprioceptive information about target position appears to provide velocity and position information about target location. Its presence permits the development of central eye-movement programmes that move the eyes in patterns that approximate but do not exactly match, temporally or spatially, the motion of the hand.
Design And Test Of The Near Infrared Mapping Spectrometer (NIMS) Focal Plane For The Galileo Jupiter Orbiter Mission

A Near Infrared Mapping Spectrometer (NIMS) will fly past Jupiter on the Galileo spacecraft in 1982. The infrared detector assembly (focal plane) used in the NIMS instrument is to be passively cooled to 80 K by radiation into space. The focal plane contains 15 InSb and two silicon detectors, each with an associated dual J-FET preamp and feedback resistor. Preliminary fabrication and test experience will be described for an experimental five-channel hybrid detector assembly. Measurements of spectral noise density along with a plasma cleaning technique will also be described. The final NIMS focal plane will contain much of the design experience gained from the experimental hybrid detector assembly.
Congenital Cytomegalovirus and Deafness.

Although the incidence of medical and neurological problems resulting from congenital cytomegalovirus (CMV) infection is relatively low, the widespread and indiscriminate nature of this infection a...
The role of hyaluronidase in experimental streptococcal infection

In a previous communication' it was reported that 8 strains of streptococci, 7 belonging to Lancefield groups B, D, and K and one Sir. viridans, were able to invade the mesoderm of the chlorioallantoic (C-A) membrane of the 13 day embryonic chick and apparently multiply within phagocytic cells. All except the strain of Sir. viridans were able to spread within the mesoderm without eliciting more than a mild inflammatory response. Twenty-five other strains representing all of the Lancefield groups A to K, inclusive, were unable to establish themselves within the mesoderm either within or outside of phagocytic cells and were apparently destroyed by the latter. In order to study the various phenomena associated with a living host infected by streptococci, it was decided to carry out a series of investigations of the various factors presumed to influence virulence and ultimately to correlate the results with the clinical source of the bacteria and their virulence for the 13 day embryonic chick and for white mice. In the present paper, 65 strains of f3 hemolytic streptococci, 3 a' and one Sir. viridans strain were employed in an investigation of the influence of hyaluronidase on the virulence of streptococci. Since the discovery of spreading fac-
Effect of a dissolved corticosteroid on the surface potential of lipid monolayers

Abstract Hydrocortisone interacts with monolayers of dipalmitoyl lecithin (DPL). Surface pressure curves indicate that the steroid molecules are squeezed out of the monolayer upon compression. Surface potential values for DPL appear to be decreased when the monolayer is spread on a subphase containing dissolved hydrocortisone at surface areas at which there is no hydrocortisone at the surface. This effect is not due to an interaction of the monolayer with the substrate. If the steroid is injected beneath the DPL monolayer, the ambiguity in interpretation of surface potential values is removed. The results of such experiments conform closely to those from the surface pressure work.
A Rope of Sand: The AFL-CIO Committee on Political Education

This paper analyses the political capacity of the American labor movement, that is, its ability to mobilize organizational resources in support of endorsed candidates. It reviews the work of the Committee on Political Education (COPE), the political arm of the AFL-CIO, at state and local levels and within local unions. It is at these levels that the political apparatus of the AFL-CIO either functions smoothly or breaks down. Our analysis of COPE reveals that the AFL-ClO lacks the organizational means to transform its endorsements into voter support at the polls. It is then argued that the market strategy of the American labor movement, its strategy to pursue distributive claims through collective bargaining rather than legislation, is responsible for COPE's incapacity.
The demands of 24/7 coverage: Using faculty perceptions to measure fairness of the schedule

Objectives: Ensuring fair, equitable scheduling of faculty who work 24-hour, 7-day-per-week (24/7) clinical coverage is a challenge for academic emergency medicine (EM). Because most emergency department care is at personally valuable times (evenings, weekends, nights), optimizing clinical work is essential for the academic mission. To evaluate schedule fairness, the authors developed objective criteria for stress of the schedule, modified the schedule to improve equality, and evaluated faculty perceptions. They hypothesized that improved equality would increase faculty satisfaction. Methods: Perceived stress was measured for types of clinical shifts. The seven daily shifts were classified as weekday, weekend, or holiday (plus one unique teaching-conference coverage shift). Faculty assigned perceived stress to shifts (ShiftStress) utilizing visual analog scales (VAS). Faculty schedules were measured (ShiftScores) for two years (1998-1999), and ShiftScore distribution of faculty was determined quarterly. Schedules were modified (1999) to reduce interindividual ShiftScore standard deviation (SD). The survey was performed pre- and postintervention. Results: Preintervention, 26 faculty (100% of eligible) assigned VAS to 22 shifts. Increased stress was perceived in progression (weekday data, 0-10 scale) from day to evening to night (2.07, 5.00, 6.67, respectively) and from weekday to weekend to holiday (day-shift data, 2.07, 4.93, 5.87). The intervention reduced interindividual ShiftScore SD by 21%. Postintervention survey revealed no change in perceived equality or satisfaction. Conclusions: Faculty perceived no improvement despite scheduling modifications that improved equality of the schedule and provided objective measures. Other predictors of stress, fairness, and satisfaction with the demanding clinical schedule must be identified to ensure the success of EM faculty.
Bronchogenic Carcinoma, Massive Hemoptysis, and Systemic Air Embolus

A 57-year-old woman with squamous carcinoma of the right lung (hilum) developed acute massive hemoptysis with syncope and hypotension. Resuscitation was complicated by the development of massive systemic air embolus, and the patient died.
Thyroid Function and Serum Lipids in Older Women: A Population-based Study

Abstract Purpose: To determine if thyroid hormone deficiency, manifested by elevated serum thyrotropin (TSH), is associated with alterations in serum lipids in an unselected population of older women. Subjects and Methods: Population-based sampling of 279 ambulatory white women over age 65 studied at four US clinical centers, randomly selected from a cohort of 9,704 participants enrolled in the Study of Osteoporotic Fractures. A third-generation chemiluminescent TSH assay and serum lipid levels—total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides—were measured on fasting sera collected at the baseline visit. The cross-sectional relationships between TSH and lipid levels were analyzed. Results: TSH was high (>5.5 mU/L) in 19 women (6.8%), and was low (≤0.1 mU/L) in 10 (3.6%). After multiple adjustment, LDL-C was 17 mg/dL or 13% higher (95% confidence interval [CI] 1%, 25%), and HDL-C was 6.5 mg/dL or 12% lower (CI −0.2%, −25%) in women with high TSH compared with those with normal TSH. The ratio of LDL-C to HDL-C was 29% greater (CI 4%, 53%) among women with elevated TSH. Although total cholesterol was 8% higher among women with high TSH, this difference was not statistically significant (CI −1%, 15%). High TSH was found in 12% of the women with the combination of high cholesterol (>240 mg/dL), high LDL-C (>160 mg/dL), and low HDL-C ( Conclusion: Among older white women, high TSH is associated with deleterious changes in serum lipids, particularly HDL-C, LDL-C, and the ratio of LDL-C to HDL-C cholesterol. Women with multiple lipid abnormalities are twice as likely to have an increased TSH.
Disrupting the Myosin Converter-Relay Interface Impairs Drosophila Indirect Flight Muscle Performance

Structural interactions between the myosin converter and relay domains have been proposed to be critical for the myosin power stroke and muscle power generation. We tested this hypothesis by mutating converter residue 759, which interacts with relay residues I508, N509, and D511, to glutamate (R759E) and determined the effect on Drosophila indirect flight muscle mechanical performance. Work loop analysis of mutant R759E indirect flight muscle fibers revealed a 58% and 31% reduction in maximum power generation (PWL) and the frequency at which maximum power (fWL) is generated, respectively, compared to control fibers at 15°C. Small amplitude sinusoidal analysis revealed a 30%, 36%, and 32% reduction in mutant elastic modulus, viscous modulus, and mechanical rate constant 2πb, respectively. From these results, we infer that the mutation reduces rates of transitions through work-producing cross-bridge states and/or force generation during strongly bound states. The reductions in muscle power output, stiffness, and kinetics were physiologically relevant, as mutant wing beat frequency and flight index decreased about 10% and 45% compared to control flies at both 15°C and 25°C. Thus, interactions between the relay loop and converter domain are critical for lever-arm and catalytic domain coordination, high muscle power generation, and optimal Drosophila flight performance.
No effect of maternal niacin defficiency on niacin metabolism in newborn brain

The effects of maternal niacin and tryptophan deficiency on: (1) total niacin levels and (2) niacinnamide entry into brain, blood, and liver of newborn rabbits were studied. The deficient maternal diet produced a decreased concentration of the oxidized niacinamide-containing vitamers in the liver (73% of controls;P<0.05) but not in the brain of newborn rabbits. In both deficient and control newborn rabbits, the entry of [14C]niacinamide into brain and liver was saturable with an increasing [14C]niacinamide concentration in plasma. Also, the formation of [14C] NAD in brain and liver and [14C]niacinamide mononucleotide in blood was saturable. In vitro, the affinity of the saturable accumulation system for [14C]niacinamide in both newborn and adult rabbit brain slices was comparable (0.9 μM). The avid saturable, uptake system for niacinamide in rabbit brain contributes to total niacin homeostasis in brain.
Recombination and expression of a cloned fragment of the DNA of Bacillus subtilis bacteriophage SP01

Abstract Fragments of the DNA of bacteriophage SPO1 can be cloned in Bacillus subtilis , the natural host for SPO1. Clones of the same fragment are either stable or unstable, depending on the vector used. SPO1 DNA contains hydroxymethyluracil instead of thymine. The cloned fragments do not contain hydroxymethyluracil, even when it is present in the cell as a consequence of SPOT infection. Yet the cloned SPOT DNA is active both in expression of its genetic information and in recombination with superinfecting SPOT DNA. SPO1 gene 17, which is probably a late gene, is expressed from the cloned fragment regardless of the orientation of insertion, suggesting that it is transcribed from its natural promoter.
What can the molecular genetics of hypertensive rats teach us about the genetics of hypertension in humans

Recent progress in molecular genetics has raised expectations that the application of powerful new techniques to established animal models of hereditary hypertension may provide important new insights in the genetic basis of human hypertension. Whereas these methods provide exciting opportunities, we shall have to revise many traditional and established strategies used in hypertension research to recognize their full potential. Although it is probably naive to anticipate the quick identification of genes involved in the pathogenesis of human hypertension from this research, these methods, if applied wisely, are likely to render important conceptual insights into the nature not only of hypertension and cardiovascular disease but of polygenic disorders in general.
Thermodynamic and kinetic characterization of hydroxyethylamine β-secretase-1 inhibitors

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR). Rate constants of association (ka) measured at 25 °C ranged from a low of 2.42×10(4) M(-1) s(-1) to the highest value of 8.3×10(5) M(-1) s(-1). Rate constants of dissociation (kd) ranged from 1.09×10(-4) s(-1) (corresponding to a residence time of close to three hours), to the fastest of 0.028 s(-1). Three compounds were selected for further thermodynamic analysis where it was shown that equilibrium binding was enthalpy driven while unfavorable entropy of binding was observed. Structural analysis revealed that upon ligand binding, the BACE-1flap folds down over the bound ligand causing an induced fit. The maximal difference between alpha carbon positions in the open and closed conformations of the flap was over 5 A. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis.
Organic reactions catalyzed by crystalline aluminosilicates: IV. Beckmann rearrangement of ketoximes to amides

Abstract Acidic crystalline aluminosilicates show catalytic activity for the rearrangement of ketoximes to amides. Optimum conditions include temperatures in the range of 250–350 °C, a nonpolar solvent, and an inert carrier gas. Under these conditions, using a hydrogen Y zeolite, 75% to 95% yields of amides have been obtained from the oxime rearrangement.
Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach

The results of treatment of desmoid tumor patients with nonsteroid antiinflammatory drugs alone or in combination with tamoxifen are described. Tumor growth was inhibited in six of seven patients. Nonsteroid antiinflammatory drugs administered along with 5-fluorouracil and cyclophosphamide and other inhibitors of T-suppressor cells were used to treat nine patients with metastatic carcinoma of the stomach. Survival of these patients was extended so that after 12 months minimal follow-up the majority are well. A prospective controlled clinical trial is indicated.
Controllability of Infinite Dimensional Systems with Control Constraints

Abstract In this paper we examine the controllability properties of infinite dimensional control systems, nonlinear in the control variable and with time varying control constraints. We derive a necessary and sufficient condition for approximate controllability, which in the case of linear, autonomous finite dimensional control systems with no control constraints reduces to the classical Kalman rank condition. We also study the problem of approximate local null-controllability and compare the controllability properties of the original and relaxed systems.
Conjugate points on a limiting extremal

Abstract Theorem 1, together with the author's extensions of the Sturmian Comparison Theorems, will suffice to establish the basic Theorem 27.3, p. 211 of Global Variational Analysis: Weierstrass Integrals on a Riemannian Manifold. Mathematical Notes, Princeton University Press, Princeton, N.J., 1976. Here and in the preceding reference there is given a Weierstrass Integral on a compact, connected, Riemannian manifold Mn, conditioned as in the above reference. Let γ be an arbitrary extremal of J joining a point P to a point Q, ≠ P on Mn. An extremal ζ of J joining A to B is termed nondegenerate if A and B are not conjugate on ζ. The index of ζ is by definition the “count” of conjugate points of A on ζ definitely preceding B. THEOREM 1. When the extremal γ is nondegenerate, extremals of J issuing from P with the same length as γ and sufficiently near γ in the sense of Frechet, are nondegenerate and have the same index as γ.
Effects of Poliovirus 3AB Protein on 3D Polymerase-catalyzed Reaction

Abstract Poliovirus RNA replication requires the activities of a viral RNA-dependent RNA polymerase, 3Dpol, in conjunction with several additional viral and likely cellular proteins. The importance of both the 3A and 3B coding regions has been documented previously by genetic tests, and their biochemical activities have been the subject of several recent investigations. In this study, we examined the previously reported stimulation of 3D-catalyzed RNA synthesis by 3AB. We show that 3AB does not stimulate RNA synthesis on templates that are stably base paired to a primer, indicating that 3AB does not stabilize or otherwise activate 3Dpol for chain elongation. Similarly, it does not alter the kinetic parameters or binding affinities of 3D for substrates. In the absence of a primer, or in the presence of a primer that does not form a stable hybrid with the template, 3AB increases the utilization of 3′-hydroxyl termini as sites for chain elongation by 3D, and thereby stimulates RNA synthesis. 3AB may interact with and stabilize these sites and/or may recruit 3Dpol to the site, resulting in stimulation of the initiation of elongation events. We propose that this activity is required for stabilizing weak interactions that occur during nucleotidyl-protein-primed initiation events in the viral RNA replication complex.
Equivalent conditions for uniform asymptotic consensus among distributed agents

A set of conditions equivalent to uniform asymptotic consensus for distributed agents involving switched stability theory, linear matrix inequalities, and graph-theoretic notions has been established. These conditions are presented for both leaderless and leader-follower situations and extend previous results to wider classes of multi-agent systems. In particular, the uniformity requirement imposed on the convergence rate of mixed matrix products not only plays a crucial role in theoretical developments, but it also meets the practical needs of reaching consensus robustly against disturbances.
Analysis of gas-surface reactions by surface temperature modulation: Experimental applications to the adsorption and oxidation of carbon monoxide on the Pt(110)-(1 × 2) surface

Abstract Surface temperature modulation has been employed to investigate the adsorption, desorption and oxidation of CO on the Pt(110)-(1 × 2) surface. Examination of the adsorption-desorption equilibrium allows a determination of the kinetic parameters describing the desorption reaction. In the limit of zero coverage, the activation energy of desorption is 36±1.5 kcal mol−1 with a first-order preexponential factor of 3 × 1014 s−1. As the coverage of CO increases, both parameters decrease in magnitude. The oxidation of CO has been studied with an emphasis on examining the kinetics of the elementary “bimolecular” surface reaction CO(a)+O(a) → CO2(g). By varying both the reactant partial pressure ratio and the steady-state temperature of the surface, the reaction rate parameters have been evaluated for a variety of combinations of adsorbate concentrations occurring at steady state. The magnitudes of both the activation energy and the preexponential factor of the reaction rate coefficient have been found to correlate well with the oxygen adatom concentration. In the low-coverage limit, the activation energy is 22±1 kcal mol−1, and the preexponential factor is 3 × 10−3 cm2 s−1. As the oxygen adatom concentration increases beyond a fractional coverage of approximately 0.15, the magnitudes of both parameters drop precipitously to values given, respectively, by 8±1 kcal mol−1 and 10−10 cm2 s−1. The decrease in the activation energy at high oxygen coverages is explained best by a decrease in the binding energies of the adsorbed reactants. The apparent decrease in the preexponential factor could well be due to the local configuration of the reactants that occurs at high oxygen coverages.
Order-recursive spectrum estimation

The use of a multiple-pole filter in the time-average estimation of the autocorrelation allows the power spectrum estimates to be recursive in the order of multiplicity of the filter pole. The recursive generation of the estimates from various filter orders provides the flexibility to select the estimator of interest in terms of the variance and spectral and temporal resolution. >
Chaotic advection and dispersion

Abstract The dispersion of passive tracers by chaotic advection is examined for the flow through a “twisted” pipe. The effect of long-time trapping by islands on particle dispersion is documented by numerical experiments. The trapping episodes lead to periods of quasi-ballistic motion, however these periods are intermittent and are interrupted by periods of chaotic motion. The effect of the longitudinal transport is to cause super-diffusive spreading of the tracer, Δ2(t)≈tv where v is empirically determined to be in the range 1
Antidiuresis and Other Renal Responses to Piperoxan in Pheochromocytoma

The clinical recognition of pheochromocytoma as a cause of hypertension is still a difficult problem for which the many tests that have been devised are at times inadequate. In this article an antidiuretic response to piperoxan in patients with pheochromocytoma is described. In view of the diuretic response of patients without pheochromocytoma, measurement of urinary flow after injection of piperoxan is suggested as a possible simple, confirmatory guide in diagnosis.
THE NEUROENDOCRINOLOGY OF OBESITY

The regulation of energy balance is enormously complex, with numerous genetic, hormonal, neural/behavioral, and societal influences. Although the current epidemic of obesity has its underpinnings in the changes in culture during the last half century, the role of the neuroendocrine system in the genesis of obesity is physiologically and therapeutically unavoidable. Increased understanding of this system has suggested organic etiologies (and therapies) for some rare and not-so-rare forms of obesity. With so many inputs, it is not implausible that dysfunction of other parts of this feedback system will be found to explain other forms of obesity in the future. Fortunately or unfortunately, diet and exercise remain the mainstays of obesity therapy. Most diet-exercise programs result in an acute 11-kg weight loss in adults; the question is whether it can be sustained without significant long-term behavior modification. In the European Sibutramine Trial of Obesity Reduction and Maintenance (STORM), 42% of treated patients dropped out; of those remaining, 77% of subjects lost more than 5% of initial body weight, but only 43% of these individuals maintained greater than 80% of this loss over 2 years. Could there be an organic component in persons who do not respond? Obesity pharmacotherapies sometimes have beneficial acute effects, but these effects are impermanent; discontinuation tends to result in a rebound weight gain, suggesting that the etiology of the obesity is still present. A useful guiding principle is that patients who do not respond to diet and exercise should undergo an initial medical evaluation, including assessments of birth weight, past medical history, weight history, family history, diet, exercise, and fasting insulin and thyroid levels. As the nosology of obesity improves, diagnostic efficiency and therapeutic success should increase, leading to a decrease in associated morbidity, mortality, and socioeconomic ramifications.
Uterine histamine in rat deciduomata.

The histamine changes accompanying the growth of decidual tissue were differentiated from the histamine changes occurring as a result of the injury used to elicit this growth. Histamine concentration decreased about 50% in decidual tissue when compared with unstimulated uteri, but total histamine content was elevated in deciduomata, being about 100 % higher than in control horns. The procedure utilized to elicit the decidual reaction consisted of cutting the uterus and then scratching it. The cut increased histamine concentration about 100 %, while the endometrial scratch caused only a slight decrease in histamine concentration. It thus appears that the response to the injury and inflammation involved in producing the decidual reaction was an increase in histamine concentration, while the decidual growth response resulted in a decrease in histamine concentration.
6(5H)-phenanthridinones. II. Preparation of substituted 6(5h)-phenanthridinones from 9-oxofluorenes†

A number of 6(5H)-phenanthridinones have been conveniently prepared from 9-oxofluorenes through the Schmidt reaction. It has been found that all amino and nitro 9-oxofluorenes thus far tried gave substituted 6(5H)-phenanthridinones with the amino or nitro group situated in the benzene ring attached to the nitrogen of the lactam group. UV and IR spectral data are presented for these compounds.
Abstract LB-215: Inhibition of Polo-like kinase 4 as an anti-cancer strategy

Polo-like kinase 4 or PLK4 is a member of a conserved family of serine/threonine protein kinases that regulate multiple cellular processes, such as cell division and checkpoint regulation of mitosis. These kinases are often deregulated in cancer. PLK4 is the most structurally divergent PLK, localizes to centrosomes and is a critical regulator of centriole duplication. Over-expression of PLK4 leads to centrosome amplification and results in chromosome instability (CIN), a common characteristic observed in many types of cancers. We found that PLK4 is upregulated in breast cancer, specifically in the basal-like subtype. PLK4 expression is induced by hypoxia and suppressed by p53 in cancer cells. Consistent with this observation, PLK4 expression in cancer cells is upregulated when they are implanted and grown as xenografts in vivo. Furthermore, RNAi-mediated depletion of PLK4 inhibits the growth of cancer cells, but not normal cells (HMEC), in vitro, and tumor growth in vivo. Interestingly, siRNA knockdown of PLK4 sensitizes cancer cells to hypoxia. These findings suggest that targeting PLK4 may be a good therapeutic strategy in treating certain cancers. To this end, we initiated a discovery program that resulted in the identification of potent PLK4 inhibitors. These novel inhibitors are potent anti-prolifeartives, cause loss of mitotic checkpoint followed by apoptotic cell death, and suppress tumor growth in xenograft models. Mechanistically, inhibition of PLK4 suppresses phosphorylation of PLK4 and Histone H3, leads to failure of centrosome clustering and formation of multipolar spindles. Interestingly, breast cancer cell response to PLK4 inhibition appears to differ among subtypes of breast cancer cells and to be influenced by receptor and mutation status, such as ER and PTEN. Since multipolar division in cancer cells is not viable, due to massive missegregation of chromosomes, inhibition of PLK4 and formation of multipolar division followed by cell death may be a unique strategy for killing cancer cells. Implications of these findings in treating cancer will also be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2011-LB-215
Mitochondrial Aging: Open Questionsa

Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate ("rate of living") and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?
Corners in Auctions

Different pricing rules in multiunit auctions provide different incentives for a bidder to corner the auction and thus require different levels of effort from the seller to deter cornering. We consider three different types of auctions: the pay-your-bid or “discriminatory” auction commonly used by the US Treasury, the lowest-winning-bid uniform-price auction used in the current Treasury experiment, and the highest-losing-bid uniform-price auction considered by Vickrey almost four decades ago. We show that the pay-your-bid auction provides the greatest incentive to corner the market, that the experimental Treasury auction provides less incentive, and that the highest-losing-bid uniform-price auction provides the least. Arguably, the less the incentive to corner the market, the easier it will be for sellers to deter cornering, and the greater their expected revenue (net of the cost to deter cornering) will be in otherwise expected-revenue-equivalent auctions.
Polymeric copper (II) complexes of hydroxy acids

Abstract A quantitative study of the equilibria involved in the interaction of Cu(II) ion with citric (H4L), malic (H3L) and tartaric (H4L) acids in aqueous medium has been carried out by means of potentiometric measurements of hydrogen ion concentrations at a constant temperature of 25 ± 0·05° and an ionic strength of 1·0 (KNO3). On the basis of concentration dependence of the equilibrium constants, it is found that Cu(II) interacts with citric acid (H4L) to form a dimer, Cu2(HL)2−2, which subsequently dissociates to give Cu2L24-. The value of the equilibrium constants are: K=[Cu2(HL)22−]/[Cu2+]2[HL3−]2=1013·2; K=[Cu2l24−][H+]2/[Cu2(HL)22−]=108·1 Equimolar interaction of Cu(II) and malic acid (H3L) results in the formation of a dimer, Kd=[Cu2(HL)2]/[Cu2+]2[HL2−]2=108·5; followed by dissociation of the dimer ( K = [ Cu 2 L 2 2- ][ H + ] 2 [ Cu 2 ( HL ) 2 ] = 10 −8·1 ) to the complex Cu2L22-. Mononuclear Cu(II) tartrate, CuH2L, exists in equilibrium with the binuclear complex Cu2(H2L)2 in the pH range 2–4. KML=[Cu(H2L)]/[Cu2+][H2L2−=102·6 Kd=[Cu2(H2L)2]/[Cu(H2L)]2=103·0 The dimeric Cu(II) tartrate undergoes dissociation and further polymerization above pH 4. Possible structures of the complex species formed are discussed.
The Natural Convection of Air Over a Heated Plate With Forward-Facing Step

An experimental study of free convection flow of air over a vertically oriented, isothermal, heated plate with a forward-facing step was done. The step height was varied from 0.3175 to 0.9525 cm, and the distance of the step from the leading edge was varied from 7.62 to 15.24 cm. Temperature profiles were measured with a thermocouple probe, and velocity profiles were measured by photographing the trajectories of small dust particles carried along with the flow. For comparison purposes the same measurements were made for a flat plate. The results are nondimensionalized for comparison with the theoretical velocity and temperature profiles for a flat plate. A discussion of how the temperature and velocity profiles deform as the fluid passes over the step and the effect of step size and location on profile shape is included. The experimentally obtained temperature profiles are used to calculate the dimensionless heat-transfer coefficient. This coefficient is characterized in terms of the size and location of the step.
Endocrine control of sexual behavior in mammals

L'auteur presente une revue critique des bases experimentales de l'hypothese neuro-endocrine du comportement sexuel des mammiferes.
Outer surface potential changes due to energization of the chloroplast thylakoid membrane

Abstract An impermeable charged paramagnetic amphiphile 4-(dodecyl dimethyl ammonium)-1-oxyl-2,2,6,6-tetramethyl piperidine bromide can be used as a probe of membrane surface potentials. Upon energization of photosystem II or photosystems I + II in illuminated spinach chloroplast thylakoids, a decrease occurs in the potential of the outer surface of these membranes of up to 14 mV.
n-3 Fatty Acids: Biochemical Actions in Cancer

A number of reports indicate that fish n-3 PUFA inhibit the development, growth and progression of several experimental tumors. There emerges a pattern of complex and diverse biochemical actions of n-3 PUFA in different animal tumor models, from the studies undertaken to date to evaluate the underlying mechanisms. These findings, along with the recent epidemiological evidence of an inverse correlation between fish intake and incidence of some human cancers, makes it worthwhile to determine the role of n-3 PUFA in cancer.