Mechanisms regulating immune surveillance of cellular stress in cancer

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57–70, 67; Cell 144:646–674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823–837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.     

Bidirectional motility of kinesin-5 motor proteins: structural determinants,cumulative functions and physiological roles

Mitotic kinesin-5 bipolar motor proteins perform essential functions in mitotic spindle dynamics by crosslinking and sliding antiparallel microtubules (MTs) apart within the mitotic spindle. Two recent studies have indicated that single molecules of Cin8, the Saccharomyces cerevisiae kinesin-5 homolog, are minus end-directed when moving on single MTs, yet switch directionality under certain experimental conditions (Gerson-Gurwitz et al., EMBO J 30:4942–4954, 2011; Roostalu et al., Science 332:94–99, 2011). This finding was unexpected since the Cin8 catalytic motor domain is located at the N-terminus of the protein, and such kinesins have been previously thought to be exclusively plus end-directed. In addition, the essential intracellular functions of kinesin-5 motors in separating spindle poles during mitosis can only be accomplished by plus end-directed motility during antiparallel sliding of the spindle MTs. Thus, the mechanism and possible physiological role of the minus end-directed motility of kinesin-5 motors remain unclear. Experimental and theoretical studies from several laboratories in recent years have identified additional kinesin-5 motors that are bidirectional, revealed structural determinants that regulate directionality, examined the possible mechanisms involved and have proposed physiological roles for the minus end-directed motility of kinesin-5 motors. Here, we summarize our current understanding of the remarkable ability of certain kinesin-5 motors to switch directionality when moving along MTs.     

Wnt–Notch signalling crosstalk in development and disease

The Notch and Wnt pathways are two of only a handful of highly conserved signalling pathways that control cell-fate decisions during animal development (Pires-daSilva and Sommer in Nat Rev Genet 4: 39–49, 2003). These two pathways are required together to regulate many aspects of metazoan development, ranging from germ layer patterning in sea urchins (Peter and Davidson in Nature 474: 635–639, 2011) to the formation and patterning of the fly wing (Axelrod et al in Science 271:1826–1832, 1996; Micchelli et al in Development 124:1485–1495, 1997; Rulifson et al in Nature 384:72–74, 1996), the spacing of the ciliated cells in the epidermis of frog embryos (Collu et al in Development 139:4405–4415, 2012) and the maintenance and turnover of the skin, gut lining and mammary gland in mammals (Clayton et al in Nature 446:185–189, 2007; Clevers in Cell 154:274–284, 2013; Doupe et al in Dev Cell 18:317–323, 2010; Lim et al in Science 342:1226–1230, 2013; Lowell et al in Curr Biol 10:491–500, 2000; van et al in Nature 435:959–963, 2005; Yin et al in Nat Methods 11:106–112, 2013). In addition, many diseases, including several cancers, are caused by aberrant signalling through the two pathways (Bolós et al in Endocr Rev 28: 339–363, 2007; Clevers in Cell 127: 469–480, 2006). In this review, we will outline the two signalling pathways, describe the different points of interaction between them, and cover how these interactions influence development and disease.     

<Emphasis Type="Italic">O</Emphasis>-Mannosylation and human disease

Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alpha-dystroglycan (α-DG). Recent studies have focused intensely on α-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of α-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on α-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway.     

Christian Huygens’ Lost and Forgotten Pamphlet of his Pendulum Invention

Until recently it was believed that Christian Huygens’ earliest publication of his pendulum invention was Horologium of 1658. He published the more famous general treatise, Horologium Oscillatorium, fifteen years later in 1673. Two years ago, an article1 ¹Whitestone, Sebastian, ‘The Identification and Attribution of Christiaan Huygens’ First Pendulum Clock', Antiquarian Horology, December (2008), 201–222. suggesting an unknown collaboration in developing the clock pendulum between Huygens and the Paris clockmaker Isaac Thuret, presented the evidence of Benjamin Martin, an 18th century educationalist and retailer of scientific material. Martin described a Huygens publication of 1657 and reproduced the illustration it contained. This illustration shows a different clock from the one drawn in Horologium and different also from those previously considered as Huygens’ earliest surviving examples. However, the illustration is similar to part of a plate in Horologium Oscillatorium and this similarity caused one historian to cast doubt on the existence of the 1657 publication.2 ²Plomp, R., ‘Letter', Antiquarian Horology, December (2009), 714–17. See also author's reply, ibid, 717–19. This article, with information presented for the first time, seeks to prove the existence of that work and thereby establish it in the canon of Huygens’ writings while re-examining the invention in the light that it casts.     

Criticism of trepidation models and advocacy of uniform precession in medieval Latin astronomy

A characteristic hallmark of medieval astronomy is the replacement of Ptolemy’s linear precession with so-called models of trepidation, which were deemed necessary to account for divergences between parameters and data transmitted by Ptolemy and those found by later astronomers. Trepidation is commonly thought to have dominated European astronomy from the twelfth century to the Copernican Revolution, meeting its demise only in the last quarter of the sixteenth century thanks to the observational work of Tycho Brahe. The present article seeks to challenge this picture by surveying the extent to which Latin astronomers of the late Middle Ages expressed criticisms of trepidation models or rejected their validity in favour of linear precession. It argues that a readiness to abandon trepidation was more widespread prior to Brahe than hitherto realized and that it frequently came as the result of empirical considerations. This critical attitude towards trepidation reached an early culmination point with the work of Agostino Ricci (De motu octavae spherae, 1513), who demonstrated the theory’s redundancy with a penetrating analysis of the role of observational error in Ptolemy’s Almagest.     

OSBP-related protein-2 (ORP2): a novel Akt effector that controls cellular energy metabolism

ORP2 is a ubiquitously expressed OSBP-related protein previously implicated in endoplasmic reticulum (ER)—lipid droplet (LD) contacts, triacylglycerol (TG) metabolism, cholesterol transport, adrenocortical steroidogenesis, and actin-dependent cell dynamics. Here, we characterize the role of ORP2 in carbohydrate and lipid metabolism by employing ORP2-knockout (KO) hepatoma cells (HuH7) generated by CRISPR-Cas9 gene editing. The ORP2-KO and control HuH7 cells were subjected to RNA sequencing, analyses of Akt signaling, carbohydrate and TG metabolism, the extracellular acidification rate, and the lipidome, as well as to transmission electron microscopy. The loss of ORP2 resulted in a marked reduction of active phosphorylated Akt(Ser473) and its target Glycogen synthase kinase 3β(Ser9), consistent with defective Akt signaling. ORP2 was found to form a physical complex with the key controllers of Akt activity, Cdc37, and Hsp90, and to co-localize with Cdc37 and active Akt(Ser473) at lamellipodial plasma membrane regions, in addition to the previously reported ER–LD localization. ORP2-KO reduced glucose uptake, glycogen synthesis, glycolysis, mRNA-encoding glycolytic enzymes, and SREBP-1 target gene expression, and led to defective TG synthesis and storage. ORP2-KO did not reduce but rather increased ER–LD contacts under basal culture conditions and interfered with their expansion upon fatty acid loading. Together with our recently published work (Kentala et al. in FASEB J 32:1281–1295, 2018), this study identifies ORP2 as a new regulatory nexus of Akt signaling, cellular energy metabolism, actin cytoskeletal function, cell migration, and proliferation.     

Cyclotomie et formes quadratiques dans l’œuvre arithmétique d’Augustin-Louis Cauchy (1829–1840)

Augustin-Louis Cauchy publie une majorité de ses recherches arithmétiques entre 1829 et 1840. Celles-ci ne sont pourtant qu’évoquées dans certaines histoires de la théorie des nombres centrées sur les lois de réciprocité ou sur la théorie des nombres algébriques. Elles y sont décrites comme contenant quelques résultats similaires à ceux de Gauss, Jacobi ou Dirichlet mais de manière incomplète et désordonnée. L’objectif de cet article est de présenter une analyse des textes arithmétiques de Cauchy publiés entre 1829 et 1840 pour montrer qu’ils contiennent au contraire un ensemble cohérent de résultats en lien avec les formes quadratiques $4p^{\mu }=x^2+ny^2$ , où $p$ est un nombre premier et $n$ un diviseur de $p-1$ . Nous discuterons également la forme particulière de ce corpus et la stratégie utilisée pour retrouver les lignes directrices du travail de Cauchy. Augustin-Louis Cauchy published most of his arithmetical research between 1829 and 1840. These are however only mentioned in some number theory history centered on reciprocity laws or on theory of algebraic numbers. They are described as containing some results similar to those of Gauss, Jacobi and Dirichlet but in a incomplete and disorganized way. The objective of this paper is to present an analysis of Cauchy’s arithmetical texts published between 1829 and 1840 to show that they contain a rather consistent set of results related to quadratic forms $4p^{\mu } = x ^2 + ny ^2 $ , where $p$ is a prime and $n$ a divisor of $ p-1 $ . We will also discuss the particular form of this body of texts and the strategy we used to find the guidelines of the work of Cauchy.     

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5–20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of d-glucose was lower than d-fructose. However, uptake of d-glucose was higher than d-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection.     

Marking out a disciplinary common ground: The role of chemical pedagogy in establishing the doctrine of affinity at the heart of British chemistry

This paper presents a case study that contributes to the current debate among historians of chemistry concerning the role and influence of pedagogy in science. Recently, Bernadette Bensaude-Vincent and her colleagues concluded that in nineteenth-century France, ‘textbooks played an important role in discipline building and in creating theories’.1 ¹A. Garcia-Belmar, B. Bensaude-Vincent and J.R. Bertomeu-Sánchez, ‘The Power of Didactic Writings: French Chemistry Textbooks of the Nineteenth Century’, in Pedagogy and the Practice of Science: Historical and Contemporary Perspectives, edited by D. Kaiser (Cambridge, MA, 2005), 243. Developing this idea further, this paper examines the dissemination of knowledge through face-to-face chemical lectures, showing that the influence of pedagogical strategy on theoretical content of the science is far from negligible. The pedagogy of William Cullen was essentially responsible for the prevalence of the doctrine of affinity in British chemistry from the 1760s onwards. Cullen used his affinity theory as a pedagogical tool that to a large extent defined his discipline, and the pedagogical pyramid that he headed similarly ensured that the doctrine would remain at the heart of British chemistry. From a pedagogical tool, the doctrine of affinity was transformed over time into a chemical tool, offering British chemists a disciplinary common ground that both set and reinforced the boundaries to their discipline.     

Isaac Newton’s ‘Of Quadrature by Ordinates’

In Of Quadrature by Ordinates (1695), Isaac Newton tried two methods for obtaining the Newton–Cotes formulae. The first method is extrapolation and the second one is the method of undetermined coefficients using the quadrature of monomials. The first method provides $n$ -ordinate Newton–Cotes formulae only for cases in which $n=3,4$ and 5. However this method provides another important formulae if the ratios of errors are corrected. It is proved that the second method is correct and provides the Newton–Cotes formulae. Present significance of each of the methods is given.     

Heterogeneous responses of canine basilar and middle cerebral arteries to serotonin at normal and high CO2 tension

The responses of basilar arteries (BAs) to serotonin were attenuated by high \(P_{CO_2 } \) (86±1 mm Hg) and the pH matched acidotic solution ( \(P_{CO_2 } \) 37±1 mm Hg), whereas the responses of middle cerebral arteries (MCAs) were not. High \(P_{CO_2 } \) decreased the basal tone of both arteries, and the changes in basal tone due to high \(P_{CO_2 } \) were not influenced by 3×10^?7 M imipramine, 10^?5 M pargyline or 10^?4 M aspirin. The responses of BAs to serotonin were attenuated by high \(P_{CO_2 } \) in the presence of imipramine, pargyline and aspirin. The responses of MCAs to serotonin were not influenced by high \(P_{CO_2 } \) in the presence of pargyline and aspirin, but attenuated by high \(P_{CO_2 } \) in the presence of imipramine.     

Insulin can induce the expression of a memory-related synaptic protein through facilitating AMPA receptor endocytosis in rat cortical neurons

Learning and memory depend on long-term synaptic plasticity including long-term potentiation (LTP) and depression (LTD). Activity-regulated cytoskeleton-associated protein (Arc) plays versatile roles in synaptic plasticity mainly through inducing F-actin formation, underlying consolidation of LTP, and promoting AMPA receptor (AMPAR) endocytosis, underlying LTD. Insulin can also induce LTD by facilitating the internalization of AMPARs. In neuroblastoma cells, insulin induced a dramatic increase in Arc mRNA and Arc protein levels, which may underlie the memory-enhancing action of insulin. Thus, a hypothesis was made that, in response to insulin, increased AMPAR endocytosis leads to enhanced Arc expression, and vice versa. Primary cultures of neonatal Sprague–Dawley rat cortical neurons were used. Using Western-blot analysis and immunofluorescent staining, our results reveal that inhibiting AMPAR-mediated responses with AMPAR antagonists significantly enhanced whereas blocking AMPAR endocytosis with various reagents significantly prevented insulin (200 nM, 2 h)-induced Arc expression. Furthermore, via surface biotinylation assay, we demonstrate that acute blockade of new Arc synthesis after insulin stimulation using Arc antisense oligodeoxynucleotide prevented insulin-stimulated AMPAR endocytosis. These findings suggest for the first time that an interaction exists between insulin-stimulated AMPAR endocytosis and insulin-induced Arc expression.     

Investigations of the coordinates in Ptolemy’s Geographike Hyphegesis Book 8

In Book 8 of his Geographike Hyphegesis Ptolemy gives coordinates for ca. 360 so-called noteworthy cities. These coordinates are the time difference to Alexandria, the length of the longest day, and partly the ecliptic distance from the summer solstice. The supposable original conversions between the coordinates in Book 8 and the geographical coordinates in the location catalogue of Books 2–7 including the underlying parameters and tabulations are here reconstructed. The results document the differences between the ${\Omega}$ - and ${\Xi}$ -recension. The known difference in the longitude of Alexandria underlying the conversion of the longitudes is examined more closely. For the ecliptic distances from the summer solstice of the ${\Omega}$ -recension, it is revealed that they were originally computed by means of a so far undiscovered approximate, linear conversion. Further it is shown that the lengths of the longest day could be based on a linear interpolation of the data in the Mathematike Syntaxis 2.6.