cssi/SciSciGPT-SciSciNet huggingface dataset:
Topotecan in chronic lymphocytic leukemia.

Background. Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease. Methods. Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III-IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 μM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique. Results. No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patient died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo. Conclusions. Although exposure of cells from patients with CLL to topotecan in vitro at 2 μM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients. Cancer 1995;75:1104–8.
Structure-activity relationship of minoxidil analogs as inhibitors of lysyl hydroxylase in cultured fibroblasts☆

The structural features that confer upon minoxidil the ability to suppress lysyl hydroxylase activity in human skin fibroblasts were investigated. Substitution of the amino group in position 2 or 6 of the pyrimidine ring with a methyl group had no significant effect on the inhibitory activity of minoxidil, whereas substitution of both amino groups with methyl groups resulted in a complete loss of inhibitory activity. Together, these observations indicate that only one of the two amino groups ortho to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Derivatives of minoxidil formed by hydroxylation at position 3 or 4 of the piperidine ring were as active as the parent compound in suppressing lysyl hydroxylase activity. However, replacement of the piperidinyl group in position 4 of the pyrimidine ring with a pyrrolidinyl, morpholinyl, or N-methylpiperazinyl group resulted in loss of inhibitory activity, demonstrating that the piperidinyl group para to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Removing the nitroxide oxygen from position 1 of the pyrimidine ring resulted in a partial loss of the specificity of minoxidil for suppression of lysyl hydroxylase activity. The results indicate that distinct structural elements determine the enzyme-suppressing effect and the antihypertensive effect of minoxidil.
Squared temperature-temperature power spectrum as a probe of the CMB bispectrum

It is now well known that mode-coupling effects associated with certain secondary effects generate higher order correlations in cosmic microwave background (CMB) temperature anisotropies, beyond the two-point function. In order to extract such a non-Gaussian signal at the three-point level, we suggest a two-point statistic in the form of an angular power spectrum involving correlations between squared temperature and temperature anisotropies. This power spectrum contains compressed information from the bispectrum and can be easily measured in data with the same techniques that have been considered for the measurement of the usual temperature-temperature anisotropy power spectrum. We study the proposed power spectrum resulting from the non-Gaussian signal generated by correlations involved with gravitational lensing angular deflections in CMB and the Sunyaev-Zel’dovich (SZ) effect due to large scale pressure fluctuations. Using the Planck frequency cleaned CMB and SZ maps, the CMB2-SZ power spectrum provides a direct estimate of the cross-power between lensing angular deflections and the SZ effect. Through an optimal filter applied to the squared CMB map, the proposed statistic allows one to obtain all information from the lensing-SZ bispectrum. The observational measurement of the lensing-SZ cross-correlation is useful to understand the relation between large scale structure pressure and dark matter fluctuations.
Kinetics of the reactions of atomic chlorine with H2S, D2S, CH3SH, and CD3SD

Time-resolved resonance fluorescence detection of atomic chlorine following 266-nm laser flash photolysis of Cl2CO/RSR'/N2 mixtures has been employed to study the kinetics of Cl reactions with H2S(k1), CH3SH(k2), D2S(k3), and CD3SD(k4) as a function of temperature (193–431 K) and pressure (25–600 torr). Arrhenius expressions which describe our results are (units are 10−11 cm3molecule−1s−1; uncertainties are 2σ, precision only) k1 = (3.69 ± 0.33) exp[(208 ± 24)/T], k2 = (11.9 ± 1.7) exp[(151 ± 38)/T], and k3 = (1.93 ± 0.32) exp[(168 ± 42)/T]. The Cl + CD3SD reaction has been studied at 299 K and 396 K; values for k4 at these two temperatures are essentially the same as those measured for k2. Our results are compared with earlier studies and the mechanistic implications of observed negative activation energies and HD kinetic isotope effects are discussed. © 1995 John Wiley & Sons, Inc.
Embodied metaphor and abstract problem solving: Testing a metaphoric fit hypothesis in the health domain

Abstract How do people evaluate candidate solutions to abstract problems that are difficult to grasp? According to conceptual metaphor theory, people can conceptualize abstract ideas in terms of well-known bodily states, even if they are not currently experiencing those bodily states. Extending this perspective, we test a novel metaphoric fit hypothesis concerning the (mis)match between embodied-metaphoric framings of an abstract problem (in these studies, depression) and candidate solutions (depression treatments). In Studies 1 and 2, framing depression metaphorically as being physically down or darkened increased the perceived effectiveness of depression medications framed metaphorically as solving those bodily problems (“lifting” and “illuminating,” respectively). Consistent with conceptual metaphor theory, this effect was mediated by subjective certainty about depression. Studies 3 and 4 manipulated problem and solution framings to test the interactive effects of metaphoric fit and misfit on solution evaluations. These findings reveal a new route by which embodied knowledge influences problem solving.
Pharmacokinetic approaches to drug distribution in the cerebrospinal fluid based on ventricular administration in beagle dogs.

Two mathematical approaches are described to approximate the distribution of compounds (e.g., drugs) in the cerebrospinal fluid (CSF) downstream of or distal to both the ventricular injection site and the cisterna magna sampling site. The first approach uses a graphic representation and is, in essence, model independent;the second approach considers the geometry and physiology of CSF distribution and clearance. In all studies, radiolabeled inulin was used as an “internal standard” since it is not metabolized and is eliminated from the CSF primarily by bulk flow. Temporal comparison of the study compound to radiolabeled inulin in the cisternal CSF allowed testing of these models in beagle dogs. One use of this data is in the estimation of the drug exposure integral for antineoplastic drugs administered in the CSF to treat leptomeningeal neoplasia.
The Value of Goodness-of-Fit Indices in Meta-Analysis: A Comment on Hall and Rosenthal.

In a useful article regarding testing for moderator variables in meta‐analysis, Hall and Rosenthal (1991) suggest, among other things, that when the sample of studies is large enough, it is acceptable to use ordinary inferential statistics such as the analysis of variance to test for moderator variables. However, because meta‐analytic data points (effect sizes) differ in important ways from those for which ordinary inferential statistics were designed, we recommend that analysts use conventional meta‐analytic statistics, which are at least potentially more informative about the literature in question. Hall and Rosenthal also suggest that tests of effect size variability should play a minimal role in meta‐analytic model tests. We concur that these tests of homogeneity cannot alone test for moderator variables and that at least tests between mean effect sizes should be performed. However, consistent with Hedges and Olkin's (1985) meta‐analytic framework, we show how homogeneity tests provide additional and ...
Diffusion in network

Abstract In this paper we study a diffusion in an orthogonal array of two-dimensional channels as the width of the channels decreases to zero and the number of channels increases to infinity. It is shown that the limit is again a diffusion process and the diffusion coefficients are computed explicitly in terms of the relative sizes of the rectangles surrounded by the channels.
On-line training of a continually adapting adaline-like network

A rigorous mathematical analysis is presented of an adaline-like network operating in continuous time with spatially continuous inputs and outputs. Weights adapt continually, whether or not a training signal is present. It is shown that consistent input-output pairs can be learned perfectly provided every pattern is repeated at least once in every N successive inputs, and the input patterns are nearly orthogonal, depending on N.
Pneumococcal septic arthritis as the initial presentation of multiple myeloma.

Summary Septic arthritis induced by Streptococcus pneumoniae is an uncommon manifestation of pneumococcal infection. Pneumococcus has been identified as the inciting pathogen in only 6% of cases of septic arthritis in recent retrospective studies (Ross et al., 2003). Approximately 50% of patients with pneumococcal septic arthritis have a preceding or concurrent extra-articular focus of infection. The septic joint evolves from hematogenous seeding of the highly vascular synovial membrane by bacteria. Polyarticular disease occurs in only approximately 36% of patients. Most pneumococcal septic arthritis occurs with coexistant joint disease, prosthesis, alcoholism, HIV infection, or rheumatoid arthritis (Baraboutis & Skoutelis, 2004; Raad & Peacock, 2004). We report a case of polyarticular septic arthritis as the first manifestation of an underlying disease. Our literature review discloses that this is the first reported case of multiple myeloma initially presenting as pneumococcal septic arthritis in the USA and the third internationally (Cuesta et al., 1992; Renou et al., 2007).
Dual modulation of gabaergic transmission by metabotropic glutamate receptors in rat ventral tegmental area

The effects of metabotropic glutamate receptor (mGluR) activation on non-dopamine (putative GABAergic) neurons and inhibitory synaptic transmission in the ventral tegmental area were examined using intracellular recordings from rat midbrain slices. Perfusion of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD; agonist for group I and II mGluRs), but not L-amino-4-phosphonobutyric acid (L-AP4; agonist for group III mGluRs), produced membrane depolarization (current clamp) and inward current (voltage clamp) in non-dopamine neurons. The t-ACPD-induced depolarization was concentration-dependent (concentration producing 50% maximal depolarization [EC(50)]=6.1+/-2.5 microM), and was blocked by the antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine, but not by tetrodotoxin and ionotropic glutamate-receptor antagonists. The t-ACPD-evoked responses were mimicked comparably by selective group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the DHPG-induced depolarization in non-dopamine neurons was greatly reduced by mGluR1-specific antagonist 7(hydroxyimino)cyclopropachromen-1a-carboxylate ethyl ester. When recorded in dopamine neurons, the frequency of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic potentials was increased by t-ACPD but not L-AP4. However, the amplitude of evoked inhibitory postsynaptic currents in dopamine neurons was reduced by all three group mGluR agonists. These results reveal a dual modulation of mGLuR activation on inhibitory transmission in midbrain ventral tegmental area: enhancing putative GABAergic neuronal excitability and thus potentiating tonic inhibitory synaptic transmission while reducing evoked synaptic transmission at inhibitory terminals.
Sleep characteristics and endocrine response in progeria

T ~ I E P R O O ~ R I A of Hutchinson-Gi l ford is a car ica ture of normal senescence tha t begins in the first year of life wi th fai lure to ga in weight, loss of subcutaneous fat, ba lding, a t rophy of the skin, and wizened facies and ends in dea th from atheroscterosis before age 20; menta t ion is un impai red . A recent extensive metabol ic invest igat ion of 2 pat ients ind ica ted a lack of g rowth hormone response to insul ininduced hypoglycemia and relat ive insulin resis tance? Growth hormone unresponsiveness to insul ininduced hypoglycemia has been described in ano ther report , 2 bu t the pa t i en t was la ter repor ted to have g rowth hormone response to the infusion of a rg in ine? T h e present study was under taken to extend previous endocr ine observations, to eva lua te growth hormone release as a funct ion of sleep stage, and to determine whe ther
Reactive oxygen species and cellular oxygen sensing

Many organisms activate adaptive transcriptional programs to help them cope with decreased oxygen (O(2)) levels, or hypoxia, in their environment. These responses are triggered by various O(2) sensing systems in bacteria, yeast and metazoans. In metazoans, the hypoxia inducible factors (HIFs) mediate the adaptive transcriptional response to hypoxia by upregulating genes involved in maintaining bioenergetic homeostasis. The HIFs in turn are regulated by HIF-specific prolyl hydroxlase activity, which is sensitive to cellular O(2) levels and other factors such as tricarboxylic acid cycle metabolites and reactive oxygen species (ROS). Establishing a role for ROS in cellular oxygen sensing has been challenging since ROS are intrinsically unstable and difficult to measure. However, recent advances in fluorescence energy transfer resonance (FRET)-based methods for measuring ROS are alleviating some of the previous difficulties associated with dyes and luminescent chemicals. In addition, new genetic models have demonstrated that functional mitochondrial electron transport and associated ROS production during hypoxia are required for HIF stabilization in mammalian cells. Current efforts are directed at determining how ROS mediate prolyl hydroxylase activity and hypoxic HIF stabilization. Progress in understanding this process has been enhanced by the development of the FRET-based ROS probe, an vivo prolyl hydroxylase reporter and various genetic models harboring mutations in components of the mitochondrial electron transport chain.
Officer, nurse, woman: the Army Nurse Corps in the Vietnam War

by Kara Dixon Vuic, Baltimore, The Johns Hopkins University Press, 2010, 271 pp., US$50 (hardback), ISBN 978‐0801893919 Going back at least as far as the mid‐nineteenth century, when Florence Night...
Influences of generalized loading parameters on FLD predictions for aluminum tube hydroforming

Abstract The present study intends to investigate the prediction of forming limit diagrams (FLDs) for tube hydroforming from the perspective of selecting various combinations of loading parameters based on plastic instability. From this perspective, certain related research efforts on plastic instability of thin-walled tubes subjected to internal fluid pressure and axial force are reviewed and six combinations of loading parameters have been identified. There are nine combinations of loading parameters, including six found in the literature, being employed to determine forming limit curves (FLCs) for tube hydroforming in the present study. The predicted FLCs are compared with experimental data obtained in a well-controlled laboratory condition. Comparisons indicate that the combination of the internal pressure p and the resultant axial force Fz + πr2p provides the best predicted right side of FLC among the nine combinations and a reasonably well-predicted left-hand side of FLC. In addition, comparison also demonstrated that the combination of p and the applied axial stress Fz/2πrt can also give a reasonable predicted left-hand side of FLC.
Three-dimensional boundary singularity method for partial-slip flows

This study extends a 3-D method of the fundamental solutions (MFS) to Stokes flows with Knudsen numbers corresponding to partial-slip flows interior and exterior to spherical boundaries. The study focuses on the distribution of the singularities outside the fluid flow domain. Local spherical coordinates systems are thus introduced to accommodate the application of the method to flows with partial-slip boundary conditions, where velocities tangent to solid walls are proportional to shear rates at surfaces. The singularities are subject to variation in location and number to investigate their impacts on numerical accuracy. For the flow about a single sphere, it is shown that the numerical accuracy improves when the singularities move towards the sphere center. When the singularities are located too far away from the observation points toward the center of sphere, the solution of the linear system fails. The reasons that cause the failure are explored and optimal location of singularities is found. The flow between two concentric spheres is used for further validation of the developed method for a combination of convex and concave surfaces. Finally the application of the method to flows about two separately spaced spheres is presented. Numerical results obtained compare favorably with analytical solutions for presented test cases. It is shown that a moderate number of singularities can be used in combination with a proper location of singularities to achieve a prescribed accuracy.
Microeconomic influences on operating leverage

Abstract The concept of operating leverage generally has been visualized in the context of linear break-even analysis. This paper evaluates the properties of two measures of the degree of operating leverage using a more general short-run microeconomic model of the firm. In this model, the degree of operating leverage is related positively to the price elasticity of demand for a firm's output, to its elasticity of supply for an input, and to its output elasticity. In addition, operating leverage measures are usually derived from models inconsistent with firm wealth maximizing behavior and are too simplistiic for complex models with stochastic demand, supply, and production functions.
Feeding Habits of the Squid, Illex illecebrosus

OBSERVATIONS have occasionally been made on the method of attack on prey by Illex in the inshore zone where it feeds mainly on small fishes1–3. This communication suggests a way in which the squid is able to capture smaller food organisms—mainly small crustaceans (Euphausiids)4—when it is schooling in the offshore zone.
Accuracy Limitations of Hyperbolic Multilateration Systems

A recently developed procedure [1] for assessing the accuracy of hyperbolic multilateration systems makes it easy to determine basic limitations on accuracy. This paper illustrates how such bounds can be derived. The results include bounds for a variety of geometries that are representative of practical ground-based and satellite-based hyperbolic systems. The results are applicable whenever the ranging errors can be treated as uncorrelated zeromean random variables. In some cases the bounds quantify general knowledge (e. g., the directional dependence of errors). In other cases the bounds represent entirely new limitations (e. g., optimum accuracies for sector-restricted and cone-restricted transmitter/receiver configurations).
Structured speech modeling

Modeling dynamic structure of speech is a novel paradigm in speech recognition research within the generative modeling framework, and it offers a potential to overcome limitations of the current hidden Markov modeling approach. Analogous to structured language models where syntactic structure is exploited to represent long-distance relationships among words , the structured speech model described in this paper makes use of the dynamic structure in the hidden vocal tract resonance space to characterize long-span contextual influence among phonetic units. A general overview is provided first on hierarchically classified types of dynamic speech models in the literature. A detailed account is then given for a specific model type called the hidden trajectory model, and we describe detailed steps of model construction and the parameter estimation algorithms. We show how the use of resonance target parameters and their temporal filtering enables joint modeling of long-span coarticulation and phonetic reduction effects. Experiments on phonetic recognition evaluation demonstrate superior recognizer performance over a modern hidden Markov model-based system. Error analysis shows that the greatest performance gain occurs within the sonorant speech class
Acoustic reflex thresholds in normal and cochlear-impaired ears: effects of no-response rates on 90th percentiles in a large sample.

Ninetieth percentile cutoffs for acoustic reflex thresholds (ARTs) were determined for a sample of 2,748 ears of 1,374 subjects with normal hearing and sensorineural loss of cochlear origin. All su...
Real-time Fourier transform with a surface-wave convolver

The generation of Fourier transforms of electronic signals in real time with an acoustic-surface-wave convolver is demonstrated. Two matched chirps propagating through each other behave as a narrowband filter in wavevector space, with the filter centre moving at a rate proportional to the acoustic velocity and the chirp rate.
The Acute Phase Response Alters Cationic Amino Acid Transporter Expression in Growing Chickens (Gallus Gallus Domesticus)

The effect of an acute phase response (APR) on cationic amino acid transporter (CAT1-3) mRNA expression in liver, muscle, bursa and thymus was determined in broiler strain chickens. The APR was initiated by injecting Salmonella typhimurium lipopolysaccharide subcutaneously (LPS; 1 mg/kg bw). In Experiment 1, CAT1-3 mRNA expression was determined at multiple time points following LPS administration. LPS increased bursa and liver total and high affinity CAT mRNA expression (P 0.05). LPS increased liver weight only (P 0.05). In Experiments 3 and 4, thymocyte proliferation and total protein content were dependent upon the media lysine concentration (P<0.001). The inability of the thymus to compete for lysine and arginine during the APR may limit the ability of thymocytes to develop during infections.
Management of Pancoast tumours

Non-small-cell lung carcinomas of the superior sulcus, frequently termed Pancoast tumours, are some of the most challenging thoracic malignant diseases to treat because of their proximity to vital structures at the thoracic inlet. Originally deemed universally fatal, Pancoast tumours are now amenable to curative treatment because of improvements in combined modality therapy and development of new techniques for resection. This review includes discussion of anatomical considerations, initial assessment, multimodality treatment, and surgical approaches for these cancers.
Bis(Pyridyl)Cadmium(II) Iodide Complexes: Thermal, Inclusion, and Structural Behavior

Abstract Bis(4-cyanopyridine)cadmium(II) iodide ( 1 ) crystallizes as infinite CdI 2 chains, in which cadmium atoms are doubly bridged by pairs of iodine atoms; 4-cyanopyridine ligands occupy trans positions to complete an octahedral coordination about the cadmium. The chains are associated into layers through self-association of the cyano groups. The layer structure of 1 is essentially unchanged as mercury(II) iodide molecules are intercalated between the layers to form 2 . Bis(4-vinylpyridine)cadmium(II) iodide ( 3 ) crystallizes in a nearly isomorphous fashion with 1 ; however, lacking a donor site capable of binding to HgI 2 , it does not form an intercalation compound similar to 2 . Bis(2-vinylpyridine)cadmium(II) iodide ( 4 ) crystallizes as a molecular species with approximate tetrahedral coordination about the four-coordinate cadmium atom; steric interactions involving the vinyl groups prevent formation of extended chains. The 4-vinylpyridine complex undergoes a thermally-induced solid-state polymerization of the ligand that is not observed in 1 , 2 or 4 .
Use of Ultra-Small-Angle X-ray Scattering To Measure Grain Size of Lamellar Styrene−Butadiene Block Copolymers

Simultaneous determination of the lamellar morphological length scale and the grain size of several low molecular weight heterogeneous styrene−butadiene block copolymers was accomplished through the use of ultra-small-angle X-ray scattering measurements. NIST's X23A3 Ultra SAXS beamline of the National Synchotron Light Source in the Brookhaven National Laboratory provided a scattering vector, q, from 0.0004 to 0.1 A-1. Many of the block copolymer specimens display a clearly resolvable peak in the Ultra SAXS region, and grain size was determined using the spherical form factor. Determination of Porod's law constant and the value of the scattering invariant provided a preliminary verification of the proposed scattering mechanism by solving for the contrast factor and the volume fraction of the grain boundaries in these specimens. Grain size in a given polymer was a function of annealing temperature and time. For the case of a block copolymer swollen with varying amounts of cumene, both the lamellar repeat d...
Molecular supercollisions: Evidence for large energy transfer in the collisional relaxation of highly vibrationally excited pyrazine by CO2

The temperature dependence of the collisional quenching of highly vibrationally excited pyrazine by CO2 molecules has been investigated for the temperature range 243–364 K using high resolution time resolved diode laser spectroscopy. Particular emphasis is placed on vibration to rotation‐translation (V→R/T) energy transfer which leaves the CO2 vibrations unexcited and occurs predominantly through short‐range repulsive forces. Vibrationally hot pyrazine is prepared by 248 nm excimer laser pumping, followed by rapid radiationless transitions to the ground electronic state. For the range of experimental cell temperatures used here, the nascent rotational population distributions of the 0000 ground state of CO2 resulting from collisions with hot pyrazine were probed at short times following excitation of pyrazine by the excimer laser pulse. The CO2 translational recoil velocity was also measured for individual rotational levels of the 0000 state. In addition, temperature dependent rate constants and probabili...
Acetylide-bridged tetracene dimers

Alkyne linked tetracene dimers were synthesized from naphthacenequinone and terminal acetylenes. The silylethynyl tetracene dimers exhibit good solubility, high photostability, and broad absorbance leading to photocurrent generation in an organic photovoltaic device.
Stochastic transient analysis of biochemical systems and its application to the design of biochemical logic gates.

In order to better characterize the behavior of biochemical systems, it is sometimes helpful andnecessary to introduce time-dependent input signals. If the state of a biochemical system withsuch signals is assumed to evolve deterministically and continuously, then it can be readily ana-lyzed by solving ordinary differential equations. However, if it assumed to evolve discretely andstochastically, then existing simulation methods cannot be applied. In this paper, we incorporateconditions for transient analysis into stochastic simulation and we develop the correspondingsimulation algorithm. Applying our method to examples, we demonstrate that it can yield newinsights into the dynamics of biochemical systems; speciﬁcally, it can be used to verify thedesign of biochemical logic gates.
Gastric and colonic metastases from breast cancer.

Metastases from carcinoma of the breast to both stomach and colon occurred in 2 patients. Differentiation from second primaries allowed postponement of surgical intervention for prolonged periods for both gastric lesions and permitted alternative therapy for the colonic lesions. Prolonged survival without surgical intervention can be expected if the proper diagnosis of metastatic cancer can be made. A vigorous diagnostic approach is therefore indicated.
Alignment of protein sequences by their profiles

The accuracy of an alignment between two protein sequences can be improved by including other detectably related sequences in the comparison. We optimize and benchmark such an approach that relies on aligning two multiple sequence alignments, each one including one of the two protein sequences. Thirteen different protocols for creating and comparing profiles corresponding to the multiple sequence alignments are implemented in the SALIGN command of MODELLER. A test set of 200 pairwise, structure-based alignments with sequence identities below 40% is used to benchmark the 13 protocols as well as a number of previously described sequence alignment methods, including heuristic pairwise sequence alignment by BLAST, pairwise sequence alignment by global dynamic programming with an affine gap penalty function by the ALIGN command of MODELLER, sequence-profile alignment by PSI-BLAST, Hidden Markov Model methods implemented in SAM and LOBSTER, pairwise sequence alignment relying on predicted local structure by SEA, and multiple sequence alignment by CLUSTALW and COMPASS. The alignment accuracies of the best new protocols were significantly better than those of the other tested methods. For example, the fraction of the correctly aligned residues relative to the structure-based alignment by the best protocol is 56%, which can be compared with the accuracies of 26%, 42%, 43%, 48%, 50%, 49%, 43%, and 43% for the other methods, respectively. The new method is currently applied to large-scale comparative protein structure modeling of all known sequences.
Histamine stimulates brain phospholipid turnover through a direct, H-1 receptor-mediated mechanism.

Abstract Intracisternal administration of histamine produced a dose-dependent increase of incorporation of 33 Pi into brain phospholipids. The effect could not be mimicked by administration of compound 48/80, indicating lack of involvement of non-neuronal histamine. The stimulation was not attenuated by prior depletion of catecholamines with reserpine, indicating that the effect of histamine on phospholipid turnover was mediated by direct histaminergic mechanisms. An H-1 receptor appeared to be involved, as demonstrated by studies with specific histaminergic agonists and antagonists. Incorporation of 33 Pi into phospholipids may be a valuable tool in evaluating cellular effects mediated through H-1 receptors.
Early Archeological Evidence for Shellfish Collecting

Geologic evidence, supported by infinite carbon-14 dates and Middle Stone Age cultural associations, indicates that two open-air shell middens recently found at Sea Harvest and Hoedjies Punt, Saldanha Bay, South Africa, date from the terminal part of the Last Interglacial, about 70,000 to 60,000 years ago. These middens are among the oldest known records for systematic human exploitation of marine resources anywhere in the world. The faunal contents of the middens suggest that the Middle Stone Age people who accumulated them utilized marine resources less intensively than their Later Stone Age successors in similar coastal settings.
Mesh fistulation into the rectum after laparoscopic ventral mesh rectopexy

INTRODUCTION Laparoscopic ventral mesh rectopexy (LVMR) is an effective method of management of functional disorders of the rectum including symptomatic rectal intussusception, and obstructed defaecation. Despite the technical demands of the procedure and common use of foreign body (mesh), the incidence of mesh related severe complications of the rectum is very low.
The political economy of Portugal's old regime: Growth and change preceding the 1974 revolution

Abstract For 40 yr, from 1928 to 1968, Antonio Salazar's doctrines were to shape the Portuguese destiny. Under his authoritarian regime the political economy was cast into a quasi-traditional mold combing two salient features - extensive state control and predominantly private ownership of the means of production. Nevertheless, under the pressure of circumstances, Salazar in the early 1960s opted for a more open development strategy, including a significant role for direct foreign investment. The liberalization of the Portuguese economy was given further impetus under Premier Marcello Caetano (1968–1974), and as a result the country underwent a period of accelerated growth and structural change. Still, on the eve of the 1974 revolution, Portugal faced major economic problems associated with concentration of political and economic power in the ‘40 families’ oligarchy and the burdensome defence of the African territories.
Average Cost Optimal Stationary Policies in Infinite State Markov Decision Processes with Unbounded Costs

We deal with infinite state Markov decision processes with unbounded costs. Three simple conditions, based on the optimal discounted value function, guarantee the existence of an expected average cost optimal stationary policy. Sufficient conditions are the existence of a distinguished state of smallest discounted value and a single stationary policy inducing an irreducible, ergodic Markov chain for which the average cost of a first passage from any state to the distinguished state is finite. A result to verify this is also given. Two examples illustrate the ease of applying the criteria.
A New Bypass Magnetorheological Fluid Damper

This study presents theoretical and experimental investigations of a novel external bypass, fail-safe, magnetorheological fluid (MRF) damper. A fail-safe MRF damper is referred to as a device that retains a minimum required damping capacity in the event of a power supply or electronic system failure. The new MRF device has a simple design, is compact, is capable of generating a considerable dynamic force range, and can be sized for specific vibration control applications. The theoretical formulation is developed based on the Herschel-Bulkley constitutive model for an annular flow. Experimental results are obtained to demonstrate the validity of the theoretical analysis.
Kinematics of robot manipulators via line transformations

Robot kinematics is an extensively researched subject and several well developed techniques for the analysis of robot manipulators and spatial mechanisms exist. Most of these methods are based on point transformations. However, far less research is in evidence for line transformations. Lines and screws are more fundamental to velocity analysis and hence line transformations are believed to be better suited for the kinematic and static analysis of manipulators. In this article, the kinematics for serial chain manipulators using line transformations is investigated. Dual number quaternions are used as spatial transformation operators since they allow compact representation of both rotations and translations. Further, the symbolic computation of the direct and inverse kinematics equations using dual number quaternions is described.
Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells

Because DNA methyltransferase (DNMT) inhibitors like azacytidine and decitabine are known to be effective in the clinic for diseases like myelodysplastic syndromes that may result in part from transcriptional dysregulation due to epigenetic changes, there is interest in developing novel DNMT inhibitors that would be more effective and less toxic. The effects of one such agent, zebularine, which inhibits DNMT and cytidine deaminase, were assessed in two human breast cancer cell lines, MDA-MB-231 and MCF-7. Zebularine treatment inhibited cell growth in a dose and time dependent manner with an IC-50 of ~100 μM and 150 μM in MDA-MB-231 and MCF-7 cells, respectively, on 96 h exposure. This was associated with increased expression of p21, decreased expression of cyclin-D, and induction of S-phase arrest. At high doses zebularine induced changes in apoptotic proteins in a cell line specific manner manifested by alteration in caspase-3, Bax, Bcl2 and PARP cleavage. Like other DNMT inhibitors, zebularine decreased expression of DNMTs post-transcriptionally as well as expression of other epigenetic regulators like methyl CpG binding proteins and global acetyl H3 and H4 protein levels. Its capacity to reexpress epigenetically silenced genes in human breast cancer cells at low doses was confirmed by its ability to induce expression of estrogen and progesterone receptor mRNA in association with changes suggestive of active chromatin at the ER promoter as evidenced by ChIP. Finally, its effect in combination with other DNMT or HDAC inhibitors like decitabine or vorinostat was explored. The combination of 50 μM zebularine with decitabine or vorinostat significantly inhibited cell proliferation and colony formation in MDA-MB-231 cells compared with either drug alone. These findings suggest that zebularine is an effective DNMT inhibitor and demethylating agent in human breast cancer cell lines and potentiates the effects of other epigenetic therapeutics like decitabine and vorinostat.
Joint inversion of normal mode and body wave data for inner core anisotropy 1. Laterally homogeneous anisotropy

[1] We use mantle and inner core sensitive normal modes to invert for laterally varying mantle models and a transversely isotropic inner core. To obtain an inner core model that is compatible with long-period mode and short-period body wave data, we incorporate mantle-corrected absolute travel time and differential travel time data in our inversions. Using this diverse data set, we investigate the dependence of inner core models upon mantle parameterization and possible radial structure within the inner core. Inner core anisotropy obtained from a simultaneous inversion for mantle and inner core structure has a weak dependence upon the parameterization within the mantle, that is, the results for the inner core are insensitive to whether the mantle is inverted only for shear velocity structure or for shear and compressional velocity structure as well as density. An inner core model with constant anisotropy is capable of fitting all types of data, but mode and absolute travel time data are more compatible with one another than with differential travel time data. Allowing for radial variations within the inner core reduces this incompatibility, and it is possible to obtain a radially dependent model that fits normal mode, absolute travel time, and differential travel time data with a variance reduction greater than 75%.
THERMALLY DOMINATED CARBON MONOXIDE EMISSION IN THE TAURUS MOLECULAR CLOUD COMPLEX

We analyze the structure of a region of the Taurus molecular cloud containing star-forming dense cores, as traced by emission from the J = 1-0 rotational transition of the carbon monoxide isotopomer, C18O. While the spatial structure of the velocity-integrated emission is rather featureless, there is substantial structure in the emission integrated over small velocity widths, and the entire three-dimensional data set (right ascension, declination, and velocity) can be broken into a collection of nearly discrete components. We construct a cloud model consisting of nine individual Gaussian components and find that the data are best replicated when these components have sizes of ~0.1 pc and velocity dispersions comparable to or smaller than the thermal velocity dispersion of molecular hydrogen at a temperature of 10 K. We find that nearly all of the molecular mass of the cloud is contained within these quiescent structures. At least two of the structures are detected in observations in the J = 4-3 line of HC3N; these two structures are likely associated with the two forming stars in the region. Our results suggest that thermally dominated structures may be common in regions containing dense cores, but that many of these structures are insufficiently dense to be detected with dense gas tracers.
New Waves in Philosophy of Technology

This review-essay examines the multi-author collection New Waves in Philosophy of Technology. Particular attention is given to the difference between Marx's and Heidegger's philosophies of technology. The differential impact of Marx and Heidegger on the essays in the collection is assessed, with some implications drawn about the theoretical background of the philosophy of technology as a whole.
Swirling flows in an annular-to-rectangular transition section

Mechanisms for generation of axial vorticity by swirling flows in rectangular nozzles have been investigated experimentally and computationally. A detailed experimental investigation is described that demonstrates the formation of axial vortices in the nozzle is dependant on the vorticity distribution at the turbine exhaust. Further, mechanisms providing for the formation of axial vortices are identified. A parallel computational investigation was carried out that not only confirmed the relationship between the turbine exhaust vorticity and the vortex patterns formed in the nozzle, but also provided details of the flowfield between the turbine discharge and the nozzle exit. On the basis of this more detailed understanding, it is now possible to "tailor" the vortex distribution at the nozzle exit by design of the turbine discharge and the intervening passage.
Fast Light in the High Gain Limit of a Brillouin Laser

We observe an increase in the cavity mode separation of a Brillouin laser with increasing pump power. This is shown to be a manifestation of fast light in the high gain limit (depleted pump).
Solar and stellar flares

New observations by space telescopes during the last ten years have led to significant advances in understanding the nature of solar flares. X–ray and UV imaging of flare emissions have confirmed that flares are powered by the sudden release of magnetic energy associated with currents flowing in the solar atmosphere. Although many different processes have been suggested as possible trigger mechanisms, the one which seems to fit the observations best is a loss of ideal–MHD equilibrium, or stability, combined with magnetic reconnection. An ideal–MHD process by itself has the drawback that it releases a very small amount of magnetic energy, but when it is coupled with magnetic reconnection, this drawback is eliminated. Stellar flares are very likely to be fundamentally similar to solar flares in that they involve the sudden release of magnetic energy associated with currents flowing in their coronae. However, it is unlikely that they all involve exactly the same type of field configuration or the same type of trigger mechanism. What these mechanisms might be will be difficult to determine without further information on the structure of stellar magnetic fields.
Third-degree burn from a grounding pad during arthroscopy

We describe a healthy 59-year-old woman who sustained a third-degree burn from a grounding pad during shoulder arthroscopy. We wish to make surgeons aware of a rare complication associated with any arthroscopic procedure in which an electrocautery/grounding pad system is used. We detail the presentation, evaluation, treatment, and definitive care and review the possible causes of this complication and the mechanism by which an electrocautery/grounding pad system functions. Although this complication is not uncommon, we believe that this is the first case report describing a burn at the grounding pad site occurring during arthroscopy.
A kinetic zipper model with intrachain interactions applied to nucleic acid hairpin folding kinetics.

Abstract Single-stranded DNA and RNA hairpin structures with 4–10 nucleotides (nt) in the loop and 5–8 basepairs (bp) in the stem fold on 10–100 μ s timescale. In contrast, theoretical estimate of first contact time of two ends of an ideal semiflexible polymer of similar lengths (with persistence length ∼2-nt) is 10–100 ns. We propose that this three-orders-of-magnitude difference between these two timescales is a result of roughness in the folding free energy surface arising from intrachain interactions. We present a statistical mechanical model that explicitly includes all misfolded microstates with nonnative Watson-Crick (WC) and non-WC contacts. Rates of interconversion between different microstates are described in terms of two adjustable parameters: the strength of the non-WC interactions (Δ G nWC ) and the rate at which a basepair is formed adjacent to an existing basepair ( k bp + ). The model accurately reproduces the temperature and loop-length dependence of the measured relaxation rates in temperature-jump studies of a 7-bp stem, single-stranded DNA hairpin with 4–20-nt-long poly(dT) loops, with Δ G nWC ≈ −2.4 kcal/mol and k bp + ≥ (1 ns) −1 , in 100 mM NaCl. Thus, our model provides a microscopic interpretation of the slow hairpin folding times as well as an estimate of the strength of intrachain interactions.
Management of a Patient with an Anterior Cruciate Ligament Rupture

This review article describes management of the patient with a torn anterior cruciate ligament (ACL). The most important finding for determining the condition of the ACL is the Lachman test, which is more reliably verified with instrumented laxity testing than with magnetic resonance imaging and the pivot shift test. Outcome after ACL reconstruction of the knee with chronic instability is the same as an acute reconstruction, as long as the damage to the menisci and cartilage are similar. With the use of nonirradiated, nonchemically treated, fresh-frozen, single-looped tibialis allografts, one can obtain similar results to autogenous double-looped, semitendinosus, and gracilis autografts; however, the use of irradiated and chemically treated allografts do not. Precise tunnel placement with the avoidance of roof and posterior cruciate ligament impingement in conjunction with the use of slippage-resistant, cortical fixation and brace-free, aggressive rehabilitation are the keys to avoiding knee stiffness, maintaining stability, rapidly rehabilitating the patient, and reliably returning them to sport at 4 months. Patients that return to sport at 4 months can expect a similar reinjury rate to those that return after 6 months. However, for those athletes younger than 18 years of age, the rate of reinjury depends on sex and the resumed level of activity and may be as high as 7% to 11% for the reconstructed ACL and 5% to 12% for the contralateral normal ACL, which should be shared with the patient and parents.