Spatial and temporal robustness of Sr/Ca‐SST calibrations in Red Sea corals : evidence for influence of mean annual temperature on calibration slopes

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Paleoceanography and Paleoclimatology 33 (2018): 443-456, doi:10.1029/2017PA003276.Sr/Ca ratios recorded in the aragonite skeleton of massive coral colonies are commonly used to reconstruct seasonal‐ to centennial‐scale variability in sea surface temperature (SST). While the Sr/Ca paleothermometer is robust in individual colonies, Sr/Ca‐SST relationships between colonies vary, leading to questions regarding the utility of the proxy. We present biweekly‐resolution calibrations of Sr/Ca from five Porites spp. corals to satellite SST across 10° of latitude in the Red Sea to evaluate the Sr/Ca proxy across both spatial and temporal scales. SST is significantly correlated with coral Sr/Ca at each site, accounting for 69–84% of Sr/Ca variability (P ≪ 0.01). Intercolony variability in Sr/Ca‐SST sensitivities reveals a latitudinal trend, where calibration slopes become shallower with increasing mean annual temperature. Mean annual temperature is strongly correlated with the biweekly‐resolution calibration slopes across five Red Sea sites (r2 = 0.88, P = 0.05), while also correlating significantly to Sr/Ca‐SST slopes for 33 Porites corals from across the entire Indo‐Pacific region (r2 = 0.26, P < 0.01). Although interannual summer, winter, and mean annual calibrations for individual Red Sea colonies are inconsistently robust, combined multicoral calibrations are significant at summer (r2 = 0.53, P ≪ 0.01), winter (r2 = 0.62, P ≪ 0.01), and mean annual time scales (r2 = 0.79, P ≪ 0.01). Our multicoral, multisite study indicates that the Sr/Ca paleothermometer is accurate across both temporal and spatial scales in the Red Sea and also potentially explains for the first time variability in Sr/Ca‐SST calibration slopes across the Indo‐Pacific region. Our study provides strong evidence supporting the robustness of the coral Sr/Ca proxy for examining seasonal to multicentury variability in global climate phenomena.Singapore Ministry of Education; National Research Foundation Singapore Grant Number: NRFF‐2012‐03; U.S. National Science Foundation Grant Number: OCE‐1031288; King Abdullah University of Science and Technology Grant Numbers: USA 00002, KSA 0001

Autonomous and self-sustained circadian oscillators displayed in human islet cells

Aims/hypothesis: Following on from the emerging importance of the pancreas circadian clock on islet function and the development of type 2 diabetes in rodent models, we aimed to examine circadian gene expression in human islets. The oscillator properties were assessed in intact islets as well as in beta cells. Methods: We established a system for long-term bioluminescence recording in cultured human islets, employing lentivector gene delivery of the core clock gene Bmal1 (also known as Arntl)-luciferase reporter. Beta cells were stably labelled using a rat insulin2 promoter fluorescent construct. Single-islet/cell oscillation profiles were measured by combined bioluminescence-fluorescence time-lapse microscopy. Results: Human islets synchronised in vitro exhibited self-sustained circadian oscillations of Bmal1-luciferase expression at both the population and single-islet levels, with period lengths of 23.6 and 23.9h, respectively. Endogenous BMAL1 and CRY1 transcript expression was circadian in synchronised islets over 48h, and antiphasic to REV-ERBα (also known as NR1D1), PER1, PER2, PER3 and DBP transcript circadian profiles. HNF1A and PDX1 exhibited weak circadian oscillations, in phase with the REV-ERBα transcript. Dispersed islet cells were strongly oscillating as well, at population and single-cell levels. Importantly, beta and non-beta cells revealed oscillatory profiles that were well synchronised with each other. Conclusions/interpretation: We provide for the first time compelling evidence for high-amplitude cell-autonomous circadian oscillators displayed in human pancreatic islets and in dispersed human islet cells. Moreover, these clocks are synchronised between beta and non-beta cells in primary human islet cell culture

Autonomous and self-sustained circadian oscillators displayed in human islet cells

Aims/hypothesis: Following on from the emerging importance of the pancreas circadian clock on islet function and the development of type 2 diabetes in rodent models, we aimed to examine circadian gene expression in human islets. The oscillator properties were assessed in intact islets as well as in beta cells. Methods: We established a system for long-term bioluminescence recording in cultured human islets, employing lentivector gene delivery of the core clock gene Bmal1 (also known as Arntl)-luciferase reporter. Beta cells were stably labelled using a rat insulin2 promoter fluorescent construct. Single-islet/cell oscillation profiles were measured by combined bioluminescence-fluorescence time-lapse microscopy. Results: Human islets synchronised in vitro exhibited self-sustained circadian oscillations of Bmal1-luciferase expression at both the population and single-islet levels, with period lengths of 23.6 and 23.9h, respectively. Endogenous BMAL1 and CRY1 transcript expression was circadian in synchronised islets over 48h, and antiphasic to REV-ERBα (also known as NR1D1), PER1, PER2, PER3 and DBP transcript circadian profiles. HNF1A and PDX1 exhibited weak circadian oscillations, in phase with the REV-ERBα transcript. Dispersed islet cells were strongly oscillating as well, at population and single-cell levels. Importantly, beta and non-beta cells revealed oscillatory profiles that were well synchronised with each other. Conclusions/interpretation: We provide for the first time compelling evidence for high-amplitude cell-autonomous circadian oscillators displayed in human pancreatic islets and in dispersed human islet cells. Moreover, these clocks are synchronised between beta and non-beta cells in primary human islet cell culture

The Expectation Monad in Quantum Foundations

The expectation monad is introduced abstractly via two composable adjunctions, but concretely captures measures. It turns out to sit in between known monads: on the one hand the distribution and ultrafilter monad, and on the other hand the continuation monad. This expectation monad is used in two probabilistic analogues of fundamental results of Manes and Gelfand for the ultrafilter monad: algebras of the expectation monad are convex compact Hausdorff spaces, and are dually equivalent to so-called Banach effect algebras. These structures capture states and effects in quantum foundations, and also the duality between them. Moreover, the approach leads to a new re-formulation of Gleason's theorem, expressing that effects on a Hilbert space are free effect modules on projections, obtained via tensoring with the unit interval.Comment: In Proceedings QPL 2011, arXiv:1210.029

ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling.

Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents

A Formal Proof of PAC Learnability for Decision Stumps

We present a formal proof in Lean of probably approximately correct (PAC) learnability of the concept class of decision stumps. This classic result in machine learning theory derives a bound on error probabilities for a simple type of classifier. Though such a proof appears simple on paper, analytic and measure-theoretic subtleties arise when carrying it out fully formally. Our proof is structured so as to separate reasoning about deterministic properties of a learning function from proofs of measurability and analysis of probabilities.Comment: 13 pages, appeared in Certified Programs and Proofs (CPP) 202

The Sheaf-Theoretic Structure Of Non-Locality and Contextuality

We use the mathematical language of sheaf theory to give a unified treatment of non-locality and contextuality, in a setting which generalizes the familiar probability tables used in non-locality theory to arbitrary measurement covers; this includes Kochen-Specker configurations and more. We show that contextuality, and non-locality as a special case, correspond exactly to obstructions to the existence of global sections. We describe a linear algebraic approach to computing these obstructions, which allows a systematic treatment of arguments for non-locality and contextuality. We distinguish a proper hierarchy of strengths of no-go theorems, and show that three leading examples --- due to Bell, Hardy, and Greenberger, Horne and Zeilinger, respectively --- occupy successively higher levels of this hierarchy. A general correspondence is shown between the existence of local hidden-variable realizations using negative probabilities, and no-signalling; this is based on a result showing that the linear subspaces generated by the non-contextual and no-signalling models, over an arbitrary measurement cover, coincide. Maximal non-locality is generalized to maximal contextuality, and characterized in purely qualitative terms, as the non-existence of global sections in the support. A general setting is developed for Kochen-Specker type results, as generic, model-independent proofs of maximal contextuality, and a new combinatorial condition is given, which generalizes the `parity proofs' commonly found in the literature. We also show how our abstract setting can be represented in quantum mechanics. This leads to a strengthening of the usual no-signalling theorem, which shows that quantum mechanics obeys no-signalling for arbitrary families of commuting observables, not just those represented on different factors of a tensor product.Comment: 33 pages. Extensively revised, new results included. Published in New Journal of Physic

Categorial Compositionality: A Category Theory Explanation for the Systematicity of Human Cognition

Classical and Connectionist theories of cognitive architecture seek to explain systematicity (i.e., the property of human cognition whereby cognitive capacity comes in groups of related behaviours) as a consequence of syntactically and functionally compositional representations, respectively. However, both theories depend on ad hoc assumptions to exclude specific instances of these forms of compositionality (e.g. grammars, networks) that do not account for systematicity. By analogy with the Ptolemaic (i.e. geocentric) theory of planetary motion, although either theory can be made to be consistent with the data, both nonetheless fail to fully explain it. Category theory, a branch of mathematics, provides an alternative explanation based on the formal concept of adjunction, which relates a pair of structure-preserving maps, called functors. A functor generalizes the notion of a map between representational states to include a map between state transformations (or processes). In a formal sense, systematicity is a necessary consequence of a higher-order theory of cognitive architecture, in contrast to the first-order theories derived from Classicism or Connectionism. Category theory offers a re-conceptualization for cognitive science, analogous to the one that Copernicus provided for astronomy, where representational states are no longer the center of the cognitive universe—replaced by the relationships between the maps that transform them

Isolation and Characterization of New Leptospira Genotypes from Patients in Mayotte (Indian Ocean)

Leptospirosis has been recognized as an increasing public health problem affecting poor people from developing countries and tropical regions. However, the epidemiology of leptospirosis remains poorly understood in remote parts of the world. In this study of patients from the island of Mayotte, we isolated 22 strains from the blood of patients during the acute phase of illness. The pathogenic Leptospira strains were characterized by serology and various molecular typing methods. Based on serological data, serogroup Mini appears to be the dominant cause of leptospirosis in Mayotte. Further molecular characterization of these isolates allowed the identification of 10 pathogenic Leptospira genotypes that could correspond to previously unknown serovars. Further progress in our understanding of the epidemiology of Leptospira circulating genotypes in highly endemic regions should contribute to the development of novel strategies for the diagnosis and prevention of this neglected emerging disease

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer