Telomeres and DNA double-strand breaks: ever the twain shall meet?

Telomeres were first recognized as a bona fide constituent of the chromosome based on their inability to rejoin with broken chromosome ends produced by radiation. Today, we recognize two essential and interrelated properties of telomeres. They circumvent the so-called end-replication problem faced by genomes composed of linear chromosomes, which erode from their termini with each successive cell division. Equally vital is the end-capping function that telomeres provide, which is necessary to deter chromosome ends from illicit recombination. This latter property is critical in facilitating the distinction between the naturally occurring DNA double-strand breaks (DSBs) found at chromosome ends (i.e., telomeres) and DSBs produced by exogenous agents. Here we discuss, in a brief historical narrative, key discoveries that led investigators to appreciate the unique properties of telomeres in protecting chromosome ends, and the consequences of telomere dysfunction, particularly as related to recombination involving radiation-induced DSBs. Dedication. In appreciation of his heart-felt commitment to research and education, and the life-long influence he has had on the lives of students and colleagues, the authors wish to dedicate this paper to Professor Joel S. Bedford. Received 21 May 2007; received after revision 28 June 2007; accepted 6 August 2007     

The “day of Brahman” in the work of Āryabhata

Summary In the astronomical treatise ryabhatya of ryabhata several verses are interpolated, namely all those verses in which either Brahman was mentioned or extremely large periods were introduced. The interpolator was known to AlBrn as ryabhata of Kusumapura, who belongs to the school of the elder ryabhata. The aim of the interpolator was to bring the teaching of the elder ryabhata into accordance with the revelation of Svayambh. Svayambh is another name for Brahm.     

The influence of N-methyl-N-β-chloroethyl hydrazines on the mitotic index of Ehrlich ascites tumor cells and the leukopoiesis of the mouse

Summary The cytostatic activity of N-methyl-N--chloroethylbenzaldehyd hydrazone, (B1) is at least equal to that of procarbazine when its effect is tested with the Ehrlich ascites tumor cells of the mouse and the Yoshida sarcoma of the rat. B1 causes a slighter decrease of mitotic cells and no shift from prophase to metaphase. These results suggest that the cytostatic effect of B1 is due to interference with cell metabolism or an effect at the cell membrane and not to an effect on cell proliferation. This assumption is supported by a considerable depression, of lymphocytes and a minor effect on granulopoiesis, which is especially sensitive towards proliferation toxins. All these findings suggest a different mechanism of action of B1 and procarbazine.     

The continuing disappearance of “pure” Ca2+ buffers

Advances in the understanding of a class of Ca²⁺-binding proteins usually referred to as “Ca²⁺ buffers” are reported. Proteins historically embraced within this group include parvalbumins (α and β), calbindin-D9k, calbindin-D28k and calretinin. Within the last few years a wealth of data has accumulated that allow a better understanding of the functions of particular family members of the >240 identified EF-hand Ca²⁺-binding proteins encoded by the human genome. Studies often involving transgenic animal models have revealed that they exert their specific functions within an intricate network consisting of many proteins and cellular mechanisms involved in Ca²⁺ signaling and Ca²⁺ homeostasis, and are thus an essential part of the Ca²⁺ homeostasome. Recent results indicate that calbindin-D28k, possibly also calretinin and oncomodulin, the mammalian β parvalbumin, might have additional Ca²⁺ sensor functions, leaving parvalbumin and calbindin-D9k as the only “pure” Ca²⁺ buffers. Received 10 September 2008; received after revision 15 October 2008; accepted 4 November 2008     

The “Unknown Heritage”: trace of a forgotten locus of mathematical sophistication

The “unknown heritage” is the name usually given to a problem type in whose archetype a father leaves to his first son 1 monetary unit and \({\frac{1}{n}}\) (n usually being 7 or 10) of what remains, to the second 2 units and \({\frac{1}{n}}\) of what remains, and so on. In the end, all sons get the same, and nothing remains. The earliest known occurrence is in Fibonacci’s Liber abbaci, which also contains a number of much more sophisticated versions, together with a partial algebraic solution for one of these and rules for all which do not follow from his algebraic calculation. The next time the problem turns up is in Planudes’s late thirteenth century Calculus according to the Indians, Called the Great. After that the simple problem type turns up regularly in Provençal, Italian and Byzantine sources. It seems never to appear in Arabic or Indian writings, although two Arabic texts (one from c. 1190) contain more regular problems where the number of shares is given; they are clearly derived from the type known from European and Byzantine works, not its source. The sophisticated versions turn up again in Barthélemy de Romans’ Compendy de la praticque des nombres (c. 1467) and, apparently inspired from there, in the appendix to Nicolas Chuquet’s Triparty (1484). Apart from a single trace in Cardano’s Practica arithmetice et mensurandi singularis, the sophisticated versions never surface again, but the simple version spreads for a while to German practical arithmetic and, more persistently, to French polite recreational mathematics. Close examination of the texts shows that Barthélemy cannot have drawn his familiarity with the sophisticated rules from Fibonacci. It also suggests that the simple version is originally either a classical, strictly Greek or Hellenistic, or a medieval Byzantine invention; and that the sophisticated versions must have been developed before Fibonacci within an environment (located in Byzantium, Provence, or possibly in Sicily?) of which all direct traces has been lost, but whose mathematical level must have been quite advanced.     

Identification of ϱ-antigenic determinants on the surface,of mouse T-lymphocytes

Summary A monospecific antiserum has been prepared in rabbits against purified -antigen, a 100,000 mol.wt glycoprotein found on the surface of mouse L-cells. This antiserum has been employed to demonstrate the presence of -antigenic determinants selectively on the surface of mouse T-, but not B-lymphocytes.We thank Drs A. Christopher and R. Hunt for advice during the course of these studies. This work was supported by grants from the U.S. Public Health Service and the American Cancer Society.     

The peritoneal “soil” for a cancerous “seed”: a comprehensive review of the pathogenesis of intraperitoneal cancer metastases

Various types of tumors, particularly those originating from the ovary and gastrointestinal tract, display a strong predilection for the peritoneal cavity as the site of metastasis. The intraperitoneal spread of a malignancy is orchestrated by a reciprocal interplay between invading cancer cells and resident normal peritoneal cells. In this review, we address the current state-of-art regarding colonization of the peritoneal cavity by ovarian, colorectal, pancreatic, and gastric tumors. Particular attention is paid to the pro-tumoral role of various kinds of peritoneal cells, including mesothelial cells, fibroblasts, adipocytes, macrophages, the vascular endothelium, and hospicells. Anatomo-histological considerations on the pro-metastatic environment of the peritoneal cavity are presented in the broader context of organ-specific development of distal metastases in accordance with Paget’s “seed and soil” theory of tumorigenesis. The activity of normal peritoneal cells during pivotal elements of cancer progression, i.e., adhesion, migration, invasion, proliferation, EMT, and angiogenesis, is discussed from the perspective of well-defined general knowledge on a hospitable tumor microenvironment created by the cellular elements of reactive stroma, such as cancer-associated fibroblasts and macrophages. Finally, the paper addresses the unique features of the peritoneal cavity that predispose this body compartment to be a niche for cancer metastases, presents issues that are topics of an ongoing debate, and points to areas that still require further in-depth investigations.     

The case of the composite Higgs: The model as a “Rosetta stone” in contemporary high-energy physics

This paper analyses the practice of model-building “beyond the Standard Model” in contemporary high-energy physics and argues that its epistemic function can be grasped by regarding models as mediating between the phenomenology of the Standard Model and a number of “theoretical cores” of hybrid character, in which mathematical structures are combined with verbal narratives (“stories”) and analogies referring back to empirical results in other fields (“empirical references”). Borrowing a metaphor from a physics research paper, model-building is likened to the search for a Rosetta stone, whose significance does not lie in its immediate content, but rather in the chance it offers to glimpse at and manipulate the components of hybrid theoretical constructs. I shall argue that the rise of hybrid theoretical constructs was prompted by the increasing use of nonrigorous mathematical heuristics in high-energy physics. Support for my theses will be offered in form of a historical–philosophical analysis of the emergence and development of the theoretical core centring on the notion that the Higgs boson is a composite particle. I will follow the heterogeneous elements which would eventually come to form this core from their individual emergence in the 1960s and 1970s, through their collective life as a theoretical core from 1979 until the present day.     

“The soul of the fact”—Poincaré and proof

Henri Poincaré acquired a reputation in his lifetime for being difficult to read. It was said that he missed out important steps in his arguments, assumed the truth of claims that would be difficult if not impossible to prove, and in short that he lacked rigour. In the years after his death this view coalesced into an exaggerated claim that his work was simply too vague, and has become a cliché. This paper argues that Poincaré was far from indifferent to rigour, and that what characterises his work is an attempt to convey a particular sense of what it is to understand a topic. Throughout his working life Poincaré was concerned to promote the understanding of many domains of mathematics and physics. This is as apparent in his views about geometry, his conventionalism, and his theory of knowledge, as it is in his work on electricity and optics, on number theory, and function theory. It is one of the ways Poincaré discharged his responsibilities as a scientist, and that it accounts not only for a surprising degree of unity in his work but also gives it its distinctive character—at once profound and elusive.     

The story of ‘Scientist: The Story of a Word’

This examination of an important paper by Sydney Ross is the first in a projected series of occasional reflections on ‘Annals of Science Classic Papers’ that have had enduring utility within the field of history of science and beyond. First the messages of the paper are examined, some well known but others, particularly Ross's own contemporary concerns about the use of the word ‘scientist’, less so. The varied uses made of the paper by scholars are then traced before Ross's biography is examined in order to try to understand how a figure professionally marginal to the field of history of science came to write such a significant piece. Ross’s interest in the topic appears to have been informed by a romantically tinged scientific progressivism and a deep concern with the importance of linguistic precision in science and in public affairs. The inspirations of the author and the interests of his audience have been only partially aligned, but the paper's insights remain of broad historical interest and have wider ramifications since the denotation ‘scientist’ and its proper application are much debated today in contests over the authority of science.     

The effect of cyclic cytidine 3′,5′-monophosphate (cCMP) on the in vitro development,hatching and attachment of the mouse blastocyst

Summary The in vitro development and attachment of hatched mouse blastocysts on the untreated substratum was enhanced by 10 M dibutyryl cCMP (dbcCMP). The result suggests that cCMP has an effect on embryonic development and on the blastocyst attachment process.25 November1986     

Values in early-stage climate engineering: The ethical implications of “doing the research”

Calls for research on climate engineering have increased in the last two decades, but there remains widespread agreement that many climate engineering technologies (in particular, forms involving global solar radiation management) present significant ethical risks and require careful governance. However, proponents of research argue, ethical restrictions on climate engineering research should not be imposed in early-stage work like in silico modeling studies. Such studies, it is argued, do not pose risks to the public, and the knowledge gained from them is necessary for assessing the risks and benefits of climate engineering technologies. I argue that this position, which I call the “broad research-first” stance, cannot be maintained in light of the entrance of nonepistemic values in climate modeling. I analyze the roles that can be played by nonepistemic political and ethical values in the design, tuning, and interpretation of climate models. Then, I argue that, in the context of early-stage climate engineering research, the embeddedness of values will lead to value judgments that could harm stakeholder groups or impose researcher values on non-consenting populations. I conclude by calling for more robust reflection on the ethics and governance of early-stage climate engineering research.     

The making of an intrinsic property: “Symmetry heuristics” in early particle physics

Mathematical invariances, usually referred to as “symmetries”, are today often regarded as providing a privileged heuristic guideline for understanding natural phenomena, especially those of micro-physics. The rise of symmetries in particle physics has often been portrayed by physicists and philosophers as the “application” of mathematical invariances to the ordering of particle phenomena, but no historical studies exist on whether and how mathematical invariances actually played a heuristic role in shaping microphysics. Moreover, speaking of an “application” of invariances conflates the formation of concepts of new intrinsic degrees of freedom of elementary particles with the formulation of models containing invariances with respect to those degrees of freedom. I shall present here a case study from early particle physics (ca. 1930–1954) focussed on the formation of one of the earliest concepts of a new degree of freedom, baryon number, and on the emergence of the invariance today associated to it. The results of the analysis show how concept formation and “application” of mathematical invariances were distinct components of a complex historical constellation in which, beside symmetries, two further elements were essential: the idea of physically conserved quantities and that of selection rules. I shall refer to the collection of different heuristic strategies involving selection rules, invariances and conserved quantities as the “SIC-triangle” and show how different authors made use of them to interpret the wealth of new experimental data. It was only a posteriori that the successes of this hybrid “symmetry heuristics” came to be attributed exclusively to mathematical invariances and group theory, forgetting the role of selection rules and of the notion of physically conserved quantity in the emergence of new degrees of freedom and new invariances. The results of the present investigation clearly indicate that opinions on the role of symmetries in fundamental physics need to be critically reviewed in the spirit of integrated history and philosophy of science.     

The ‘Chemistry of Space’: The Sources of Hermann Grassmann's Scientific Achievements

Albert Lewis's article (Annals of Science, 1977) analysing the influence of Friedrich Schleiermacher on Hermann Grassmann, stimulated many different studies on the founder of n-dimensional outer algebra.

Following a brief outline of the various, sometimes diverging, analyses of Grassmann's creative thinking, new research is presented which confirms Lewis's original contribution and widens it considerably. It will be shown that:

i.?Grassmann, although a self-taught mathematician, was at the centre of a hitherto understated intellectual trend, which was defining for Germany. Initiated by Pestalozzi's concept of elementary mathematical education and culminating in the modern mathematics of the late 19th Century, it was reflected in the contributions of Grassmann, Riemann, Jacobi and Eisenstein.

ii.?Hermann Grassmann, his father Justus, and his brother Robert were all demonstrably influenced by Schleiermacher's dialectic; however the two brothers responded to it in very different ways.

iii.?Whilst the more philosophical parts of Hermann's 1844 Extension Theory are characterised by the influence of Schleiermacher and also by the mathematical knowledge of his father, the entire development of this work is the unfolding of a single idea based on the father's interpretation of combinatorial multiplication as a ‘chemical conjunction‘, which was developed largely dialectically by Hermann.