The DNA double-strand “breakome” of mouse spermatids

De novo germline mutations arise preferentially in male owing to fundamental differences between spermatogenesis and oogenesis. Post-meiotic chromatin remodeling in spermatids results in the elimination of most of the nucleosomal supercoiling and is characterized by transient DNA fragmentation. Using three alternative methods, DNA from sorted populations of mouse spermatids was used to confirm that double-strand breaks (DSB) are created in elongating spermatids and repaired at later steps. Specific capture of DSB was used for whole-genome mapping of DSB hotspots (breakome) for each population of differentiating spermatids. Hotspots are observed preferentially within introns and repeated sequences hence are more prevalent in the Y chromosome. When hotspots arise within genes, those involved in neurodevelopmental pathways become preferentially targeted reaching a high level of significance. Given the non-templated DNA repair in haploid spermatids, transient DSBs formation may, therefore, represent an important component of the male mutation bias and the etiology of neurological disorders, adding to the genetic variation provided by meiosis.     

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 “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.     

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 product of the γ-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis

Presenilin-1 (PS1) gene encodes the catalytic component of γ-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/γ-secretase cleavage of efnB2 ligand promotes EphB4 receptor-dependent angiogenesis in vitro. EfnB2/CTF2 increases endothelial cell sprouting and tube formation, stimulates the formation of angiogenic complexes that include VE-cadherin, Raf-1 and Rok-α, and increases MLC2 phosphorylation. These functions are mediated by the PDZ-binding domain of efnB2. Acute downregulation of PS1 or inhibition of γ-secretase inhibits the angiogenic functions of EphB4 while absence of PS1 decreases the VE-cadherin angiogenic complexes of mouse brain. Our data reveal a mechanism by which PS1/γ-secretase regulates efnB2/EphB4 mediated angiogenesis.     

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 concept of “character” in Dirichlet’s theorem on primes in an arithmetic progression

In 1837, Dirichlet proved that there are infinitely many primes in any arithmetic progression in which the terms do not all share a common factor. We survey implicit and explicit uses of Dirichlet characters in presentations of Dirichlet’s proof in the nineteenth and early twentieth centuries, with an eye toward understanding some of the pragmatic pressures that shaped the evolution of modern mathematical method.     

Searching for “signal 2”: costimulation requirements of γδ T cells

T cell activation requires the integration of signals that arise from various types of receptors. Although TCR triggering is a necessary condition, it is often not sufficient to induce full T-cell activation, as reflected in cell proliferation and cytokine secretion. This has been firmly demonstrated for conventional αβ T cells, for which a large panel of costimulatory receptors has been identified. By contrast, the area remains more obscure for unconventional, innate-like γδ T cells, as the literature has been scarce and at times contradictory. Here we review the current state of the art on the costimulatory requirements of γδ T cell activation. We highlight the roles of members of the immunoglobulin (like CD28 or JAML) or tumour necrosis factor receptor (like CD27) superfamilies of coreceptors, but also of more atypical costimulatory molecules, such as NKG2D or CD46. Finally, we identify various areas where our knowledge is still markedly insufficient, hoping to provoke future research on γδ T cell costimulation.     

“The True” in Gottlob Frege's “Über die Grundlagen der Geometrie”

In this essay, I examine the metaphysical and metalogical ramifications of Gottlob Frege's controversy with David Hilbert and Alwin Korselt, over Hilbert's Grundlagen der Geometrie. These ramifications include(1) Korselt's original appeals to general metatheoretic Deutungen (interpretations);(2) Hilbert's puzzling belief that whatever is consistent in some sense exists; and(3) Frege's semantic monist conviction that theoretical sense and reference (mathematical and other) must be eindeutig lösbar (uniquely solvable).My principal conclusions are(4) that Frege's position in (3) represented a pervasively dogmatic presumption that his newly discovered quantification theory must have a propositional metatheory (the True; the False); and(5) that this needless assumption adversely affected not only his polemic against the moderate semantic relativism of Hilbert and Korselt, but also his reception of type-theoretic ideas, and greatly facilitated his vulnerability to the sort of self-referential inconsistency Russell discovered in Grundgesetz V.These conclusions also seem to me to provide a conceptual framework for several of Frege's other arguments and reactions which might seem more particular and disparate. These include(6) his arbitrary restrictions on the range of second-order quantification, which undercut his own tentative attempts to give accounts of independence and semantic consequence;(7) his uncharacteristic hesitation, even dismay, at the prospect that such accounts might eventuate in a genuinely quantificational metamathematics, whose Gegenstände (objects) might themselves be Gedanken (thoughts); and, perhaps most revealingly(8) his otherwise quite enigmatic, quasi-stoic doctrine that genuine formal deduction must be from premises that are true.A deep reluctance to pluralize or iterate the transition from theory to meta-theory would also be consonant, of course, with Frege's vigorous insistence that there can be only one level each of linguistic Begriffe (concepts) and Gegenstände (objects). With hindsight, such an assumption may seem more gratuitous in the philosophy of language (where it contributed, I would argue, to Wittgenstein's famous transition to the mystical in 6.45 and 6.522 of the Tractatus); but its more implausible implications in this wider context seemed to emerge more slowly.In the mathematical test-case discussed here, however, such strains were immediately and painfully apparent; the first models of hyperbolic geometry were described some thirty years before Frege drafted his polemic against Hilbert's pioneering exposition. It is my hope that a careful study of Frege's lines of argument in this relatively straightforward mathematical controversy may suggest other, parallel approaches to the richer and more ambiguous problems of his philosophy of language.Niemand kann zwei Herren dienen. Man kann nicht der Wahrheit dienen und der Unwahrheit. Wenn die euklidische Geometrie wahr ist, so ist die nichteuklidische Geometrie falsch, und wenn die nichteuklidische wahr ist, so ist die euklidische Geometrie falsch.No one can serve two masters. One cannot serve truth and untruth. If Euclidean geometry is true, non-Euclidean geometry is false, and if non-Euclidean [geometry] is true, Euclidean geometry is false. Über Euklidische Geometrie [Frege 1969], p. 183.