Anticipating the species jump: surveillance for emerging viral threats.

Zoonotic disease surveillance is typically triggered after animal pathogens have already infected humans. Are there ways to identify high-risk viruses before they emerge in humans? If so, then how and where can identifications be made and by what methods? These were the fundamental questions driving a workshop to examine the future of predictive surveillance for viruses that might jump from animals to infect humans. Virologists, ecologists and computational biologists from academia, federal government and non-governmental organizations discussed opportunities as well as obstacles to the prediction of species jumps using genetic and ecological data from viruses and their hosts, vectors and reservoirs. This workshop marked an important first step towards envisioning both scientific and organizational frameworks for this future capability. Canine parvoviruses as well as seasonal H3N2 and pandemic H1N1 influenza viruses are discussed as exemplars that suggest what to look for in anticipating species jumps. To answer the question of where to look, prospects for discovering emerging viruses among wildlife, bats, rodents, arthropod vectors and occupationally exposed humans are discussed. Finally, opportunities and obstacles are identified and accompanied by suggestions for how to look for species jumps. Taken together, these findings constitute the beginnings of a conceptual framework for achieving a virus surveillance capability that could predict future species jumps

Talking it through: using specialist coaching to enhance teachers’ knowledge from speech and language sciences

Teachers’ knowledge for effective pedagogies can be enhanced by drawing on a range of specific expertise held by those working in other disciplines or professions. In this article, we explore this potential through a focus on enhancing research-informed communication rich pedagogies in primary and early years’ settings. The specific example is that of speech and language therapists using video-based coaching with teachers. Our research provides case study evidence and demonstrates that this professional development approach brings speech and language therapy research and expertise into the practice domain of teachers. This is a dynamic, reciprocal and co-constructive relationship between the participants. The focus on this paper is on how it can enable teachers to extend their understanding and develop a more nuanced understanding of specialist evidence of speech, language and communication for, and in, practice

Large entropy production inside black holes: a simple model

Particles dropped into a rotating black hole can collide near the inner horizon with enormous energies. The entropy produced by these collisions can be several times larger than the increase in the horizon entropy due to the addition of the particles. In this paper entropy is produced by releasing large numbers of neutrons near the outer horizon of a rotating black hole such that they collide near the inner horizon at energies similar to those achieved at the Relativistic Heavy Ion Collider. The increase in horizon entropy is approximately 80 per dropped neutron pair, while the entropy produced in the collisions is 160 per neutron pair. The collision entropy is produced inside the horizon, so this excess entropy production does not violate Bousso's bound limiting the entropy that can go through the black hole's horizon. The generalized laws of black hole thermodynamics are obeyed. No individual observer inside the black hole sees a violation of the second law of thermodynamicsComment: 10 page

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

This is the final version. Available from Springer via the DOI in this record. Data availability: This review did not generate any new data.In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.Wellcome TrustNational Institute of Health Research (NIHR)Royal Societ

Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth

This is the final version. Available on open access from the American Society for Clinical Investigation via the DOI in this recordWellcome TrustDiabetes UKNational Institute for Health and Care Research (NIHR

Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling

Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1

Conformally rescaled spacetimes and Hawking radiation

We study various derivations of Hawking radiation in conformally rescaled metrics. We focus on two important properties, the location of the horizon under a conformal transformation and its associated temperature. We find that the production of Hawking radiation cannot be associated in all cases to the trapping horizon because its location is not invariant under a conformal transformation. We also find evidence that the temperature of the Hawking radiation should transform simply under a conformal transformation, being invariant for asymptotic observers in the limit that the conformal transformation factor is unity at their location.Comment: 22 pages, version submitted to journa

The holographic principle

There is strong evidence that the area of any surface limits the information content of adjacent spacetime regions, at 10^(69) bits per square meter. We review the developments that have led to the recognition of this entropy bound, placing special emphasis on the quantum properties of black holes. The construction of light-sheets, which associate relevant spacetime regions to any given surface, is discussed in detail. We explain how the bound is tested and demonstrate its validity in a wide range of examples. A universal relation between geometry and information is thus uncovered. It has yet to be explained. The holographic principle asserts that its origin must lie in the number of fundamental degrees of freedom involved in a unified description of spacetime and matter. It must be manifest in an underlying quantum theory of gravity. We survey some successes and challenges in implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2: reference adde

Acute Chloroform Ingestion Successfully Treated with Intravenously Administered N-acetylcysteine

Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases

Consequentialism and Virtue

We examine the following consequentialist view of virtue: a trait is a virtue if and only if it has good consequences in some relevant way. We highlight some motivations for this basic account, and offer twelve choice points for filling it out. Next, we explicate Julia Driver’s consequentialist view of virtue in reference to these choice points, and we canvass its merits and demerits. Subsequently, we consider three suggestions that aim to increase the plausibility of her position, and critically analyze them. We conclude that one of those proposed revisions would improve her account. NOTE: I will self-archive the paper after the 24 month embargo period ends. If you want a copy, just email me