α-Adrenoceptor blocking action of hymenin,a novel marine alkaloid

Summary In the rabbit isolated aorta, hymenin (10^–6 M) a novel marine alkaloid, caused a parallel rightward shift of the dose-response curve for norepinephrine without affecting that for histamine or KCl, suggesting that hymenin is a competitive antagonist of -adrenoceptors in vascular smooth muscles.Acknowledgments. We thank Ms A. Kajiwara and Ms M. Hamashima of this institute for their technical assistance, and Prof. Y. Hirata of Meijo University for his encouragement.     

Hymenin, a novel alpha-adrenoreceptor blocking agent from the Okinawan marine sponge Hymeniacidon sp

A novel bromine-containing alkaloid, hymenin, has been isolated from the Okinawan marine sponge Hymeniacidon sp. as a potent alpha-adrenoceptor blocking agent and its structure determined to be 1 on the basis of the spectral data.     

Hymenin,a novel α-adrenoceptor blocking agent from the Okinawan marine spongeHymeniacidon sp.

Summary A novel bromine-containing alkaloid, hymenin, has been isolated from the Okinawan marine spongeHymeniacidon sp. as a potent -adrenoceptor blocking agent and its structure determined to be1 on the basis of the spectral data.     

Newton's Easy Quadratures ``Omitted for the Sake of Brevity'

In the 1687 Principia, Newton gave a solution to the direct problem (given the orbit and center of force, find the central force) for a conic-section with a focal center of force (answer: a reciprocal square force) and for a spiral orbit with a polar center of force (answer: a reciprocal cube force). He did not, however, give solutions for the two corresponding inverse problems (given the force and center of force, find the orbit). He gave a cryptic solution to the inverse problem of a reciprocal cube force, but offered no solution for the reciprocal square force. Some take this omission as an indication that Newton could not solve the reciprocal square, for, they ask, why else would he not select this important problem? Others claim that ``it is child's play' for him, as evidenced by his 1671 catalogue of quadratures (tables of integrals). The answer to that question is obscured for all who attempt to work through Newton's published solution of the reciprocal cube force because it is done in the synthetic geometric style of the 1687 Principia rather than in the analytic algebraic style that Newton employed until 1671. In response to a request from David Gregory in 1694, however, Newton produced an analytic version of the body of the proof, but one which still had a geometric conclusion. Newton's charge is to find both ``the orbit' and ``the time in orbit.' In the determination of the dependence of the time on orbital position, t(r), Newton evaluated an integral of the form ∫dx/x <sup>n</sup> to calculate a finite algebraic equation for the area swept out as a function of the radius, but he did not write out the analytic expression for time t = t(r), even though he knew that the time t is proportional to that area. In the determination of the orbit, θ (r), Newton obtained an integral of the form ∫dx/√(1−x<sup>2</sup>) for the area that is proportional to the angle θ, an integral he had shown in his 1669 On Analysis by Infinite Equations to be equal to the arcsin(x). Since the solution must therefore contain a transcendental function, he knew that a finite algebraic solution for θ=θ(r) did not exist for ``the orbit' as it had for ``the time in orbit.' In contrast to these two solutions for the inverse cube force, however, it is not possible in the inverse square solution to generate a finite algebraic expression for either ``the orbit' or ``the time in orbit.' In fact, in Lemma 28, Newton offers a demonstration that the area of an ellipse cannot be given by a finite equation. I claim that the limitation of Lemma 28 forces Newton to reject the inverse square force as an example and to choose instead the reciprocal cube force as his example in Proposition 41. (Received August 14, 2002) Published online March 26, 2003 Communicated by G. Smith     

The emerging role of galectins in high-fatality cancers

Although we witnessed considerable progress in the prevention and treatment of cancer during the past few decades, a number of cancers remain difficult to treat. The main reasons for this are a lack of effective biomarkers necessary for an early detection and inefficient treatments for cancer that are diagnosed at late stages of the disease. Because of their alarmin-like properties and their protumorigenic role during cancer progression, members of the galectin family are uniquely positioned to provide information that could be used for the exploration of possible avenues for the treatment of high fatality cancer (HFC). A rapid overview of studies that examined the expressions and functions of galectins in cancer cells reveals that they play a central role in at least three major features that characterize HFCs: (1) induction of systemic and local immunosuppression, (2) chemoresistance of cancer cells, and (3) increased invasive behavior. Defining the galectinome in HFCs will also lead to a better understanding of tumor heterogeneity while providing critical information that could improve the accuracy of biomarker panels for a more personalized treatment of HFCs. In this review, we discuss the relevance of the galectinome in HFC and its possible contribution to providing potential solutions.     

Fluctuation and response in biology

In 1905, Albert Einstein proposed that the forces that cause the random Brownian motion of a particle also underlie the resistance to macroscopic motion when a force is applied. This insight, of a coupling between fluctuation (stochastic behavior) and responsiveness (non-stochastic behavior), founded an important branch of physics. Here we argue that his insight may also be relevant for understanding evolved biological systems, and we present a ‘fluctuation–response relationship’ for biology. The relationship is consistent with the idea that biological systems are similarly canalized to stochastic, environmental, and genetic perturbations. It is also supported by in silico evolution experiments, and by the observation that ‘noisy’ gene expression is often both more responsive and more ‘evolvable’. More generally, we argue that in biology there is (and always has been) an important role for macroscopic theory that considers the general behavior of systems without concern for their intimate molecular details.     

The theory theory thrice over: the child as scientist, Superscientist or social institution?

Alison Gopnik and Andrew Meltzoff have argued for a view they call the ‘theory theory’: theory change in science and children are similar. While their version of the theory theory has been criticized for depending on a number of disputed claims, we argue that there is a fundamental problem which is much more basic: the theory theory is multiply ambiguous. We show that it might be claiming that a similarity holds between theory change in children and (i) individual scientists, (ii) a rational reconstruction of a Superscientist, or (iii) the scientific community. We argue that (i) is false, (ii) is non-empirical (which is problematic since the theory theory is supposed to be a bold empirical hypothesis), and (iii) is either false or doesn't make enough sense to have a truth-value. We conclude that the theory theory is an interesting failure. Its failure points the way to a full, empirical picture of scientific development, one that marries a concern with the social dynamics of science to a psychological theory of scientific cognition.     

Interferon-alpha and transforming growth factor-β co-induce growth inhibition of human tumor cells

A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-alpha and TGF-beta, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes.     

Revisiting Targeted Factors

This paper proposes new methods for ‘targeting’ factors estimated from a big dataset. We suggest that forecasts of economic variables can be improved by tuning factor estimates: (i) so that they are both more relevant for a specific target variable; and (ii) so that variables with considerable idiosyncratic noise are down‐weighted prior to factor estimation. Existing targeted factor methodologies are limited to estimating the factors with only one of these two objectives in mind. We therefore combine these ideas by providing new weighted principal components analysis (PCA) procedures and a targeted generalized PCA (TGPCA) procedure. These methods offer a flexible combination of both types of targeting that is new to the literature. We illustrate this empirically by forecasting a range of US macroeconomic variables, finding that our combined approach yields important improvements over competing methods, consistently surviving elimination in the model confidence set procedure. Copyright © 2016 John Wiley & Sons, Ltd.     

Endogenous retroviruses

Xenotransplantation is defined by the PHS as any procedure that involves the transplantation, implantation or infusion into a human recipient of either (a) live cells, tissues or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs (Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation). Use of pigs for human xenotransplantation raises concerns about the risks of transfer of infectious agents from the pig cells to xenotransplantation recipients. The observation that the porcine germline harbors genetic loci encoding porcine endogenous retroviruses (PERVs) that are in some cases infectious for human cells has resulted in renewed scientific interest in PERVs. However, in spite of the past 10 years of investigation, the actual risk for PERV infection, replication, and pathogenic outcome in human recipients of xenotransplantation products is still undefined. (Part of a Multi-author Review)     

Evaluating the OECD’s main economic indicators at anticipating recessions*

Using receiver operating characteristic (ROC) techniques, we evaluate the predictive content of the monthly main economic indicators (MEI) of the Organization for Economic Co‐operation and Development (OECD) for predicting both growth cycle and business cycle recessions at different horizons. From a sample that covers 123 indicators for 32 OECD countries as well as for Brazil, China, India, Indonesia, the Russian Federation, and South Africa, our results suggest that the OECD's MEI show a high overall performance in providing early signals of economic downturns worldwide, albeit they perform a bit better at anticipating business cycles than growth cycles. Although the performance for OECD and non‐OECD members is similar in terms of timeliness, the indicators are more accurate at anticipating recessions for OECD members. Finally, we find that some single indicators, such as interest rates, spreads, and credit indicators, perform even better than the composite leading indicators.     

Effects of difficulty on judgemental probability forecasting of control response efficacy

A judgemental control task was framed as a problem of medical decision making. The control parameter of a recursive system (i.e. a patient) was initially set so that output (i.e. a diagnostic index) fell outside a designated criterion range (corresponding to health). Subjects were told to bring the system's output into the designated range by resetting this control parameter (by specifying the dose of a drug). After each of these control responses, they made a probabilistic forecast that it would have the desired effect. It was found that these forecasts were more overconfident when the control task was more difficult but that the reason for this varied. When difficulty was manipulated across subjects, there was little evidence that lower control performance was associated with any lowering of the probabilistic forecasts. When difficulty was manipulated within subjects, they did lower their forecasts for more difficult task variants but did so insufficiently. In fact, relations between probabilistic forecasts of control response efficacy and proportion of those responses that were actually effective was linear with a slope of 0.44.     

Predictivism and the periodic table

This is a comment on the paper by Barnes (2005) and the responses from Scerri (2005) and Worrall (2005), debating the thesis (‘predictivism’) that a fact successfully predicted by a theory is stronger evidence than a similar fact known before the prediction was made. Since Barnes and Scerri both use evidence presented in my paper on Mendeleev’s periodic law (Brush, 1996) to support their views, I reiterate my own position on predictivism. I do not argue for or against predictivism in the normative sense that philosophers of science employ, rather I describe how scientists themselves use facts and predictions to support their theories. I find wide variations, and no support for the assumption that scientists use a single ‘Scientific Method’ in deciding whether to accept a proposed new theory.     

Forecasting system energy demand

This paper presents the results of the Electric Power Research Institute Short Range Forecasting Project (EPRI-SRF) performed by the Load Forecasts Department, Economics and Forecasts Division of Ontario Hydro, Ontario, Canada. In this study a variety of short-range forecasting techniques are applied to Ontario Hydro monthly data on total system energy demand. These techniques are available in a software package (FORECAST MASTER) developed for EPRI by two consultants—Scientific Systems, Inc. (SSI) and Quantitativ Economic Research, Inc. (QUERI). The methods used for this study were the univariate Box-Jenkins method, the multivariate state-space method, Bayesian vector autoregression and autoregress ve econometric regression. A comparison of the models developed show that the econometric models perform the best overall. The state-space models are more suitable for very short-term (one-step ahead) forecasts. Although the Box-Jenkins method has the advantage of simplicity in terms of estimation and data requirement, its performance was not as good as that of the others. Bayesian vector autoregresson results indicate that this program needs some modification for monthly data.     

GRW as an ontology of dispositions

The paper argues that the formulation of quantum mechanics proposed by Ghirardi, Rimini and Weber (GRW) is a serious candidate for being a fundamental physical theory and explores its ontological commitments from this perspective. In particular, we propose to conceive of spatial superpositions of non-massless microsystems as dispositions or powers, more precisely propensities, to generate spontaneous localizations. We set out five reasons for this view, namely that (1) it provides for a clear sense in which quantum systems in entangled states possess properties even in the absence of definite values; (2) it vindicates objective, single-case probabilities; (3) it yields a clear transition from quantum to classical properties; (4) it enables to draw a clear distinction between purely mathematical and physical structures, and (5) it grounds the arrow of time in the time-irreversible manifestation of the propensities to localize.     

The curvature argument

Dasgupta (2015) has recently put forward a novel argument, which he calls the ‘curvature argument’, that aims to show that Galilean spacetime is not an ideal setting for our classical theory of motion. This paper examines the curvature argument and argues that it is not sound. The discussion yields a remark about the conditions under which a ‘symmetry argument’ demonstrates that a particular spacetime is a non-ideal setting for our theory of motion.     

New insights into copper monooxygenases and peptide amidation: structure, mechanism and function

Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-C alpha bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the stereospecific hydroxylation of the glycine alpha-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL; EC 4.3.2.5), generates alpha-amidated peptide product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates. The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis. Since PHM is homologous in sequence and mechanism to dopamine beta-monooxygenase (DBM; EC 1.14.17.1), the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM.     

Modelling time series with season‐dependent autocorrelation structure

Time series with season‐dependent autocorrelation structure are commonly modelled using periodic autoregressive moving average (PARMA) processes. In most applications, the moving average terms are excluded for ease of estimation. We propose a new class of periodic unobserved component models (PUCM). Parameter estimates for PUCM are readily interpreted; the estimated coefficients correspond to variances of the measurement noise and of the error terms in unobserved components. We show that PUCM have correlation structure equivalent to that of a periodic integrated moving average (PIMA) process. Results from practical applications indicate that our models provide a natural framework for series with periodic autocorrelation structure both in terms of interpretability and forecasting accuracy. Copyright © 2008 John Wiley & Sons, Ltd.