Suppressing spacetime emergence

One of the primary tasks in building a quantum theory of gravity is discovering how to save spatiotemporal phenomena using a theory which, putatively, does not include spacetime. Some have taken this task a step further and argue for the actual emergence of spacetime from a non-spatiotemporal ontology in the low-energy regime. In this paper, it is argued that the account of spacetime emergence presented in Huggett and Wüthrich (2013) and then assumed in Baron (2019), Crowther (2016), Wüthrich (2017), and Wüthrich and Lam (2018) fails to accomplish the task to which it is set. There is a prima facie contradiction between the scale-independent ontology of spacetime in GR and the scale-dependent account of emergence proposed by this literature. One can avoid this contradiction but only at the cost of changing the target of emergence and by endorsing a perspectival theory of ontology – a view I call “ontic-perspectivism”. Though this paper explicitly addresses spacetime emergence, many of the following arguments are applicable to other accounts where objects of ontology, or their properties, are claimed to emerge in the low-energy regime.     

“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.     

Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1

Previously, we found that two isoforms of the ZNF268 gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis.     

A uniform numbering system for indole alkaloids

Résumé Nous proposons un mode uniforme de numérotation pour le squelette des alcaloïdes indoliques complexes. Il est basé sur le fait que tous ces composés sont susceptibles d'être coupés en éléments identiques.

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This is a precis of a suggestion discussed at the fifth annual meeting, American Society of Pharmacognosy, Symposium on the Chemistry and Biological Activity of Catharanthus, Vinca and Related Indole Alkaloids, Pittsburgh (Pennsylvania), June, 1964.     

<Emphasis Type="Italic">Yersinia pseudotuberculosis</Emphasis> supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4⁺ T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4⁺ T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3⁺ regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4⁺ T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4⁺ T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3⁺ Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4⁺ T cell subsets by altering their TCR downstream signaling.     

Kuhn’s Structure of Scientific Revolutions between sociology and epistemology

The aim of the paper is to clarify Kuhn’s theory of scientific revolutions. We propose to discriminate between a scientific revolution, which is a sociological event of a change of attitude of the scientific community with respect to a particular theory, and an epistemic rupture, which is a linguistic fact consisting of a discontinuity in the linguistic framework in which this theory is formulated. We propose a classification of epistemic ruptures into four types. In the paper, each of these types of epistemic ruptures is illustrated by examples from physics. The classification of epistemic ruptures can be used as a basis for a classification of scientific revolutions and thus for a refinement of our view of the progress of science.     

The nucleotide-binding proteins Nubp1 and Nubp2 are negative regulators of ciliogenesis

Nucleotide-binding proteins Nubp1 and Nubp2 are MRP/MinD-type P-loop NTPases with sequence similarity to bacterial division site-determining proteins and are conserved, essential proteins throughout the Eukaryotes. They have been implicated, together with their interacting minus-end directed motor protein KIFC5A, in the regulation of centriole duplication in mammalian cells. Here we show that Nubp1 and Nubp2 are integral components of centrioles throughout the cell cycle, recruited independently of KIFC5A. We further demonstrate their localization at the basal body of the primary cilium in quiescent vertebrate cells or invertebrate sensory cilia, as well as in the motile cilia of mouse cells and in the flagella of Chlamydomonas. RNAi-mediated silencing of nubp-1 in C. elegans causes the formation of morphologically aberrant and additional cilia in sensory neurons. Correspondingly, downregulation of Nubp1 or Nubp2 in mouse quiescent NIH 3T3 cells markedly increases the number of ciliated cells, while knockdown of KIFC5A dramatically reduces ciliogenesis. Simultaneous double silencing of Nubp1 + KIFC5A restores the percentage of ciliated cells to control levels. We document the normal ciliary recruitment, during these silencing regimes, of basal body proteins critical for ciliogenesis, namely CP110, CEP290, cenexin, Chibby, AurA, Rab8, and BBS7. Interestingly, we uncover novel interactions of Nubp1 with several members of the CCT/TRiC molecular chaperone complex, which we find enriched at the basal body and recruited independently of the Nubps or KIFC5A. Our combined results for Nubp1, Nubp2, and KIFC5A and their striking effects on cilium formation suggest a central regulatory role for these proteins, likely involving CCT/TRiC chaperone activity, in ciliogenesis.     

Tumor suppressor C-RASSF proteins

Human genome has ten genes that are collectedly called Ras association domain family (RASSF). RASSF is composed of two subclasses, C-RASSF and N-RASSF. Both N-RASSF and C-RASSF encode Ras association domain-containing proteins and are frequently suppressed by DNA hypermethylation in human cancers. However, C-RASSF and N-RASSF are quite different. Six C-RASSF proteins (RASSF1–6) are characterized by a C-terminal coiled-coil motif named Salvador/RASSF/Hippo domain, while four N-RASSF proteins (RASSF7–10) lack it. C-RASSF proteins interact with mammalian Ste20-like kinases—the core kinases of the tumor suppressor Hippo pathway—and cross-talk with this pathway. Some of them share the same interacting molecules such as MDM2 and exert the tumor suppressor role in similar manners. Nevertheless, each C-RASSF protein has distinct characters. In this review, we summarize our current knowledge of how C-RASSF proteins play tumor suppressor roles and discuss the similarities and differences among C-RASSF proteins.     

Space–time philosophy reconstructed via massive Nordström scalar gravities? Laws vs. geometry,conventionality, and underdetermination

What if gravity satisfied the Klein–Gordon equation? Both particle physics from the 1920–30s and the 1890s Neumann–Seeliger modification of Newtonian gravity with exponential decay suggest considering a “graviton mass term” for gravity, which is algebraic in the potential. Unlike Nordström׳s “massless” theory, massive scalar gravity is strictly special relativistic in the sense of being invariant under the Poincaré group but not the 15-parameter Bateman–Cunningham conformal group. It therefore exhibits the whole of Minkowski space–time structure, albeit only indirectly concerning volumes. Massive scalar gravity is plausible in terms of relativistic field theory, while violating most interesting versions of Einstein׳s principles of general covariance, general relativity, equivalence, and Mach. Geometry is a poor guide to understanding massive scalar gravity(s): matter sees a conformally flat metric due to universal coupling, but gravity also sees the rest of the flat metric (barely or on long distances) in the mass term. What is the ‘true’ geometry, one might wonder, in line with Poincaré׳s modal conventionality argument? Infinitely many theories exhibit this bimetric ‘geometry,’ all with the total stress–energy׳s trace as source; thus geometry does not explain the field equations. The irrelevance of the Ehlers–Pirani–Schild construction to a critique of conventionalism becomes evident when multi-geometry theories are contemplated. Much as Seeliger envisaged, the smooth massless limit indicates underdetermination of theories by data between massless and massive scalar gravities—indeed an unconceived alternative. At least one version easily could have been developed before General Relativity; it then would have motivated thinking of Einstein׳s equations along the lines of Einstein׳s newly re-appreciated “physical strategy” and particle physics and would have suggested a rivalry from massive spin 2 variants of General Relativity (massless spin 2, Pauli and Fierz found in 1939). The Putnam–Grünbaum debate on conventionality is revisited with an emphasis on the broad modal scope of conventionalist views. Massive scalar gravity thus contributes to a historically plausible rational reconstruction of much of 20th–21st century space–time philosophy in the light of particle physics. An appendix reconsiders the Malament–Weatherall–Manchak conformal restriction of conventionality and constructs the ‘universal force’ influencing the causal structure.Subsequent works will discuss how massive gravity could have provided a template for a more Kant-friendly space–time theory that would have blocked Moritz Schlick׳s supposed refutation of synthetic a priori knowledge, and how Einstein׳s false analogy between the Neumann–Seeliger–Einstein modification of Newtonian gravity and the cosmological constant Λ generated lasting confusion that obscured massive gravity as a conceptual possibility.     

Retinoic acid maintains human skeletal muscle progenitor cells in an immature state

Muscle satellite cells are resistant to cytotoxic agents, and they express several genes that confer resistance to stress, thus allowing efficient dystrophic muscle regeneration after transplantation. However, once they are activated, this capacity to resist to aggressive agents is diminished resulting in massive death of transplanted cells. Although cell immaturity represents a survival advantage, the signalling pathways involved in the control of the immature state remain to be explored. Here, we show that incubation of human myoblasts with retinoic acid impairs skeletal muscle differentiation through activation of the retinoic-acid receptor family of nuclear receptor. Conversely, pharmacologic or genetic inactivation of endogenous retinoic-acid receptors improved myoblast differentiation. Retinoic acid inhibits the expression of early and late muscle differentiation markers and enhances the expression of myogenic specification genes, such as PAX7 and PAX3. These results suggest that the retinoic-acid-signalling pathway might maintain myoblasts in an undifferentiated/immature stage. To determine the relevance of these observations, we characterised the retinoic-acid-signalling pathways in freshly isolated satellite cells in mice and in siMYOD immature human myoblasts. Our analysis reveals that the immature state of muscle progenitors is correlated with high expression of several genes of the retinoic-acid-signalling pathway both in mice and in human. Taken together, our data provide evidences for an important role of the retinoic-acid-signalling pathway in the regulation of the immature state of muscle progenitors.     

A loose and separate certainty: Caves, Fuchs and Schack on quantum probability one

Carlton Caves, Fuchs, and Schack (2002) have recently appealed to an argument of mine (Stairs, 1983) to address a problem for their subjective Bayesian account of quantum probability. The difficulty is that on the face of it, quantum mechanical probabilities of one appear to be objective, but in that case, the Born Rule would yield a continuum of probabilities between zero and one. If so, we end up with objective probabilities strictly between zero and one. The authors claim that objective probabilities of one leads to a dilemma: give up locality or fall into contradiction. I argue that this conclusion depends on an overly strong interpretation of objectivism about quantum probabilities.     

Germline-specific dgcr8 knockout in zebrafish using a BACK approach

Zebrafish is an important model to study developmental biology and human diseases. However, an effective approach to achieve spatial and temporal gene knockout in zebrafish has not been well established. In this study, we have developed a new approach, namely bacterial artificial chromosome-rescue-based knockout (BACK), to achieve conditional gene knockout in zebrafish using the Cre/loxP system. We have successfully deleted the DiGeorge syndrome critical region gene 8 (dgcr8) in zebrafish germ line and demonstrated that the maternal-zygotic dgcr8 (MZdgcr8) embryos exhibit MZdicer-like phenotypes with morphological defects which could be rescued by miR-430, indicating that canonical microRNAs play critical role in early development. Our findings establish that Cre/loxP-mediated tissue-specific gene knockout could be achieved using this BACK strategy and that canonical microRNAs play important roles in early embryonic development in zebrafish.     

Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions

Nesprin-1 is a core component of a protein complex connecting nuclei to cytoskeleton termed LINC (linker of nucleoskeleton and cytoskeleton). Nesprin-1 is anchored to the nuclear envelope by its C-terminal KASH domain, the disruption of which has been associated with neuronal and neuromuscular pathologies, including autosomal recessive cerebellar ataxia and Emery–Dreifuss muscular dystrophy. Here, we describe a new and unexpected role of Drosophila Nesprin-1, Msp-300, in neuromuscular junction. We show that larvae carrying a deletion of Msp-300 KASH domain (Msp-300 ^?KASH ) present a locomotion defect suggestive of a myasthenia, and demonstrate the importance of muscle Msp-300 for this phenotype, using tissue-specific RNAi knock-down. We show that Msp-300 ^?KASH mutants display abnormal neurotransmission at the larval neuromuscular junction, as well as an imbalance in postsynaptic glutamate receptor composition with a decreased percentage of GluRIIA-containing receptors. We could rescue Msp-300 ^?KASH locomotion phenotypes by GluRIIA overexpression, suggesting that the locomotion impairment associated with the KASH domain deletion is due to a reduction in junctional GluRIIA. In summary, we found that Msp-300 controls GluRIIA density at the neuromuscular junction. Our results suggest that Drosophila is a valuable model for further deciphering how Nesprin-1 and LINC disruption may lead to neuronal and neuromuscular pathologies.     

No communication without manipulation: A causal-deflationary view of information

In this paper, we shall describe a new account of information in communicational contexts, namely, a causal-deflationary one. Our approach draws from Timpson's deflationary view and supplies the field of philosophy of information with new tools that will help to clarify the underlying structure of communication: information is an abstract entity that must be involved in a causal link in order to achieve communication. In light of our account, communication is not merely the existence of statistical correlations between source and receiver, as usually understood from a purely formal view. Instead, communication is an asymmetric phenomenon involving causal notions: the destination system must be able to be causally manipulated by intervening on the source for successful communication. In a nutshell, we shall support the following lemma: no communication without manipulation.     

Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair

MicroRNAs (miRNAs) coordinate vascular repair by regulating injury-induced gene expression in vascular smooth muscle cells (SMCs) and promote the transition of SMCs from a contractile to a proliferating phenotype. However, the effect of miRNA expression in SMCs on neointima formation is unclear. Therefore, we studied the role of miRNA biogenesis by Dicer in SMCs in vascular repair. Following wire-induced injury to carotid arteries of Apolipoprotein E knockout (Apoe ^?/?) mice, miRNA microarray analysis revealed that the most significantly regulated miRNAs, such as miR-222 and miR-21-3p, were upregulated. Conditional deletion of Dicer in SMCs increased neointima formation by reducing SMC proliferation in Apoe ^?/? mice, and decreased mainly the expression of miRNAs, such as miR-147 and miR-100, which were not upregulated following vascular injury. SMC-specific deletion of Dicer promoted growth factor and inflammatory signaling and regulated a miRNA–target interaction network in injured arteries that was enriched in anti-proliferative miRNAs. The most connected miRNA in this network was miR-27a-3p [e.g., with Rho guanine nucleotide exchange factor 26 (ARHGEF26)], which was expressed in medial and neointimal SMCs in a Dicer-dependent manner. In vitro, miR-27a-3p suppresses ARHGEF26 expression and inhibits SMC proliferation by interacting with a conserved binding site in the 3′ untranslated region of ARHGEF26 mRNA. We propose that Dicer expression in SMCs plays an essential role in vascular repair by generating anti-proliferative miRNAs, such as miR-27a-3p, to prevent vessel stenosis due to exaggerated neointima formation.