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.     

The ascendancy of the Laplace transform and how it came about

The modern Laplace transform is relatively recent. It was first used by Bateman in 1910, explored and codified by Doetsch in the 1920s and was first the subject of a textbook as late as 1937. In the 1920s and 1930s it was seen as a topic of front-line research; the applications that call upon it today were then treated by an older technique — the Heaviside operational calculus. This, however, was rapidly displaced by the Laplace transform and by 1950 the exchange was virtually complete. No other recent development in mathematics has achieved such ready popularisation and acceptance among the users of mathematics and the designers of undergraduate curricula.     

<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.     

Thyroid hormone actions in liver cancer

The thyroid hormone 3,3′,5-triiodo-l-thyronine (T₃) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T₃/TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T₃/TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs).     

Differential molecular regulation of processing and membrane expression of Type-I BMP receptors: implications for signaling

The Type-I bone morphogenetic protein receptors (BMPRs), BMPR1A and BMPR1B, present the highest sequence homology among BMPRs, suggestive of functional similitude. However, sequence elements within their extracellular domain, such as signal sequence or N-glycosylation motifs, may result in differential regulation of biosynthetic processing and trafficking and in alterations to receptor function. We show that (i) BMPR1A and the ubiquitous isoform of BMPR1B differed in mode of translocation into the endoplasmic reticulum; and (ii) BMPR1A was N-glycosylated while BMPR1B was not, resulting in greater efficiency of processing and plasma membrane expression of BMPR1A. We further demonstrated the importance of BMPR1A expression and glycosylation in ES-2 ovarian cancer cells, where (i) CRISPR/Cas9-mediated knockout of BMPR1A abrogated BMP2-induced Smad1/5/8 phosphorylation and reduced proliferation of ES-2 cells and (ii) inhibition of N-glycosylation by site-directed mutagenesis, or by tunicamycin or 2-deoxy-d-glucose treatments, reduced biosynthetic processing and plasma membrane expression of BMPR1A and BMP2-induced Smad1/5/8 phosphorylation.     

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.     

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.     

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.     

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.     

The development of the Laplace transform, 1737–1937

This paper, the first of two, follows the development of theLaplace Transform from its earliest beginnings withEuler, usually dated at 1737, to the year 1880, whenSpitzer was its major, if himself relatively minor, protagonist. The coverage aims at completeness, and shows the state which the technique reached in the hands of its greatest exponent to that time,Petzval. A sequel will trace the development of the modern theory from its beginnings withPoincaré to its present form, due toDoetsch.     

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.     

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.     

Pre-Euclidean geometry and Aeginetan coin design: some further remarks

Some ancient Greek coins from the island state of Aegina depict peculiar geometric designs. Hitherto they have been interpreted as anticipations of some Euclidean propositions. But this paper proposes geometrical constructions which establish connections to pre-Euclidean treatments of incommensurability. The earlier Aeginetan coin design from about 500 bc onwards appears as an attempt not only to deal with incommensurability but also to conceal it. It might be related to Plato’s dialogue Timaeus. The newer design from 404 bc onwards reveals incommensurability, namely in the context of ‘doubling the square’. It thereby covers the same topic but a different geometry as passages in Plato’s dialogue Meno (385 bc). This coin design incorporates important elements of ancient Greek geometrical analysis of the fifth century bc like the gnomon, Hippocrates’ squaring of the lunule (ca. 430 bc), and a geometrical version of monetary equivalence. Through this venue, the design’s conceptual lineage might be traced as far back as Heraclitus’ cosmology of about 500 bc.