Effect of growth factor deficiency on nystatin sensitivity inSaccharomyces cerevisiae

Summary The nystatin sensitivity, as well as the levels of total sterols and individual phospholipids ofSaccharomyces cerevisiae are influenced by variations in the supply of growth factors.     

Genetic analysis of the kinome and phosphatome in cancer

Protein phosphorylation is a well-characterized biochemical process for reversible regulation of protein activity. Protein kinases and protein phosphatases are the key complementary players in this process, and through their coordinated activity cell homeostasis is tightly controlled. If these enzymes display aberrant activity, cells may undergo unrestrained growth, thus giving rise to complex diseases such as cancer. The technological platform gathered during the Human Genome Project recently allowed the systematic identifi cation of the genetic alterations present in the kinase (the kinome) and the phosphatase (the phosphatome) gene families. These studies suggest that most if not all human tumors carry genetic alterations in at least one phosphatase or kinase gene. Here we integrate the biochemical knowledge on the properties of these molecules with the information collected through their systematic genetic analysis in cancer. We also analyze why the molecular profi ling of the kinome and phosphatome in individual cancers is revolutionizing basic and clinical oncology.Received 13 May 2005; received after revision 30 May 2005; accepted 22 June 2005     

PSF and CMF,autocrine factors that regulate gene expression during growth and early development ofDictyostelium

Throughout growth and development,Dictyostelium cells secrete autocrine factors that accumulate in proportion to cell density. At sufficient concentration, these factors cause changes in gene expression. VegetativeDictyostelium cells continuously secrete prestarvation factor (PSF). The bacteria upon which the cells feed inhibit their response to PSF, allowing the cells to monitor their own density in relation to that of their food supply. At high PSF/bacteria ratios, which occur during late exponential growth, PSF induces the expression of several genes whose products are needed for cell aggregation. When the food supply has been depleted, PSF production declines, and a second density-sensing pathway is activated. Starving cells secrete conditioned medium factor (CMF), a glycoprotein of Mr 80 kDa that is essential for the development of differentiated cell types. Antisense mutagenesis has shown that cells lacking CMF cannot aggregate, and preliminary data suggest that CMF regulates cAMP signal transduction. Calculations indicate that a mechanism of simultaneously secreting and recognizing a signal molecule, as used byDictyostelium to monitor cell density, could also be used to determine the total number of cells in a tissue.     

Improving the Timeliness of Turning Signals for Business Cycles with Monthly Data

The conventional growth rate measures (such as month‐on‐month, year‐on‐year growth rates and 6‐month smoothed annualized rate adopted by the US Bureau of Labor Statistics and Economic Cycle Research Institute) are popular and can be easily obtained by computing the growth rate for monthly data based on a fixed comparison benchmark, although they do not make good use of the information underlying the economic series. By focusing on the monthly data, this paper proposes the k‐month kernel‐weighted annualized rate (k‐MKAR), which includes most existing growth rate measures as special cases. The proposed k‐MKAR measure involves the selection of smoothing parameters that are associated with the accuracy and timeliness for detecting the change in business turning points. That is, the comparison base is flexible and is likely to vary for different series under consideration. A data‐driven procedure depending upon the stepwise multiple reality check test for choosing the smoothing parameters is also suggested in this paper. The simple numerical evaluation and Monte Carlo experiment are conducted to confirm that our measures (in particular the two‐parameter k‐MKAR) improve the timeliness subject to a certain degree of accuracy. The business cycle signals issued by the Council for Economic Planning and Development over the period from 1998 to 2009 in Taiwan are taken as an example to illustrate the empirical application of our method. The empirical results show that the k‐MKAR‐based score lights are more capable of reflecting turning points earlier than the conventional year‐on‐year measure without sacrificing accuracy. Copyright © 2016 John Wiley & Sons, Ltd.     

Newton's Contribution to the Science of Heat

The contents of Scala Graduum Caloris are described, supplemented by unpublished material. Both temperature measurements by his linseed oil thermometer and those based upon his law of cooling are shown to be reasonably accurate to 300°C, but above that value they are much too low. The apparent agreement and the deviation are explained by the differences between the assumptions that Newton made in deriving his law of cooling and the conditions in which he used it. Newton's attempts to link terrestrial and celestial science in applications in the Principia are shown to fail from his confounding the concepts of temperature, heat and radiant intensity and his ignorance of most factors affecting the temperature rise of irradiated materials. Other comments on varied aspects of heat, mainly published in the Queries, are set out and analysed. His originality is assessed.     

Forecasting the recent behavior of US business fixed investment spending: an analysis of competing models

We evaluate forecasting models of US business fixed investment spending growth over the recent 1995:1–2004:2 out‐of‐sample period. The forecasting models are based on the conventional Accelerator, Neoclassical, Average Q, and Cash‐Flow models of investment spending, as well as real stock prices and excess stock return predictors. The real stock price model typically generates the most accurate forecasts, and forecast‐encompassing tests indicate that this model contains most of the information useful for forecasting investment spending growth relative to the other models at longer horizons. In a robustness check, we also evaluate the forecasting performance of the models over two alternative out‐of‐sample periods: 1975:1–1984:4 and 1985:1–1994:4. A number of different models produce the most accurate forecasts over these alternative out‐of‐sample periods, indicating that while the real stock price model appears particularly useful for forecasting the recent behavior of investment spending growth, it may not continue to perform well in future periods. Copyright © 2007 John Wiley & Sons, Ltd.     

Disinhibition of neurite growth to repair the injured adult CNS: Focusing on Nogo

Investigations into mechanisms that restrict the recovery of functions after an injury to the brain or the spinal cord have led to the discovery of specific neurite growth inhibitory factors in the adult central nervous system (CNS) of mammals. Blocking their growth-suppressive function resulted in disinhibition of axonal growth, i.e. growth of cultured neurons on inhibitory CNS tissue in vitro and regeneration of injured axons in vivo. The enhanced regenerative and compensatory fibre growth was often accompanied by a substantial improvement in the functional recovery after CNS injury. The first clinical studies to assess the therapeutic potential of compounds that neutralize growth inhibitors or interfere with their downstream signalling are currently in progress. This review discusses recent advances in the understanding of how the ‘founder molecule’ Nogo-A and other glialderived growth inhibitors restrict the regeneration and repair of disrupted neuronal circuits, thus limiting the functional recovery after CNS injuries. Received 5 April 2007; received after revision 28 September 2007; accepted 1 October 2007     

Hidden depths: Halley, hell and other people

During the long eighteenth century, boundaries between theology and natural philosophy, between imaginary and factual travel narratives, between fiction and social commentary, were far more fluid than they are today. To explore these relationships, this paper links Mary Shelley’s Frankenstein—a book often hailed as the first science fiction novel—to two earlier works which are now less well known: Edmond Halley’s article about terrestrial magnetism, in which he suggested that God had created inhabited illuminated cavities inside the earth; and a satirical fantasy voyage written by the Danish author Ludvig Holberg, but published anonymously as Niels Klim’s journey to the underground and immediately translated into many languages. Attention is focussed on how the ambiguous presentation of these and other texts blurs any straightforward classification of genres. The aim of examining these writers together is not to search for direct mappings from one project to another, but instead to introduce Holberg’s unfamiliar yet important book and also to cast new light on Frankenstein, one of England’s most famous works of literature.     

Transgenic and mutant animal models to study mechanism of protection of red cell genetic defects against malaria

Malaria, caused by members of the genusPlasmodia, is still the most prevalent parasitic disease in the world. In an attempt to understand genetic factors conferring resistance to malaria, mouse models of thalassemia, sickle trait, and ankyrin and spectrin deficiency were studied during infection with species of malaria infectious to rodents. Although growth ofP. falciparum is not inhibited in thalassemic erythrocytes in culture, mice carrying a -thalassemia mutation were protected fromPlasmodium chabaudi adami, supporting epidemiologic findings. Transgenic mice expressing ^s hemoglobin were also significantly protected from two species of rodent malaria. Importantly, a significant role for the spleen in protection in the ^s transgenic mice was found. Finally, mice deficient in spectrin and ankyrin were studied with respect to their ability to support the growth of malaria. It was found that spectrin deficient mice were almost completely refractory toP. chabaudi adami andP. berghei. These models will allow further study of host factors in resistance to malaria.     

New approaches to therapy of cancers of the stomach,colon and pancreas based on peptide analogs

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.Received 20 November 2003; accepted 6 January 2004     

Ras proteins in the control of the cell cycle and cell differentiation

The Ras family of small GTPases includes three closely related proteins: H-, K-, and N-Ras. Ras proteins are involved in the transduction of signals elicited by activated surface receptors, acting as key components by relaying signals downstream through diverse pathways. Mutant, constitutively activated forms of Ras proteins are frequently found in cancer. While constitutive Ras activation induces oncogenic-like transformation in immortalized fibroblasts, it causes growth arrest in primary vertebrate cells. Induction of p53 and cyclin-dependent kinase inhibitors such as p15^INK4b, p16^INK4a, p19^ARF, and p21^WAF1 accounts for this response. Interestingly, while ras has usually been regarded as a transforming oncogene, the analysis of Ras function in most of the cellular systems studied so far indicates that the promotion of differentiation is the most prominent effect of Ras. While in some cell types, particularly muscle, Ras inhibits differentiation, in others such as neuronal, adipocytic, or myeloid cells, Ras induces differentiation, in some cases accompanied by growth arrest. Several possible mechanisms for the pleiotropic effects of Ras in animal cells are discussed. Received 8 March 2000; received after revision 24 May 2000; accepted 24 May 2000     

Newton’s De gravitatione: a review and reassessment

The widely accepted supposition that Newton’s De gravitatione was written in 1684/5 just before composing the Principia is examined. The basis for this determination has serious difficulties starting with the failure to examine the numerical estimates for the resistance of aether. The estimated range is not nearly nil as claimed but comparable with air at or near the earth’s surface. Moreover, the evidence provided most likely stems from experiments by Boyle, Hooke, and others in the 1660s and does not use evidence available in the late 1684. The document supports Newton’s contention that the aether medium incorporates very large voids thereby proving that body and space differ but does by no means completely reject its corporeal nature or eliminate its resistance. Newton’s use of the term inertia provides no conclusive evidence for a late date as often claimed and his definition of gravitas is difficult to reconcile with a late one.     

The Reception of Miller's Ether-Drift Experiments in the USA: The History of a Controversy in Relativity Revolution

This paper analyses documents from several US archives in order to examine the controversy that raged within the US scientific community over Dayton C. Miller's ether-drift experiments. In 1925, Miller announced that his repetitions of the famous Michelson-Morley experiment had shown a slight but positive result: an ether-drift of about 10 kilometres per second. Miller's discovery triggered a long debate in the US scientific community about the validity of Einstein's relativity theories. Between 1926 and 1930 some researchers repeated the Michelson-Morley experiment, but no one found the same effect as Miller had. The inability to confirm Miller's result, paired with the fact that no other ether theory existed that could compete with special relativity theory, made his result an enigmatic one. It thus remained of little interest to the scientific community until 1954, when Robert S. Shankland and three colleagues reanalysed the data and proposed that Miller's periodic fringe shift could be attributed to temperature effects. Whereas most of the scientific community readily accepted this explanation as the conclusion of the matter, some contemporary anti-relativists have contested Shankland's methodology up to now. The historical accounts of Miller's experiments provide contradictory reports of the reaction of the US scientific community and do not analyse the mechanisms of the controversy. I will address this shortcoming with an examination of private correspondence of several actors involved in these experiments between 1921 and 1955. A complex interconnection of epistemic elements, sociological factors, and personal interests played a fundamental role in the closure of this experimental controversy in the early 1930s, as well as in the reception of Shankland's reanalysis in the 1950s.     

A study of granulated metrial gland cell differentiation in pregnant,macrophage-deficient,osteopetrotic (op/op) mice

A population of uterine natural killer (NK) cells, commonly called granulated metrial gland (GMG) cells, differentiates in the mouse uterus during normal pregnancy. Little is known regarding the process of differentiation of GMG cells or of other NK cell subsets. It has been suggested that macrophage precursors, under the combined influences of the cytokine growth factors colony stimulating factor-1 (CSF-1) and interleukin-2, become NK-cell like in morphology, pattern of target cell lysis and surface antigen phenotype. Mice expressing the mutation osteopetrosis (op/op) are unable to produce the cytokine CSF-1. To determine whether CSF-1 is required for the successful differentiation of uterine NK cells, implantation sites in pregnant,op/op mice were studied histologically. GMG cell differentiation appeared to progress normally inop/op mice studied between days 7 and 14 of gestation. Thus, the growth factor CSF-1 is not required for differentiation of the uterine NK cell subset known as GMG cells and probably GMG cells do not differentiate from macrophage precursor cells which are deficient inop/op mice.     

Production of insulin-like growth factor I (IGF-I) and IGF-binding proteins by rat intestinal stromal cells in vitro

To determine if intestinal stromal cells secrete diffusible factors such as insulin-like growth factors (IGFs) capable of regulating epithelial cell growth in vitro, stromal cells were isolated by enzymatic digestion of rat intestine. Incorporation of [³H]thymidine into DNA and [¹⁴C]leucine into protein of IEC-6 cells, a model intestinal epithelial cell line, was significantly increased (two- to threefold) when the IEC-6 cells were co-cultured with stromal cells, relative to IEC-6 cells grown alone. Medium conditioned by stromal cells stimulated DNA synthesis of IEC-6 cells in a dose-dependent manner. Analysis of the conditioned medium revealed that intestinal stromal cells secreted IGF-I, but little IGF-II, in addition to an M _r 32,000 IGF-binding protein (IGFBP-2) and an IGFBP having M _r∼ 24,000. We conclude that rat intestinal stromal cells secrete one or more diffusible factors, which may include IGF-I and IGFBPs, capable of stimulating proliferation of IEC-6 cells in vitro. Received 25 August 1997; received after revision 7 November 1997; accepted 20 November 1997     

Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development

Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin, and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly, and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues of a substrate, thus forming S₄ through S₃′ subsites. Hydrophobic and aromatic amino acids are preferred at the P₁ and P₁′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors, including steroid hormones. Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001     

Hydroxyproline-rich glycoproteins in plant reproductive tissues: structure, functions and regulation

The plant reproductive process of pollination involves a series of interactions between the male gametophyte (the pollen grain or pollen tube) and extracellular matrix (ECM) molecules secreted by different cell types along the pollen tube growth pathway in the female organ, the pistil. These interactions are believed to signal and regulate the pollen tube growth process to effect successful delivery of the sperm cells to the ovules where fertilization takes place. Hydroxyproline-rich glycoproteins secreted by plant cells are believed to play a broad range of functions, ranging from providing structural integrity to mediating cell-cell interactions and communication. The pistil and pollen tube ECM is enriched in these highly glycosylated proteins. Our discussions here will focus on a number of these proteins for which most information has been available, from Nicotiana tabacum, its self-incompatible relative N. alata, and Zea mays. In addition, the regulation of the synthesis and glyco-modification of one of these proteins, TTS (transmitting tissue-specific) protein from N. tabacum will be discussed in the light of how differential glycosylation may be used to regulate molecular interactions within the ECM.     

Proteinases in cutaneous wound healing

Cutaneous wound healing is a complex and highly coordinated process where a number of different cell types participate to renew the damaged tissue under the strict regulation of soluble and insoluble factors. One of the most versatile processes involved in wound repair is proteolysis. During cell migration, proteins of extracellular matrix are cleaved, often creating biologically active cleavage products, and proteolysis of cellular contacts leads to increased cell motility and division. Moreover, proteases activate various growth factors and other proteases in wound and regulate growth factor signaling by shedding growth factor receptors on cell surface. Normally, proteolysis is strictly controlled, and changes in protease activity are associated with alterations in wound closure and scar formation. Here, we present the current view on the role of metalloproteinases and the plasmin-plasminogen system in normal and aberrant cutaneous wound repair and discuss their role as potential therapeutic targets for chronic ulcers or fibrotic scars. Received 07 July 2008; received after revision 11 August 2008; accepted 13 August 2008     

Relations between Karl Popper and Michael Polanyi

Karl Popper and Michael Polanyi grew up in central Europe and, having escaped from Nazism, went on to pursue academic careers in Britain where they wrote prolifically on science and politics. Popper and Polanyi corresponded with each other, and met for discussions in the late 1940s and early 50s, but they seldom referred to each other in their publications. This article examines their correspondence so as to produce a picture of their intellectual relations. The most important of the letters was one that Popper wrote in 1952, which we reproduce in its entirety, indicating his dissatisfaction with ideas that Polanyi had expressed in a paper of that year, ‘The Stability of Beliefs’. In this paper, Polanyi used the example of the framework of Zande witchcraft to shed analogical light on science and other systems of belief, arguing that ‘frameworks of belief’ equip their adherents with intellectual powers whose use reinforces commitment to the framework, inoculating adherents against criticism. Polanyi’s 1952 paper and his 1951 and 1952 Gifford Lectures (to which that paper is intimately tied) are the first articulation of Polanyi’s sharp rejection of the modern critical philosophical tradition that by implication included Popper’s philosophical ideas. The 1952 paper is also part of Polanyi’s constructive philosophical effort to set forth a fiduciary philosophy emphasizing commitment. Popper regarded Polanyi’s position as implying cognitive relativism and irrationalism, and from the time of Polanyi’s 1952 paper their personal relationship became strained. Discord between them became publicly manifest when Polanyi subtitled his book Personal Knowledge (1958), Towards a post-critical philosophy, and Popper lambasted the idea of a ‘post-critical’ philosophy in his Preface in The Logic of Scientific Discovery (1959).