With mouse age comes wisdom : a review and suggestions of relevant mouse models for age-related conditions

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models

KORČULA IN INTERNATIONAL AND HOME RELATIONS

The ancient Dalmatian autonomous communes, Korčula included, excel the usual average development in a number of ways. While the commune of Korčula included the whole island, the city lies in its extreme north-eastern strategical part. Important pre-historical finds, discovered in the Vela Splilja cave in the vicinity of Vela Luka, remind those found on the Hvar Island. The first author to mention Korčula was an ancient Greek one, the 4th century B. C. writer Pseudo-Skalax, who called the island Kerkyra mèlaina. There is a variant form i. e. Korkyra mèlaina, Latin Corcyra nigra, or only Korkyra or Corcyra, respectively. According to ancient authors, the city was founded by Cnidans. A grecian inscription, telling about the colonisation by Grecian settlers, and the foundation of the city, found near Lumbarda, is one of the most important. A Roman inscription refers to the temple of the deity Venera Pelagia. Reliable information about the present city go back to the mid-10th century A. D. Significant finds, dating from the early middle ages, were discovered on the Majsan Islet situated to the east of the city. The city statute, dating from 1265 (the oldest in Dalmatia) has been preserved. Its institutions concerning the salvage of shipwrecked vessels, with their 15th century modifications, are progressive ones. One of the first agrarian reforms in this country took place during the period from 1409 to 1411. The 15th century regulations concerning the construction of the city were also very progressive. The building of ships and quarrying of stone reached an extraordinary development. The latter was crowned by construction of buildings and artistic stone-cutting. The quarried stone was also copiously exported. The planning of the city was a regular, semielliptical one. Owing to its strategical position, the city and its environs were the scene of a series of battles: in the years 1000, 1298, 1354, 1409, 1483, and 1571. The Russians and the French collided there in the Napoleonic time. The city has seen several sieges and blockades. The English held Korčula from 1813 to 1815 and left two monuments there. In addition to excellent buildings, among which belongs the Cathedral, Korčula boasts other monuments, such as two 15th century polyptychs painted by Blaž of Trogir, Byzantine ikons, the altar canvas by Tintoretto, some paintings by Tripun Kokolja, a silver cross by the 15th century Dubrovnik master Progonović, a painted crucifix from the same century by George Petrović (now in the church of the Franciscan monastery at Orebić), and 16th century sculptures cut in wood by Frano Čučić from Korčula. A 12th century Korčulan anthology contains information from the times of the Croatian national dynasty. The beginnings of literature in the Croatian language can be traced as far back as the 14th century, but the poets of importance appear from the 16th century on: Ivan Vidali, Petar Kanavelić, and Augustin Draginić being the most notable among them. Their work is permeated by the Croatian and Slavic patriotism. The Croatian national life in Korčula has showed itself in various ways, such as through folk-songs, warrior dances with swords in the villages (»Kumpanija«) and in the city (»Moreška«) with dialogues in the Croatian language. The »Moreška« dance has a cosmopolitan character. A number of famous men were born on the island. Some of them became famous abroad. The sculptor Frane Kršinić from Lumbarda is worthly of mentioning among those living at present. Korčula’s past, particularly its values in the fields of culture and art have been scientifically extolled by Cvito Fisković, the person celebrated by us to-day

No observational constraints from hypothetical collisions of hypothetical dark halo primordial black holes with galactic objects

It was suggested by several authors that hypothetical primordial black holes (PBHs) may contribute to the dark matter in our Galaxy. There are strong constraints based on the Hawking evaporation that practically exclude PBHs with masses m~1e15-1e16g and smaller as significant contributors to the Galactic dark matter. Similarly, PBHs with masses greater than about 1e26g are practically excluded by the gravitational lensing observation. The mass range between 10e16g<m<10e26g is unconstrained. In this paper, we examine possible observational signatures in the unexplored mass range, investigating hypothetical collisions of PBHs with main sequence stars, red giants, white dwarfs, and neutron stars in our Galaxy. This has previously been discussed as possibly leading to an observable photon eruption due to shock production during the encounter. We find that such collisions are either too rare to be observed (if the PBH masses are typically larger than about 1e20g), or produce too little power to be detected (if the masses are smaller than about 1e20g).Comment: Accepted for publication in The Astrophysical Journa

The PANDA GEM-based TPC Prototype

We report on the development of a GEM-based TPC prototype for the PANDA experiment. The design and requirements of this device will be illustrated, with particular emphasis on the properties of the recently tested GEM-detector, the characterization of the read-out electronics and the development of the tracking software that allows to evaluate the GEM-TPC data.Comment: submitted to NIMA 4 pages, 6 picture

Bayes and health care research.

Bayes’ rule shows how one might rationally change one’s beliefs in the light of evidence. It is the foundation of a statistical method called Bayesianism. In health care research, Bayesianism has its advocates but the dominant statistical method is frequentism. There are at least two important philosophical differences between these methods. First, Bayesianism takes a subjectivist view of probability (i.e. that probability scores are statements of subjective belief, not objective fact) whilst frequentism takes an objectivist view. Second, Bayesianism is explicitly inductive (i.e. it shows how we may induce views about the world based on partial data from it) whereas frequentism is at least compatible with non-inductive views of scientific method, particularly the critical realism of Popper. Popper and others detail significant problems with induction. Frequentism’s apparent ability to avoid these, plus its ability to give a seemingly more scientific and objective take on probability, lies behind its philosophical appeal to health care researchers. However, there are also significant problems with frequentism, particularly its inability to assign probability scores to single events. Popper thus proposed an alternative objectivist view of probability, called propensity theory, which he allies to a theory of corroboration; but this too has significant problems, in particular, it may not successfully avoid induction. If this is so then Bayesianism might be philosophically the strongest of the statistical approaches. The article sets out a number of its philosophical and methodological attractions. Finally, it outlines a way in which critical realism and Bayesianism might work together. </p

Comparison of phenotypic and genotypic tropism determination in triple-class-experienced HIV patients eligible for maraviroc treatment

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the correlation with phenotypic tropism tests (PTTs) in patients accessing routine HIV care. METHODS: Forty-nine consecutive plasma samples for which an original Trofile(TM) assay was performed were obtained from triple-class-experienced patients in need of a therapy change. Viral tropism was defined as the consensus of three or more tropism calls obtained from the combination of two independent population PTT assays (Trofile Biosciences, San Francisco, CA, USA, and Virco, Beerse, Belgium), population GTTs and GTTs based on ultra-deep sequencing. If no consensus was reached, a clonal PTT was performed in order to finalize the tropism call. This two-step approach allowed the definition of a reference tropism call. RESULTS: According to the reference tropism result, 35/49 samples were CCR5 tropic (R5) (patients eligible for maraviroc treatment) and 14/49 were assigned as non-R5 tropic. The non-R5 samples [patients not eligible for maraviroc treatment according to the FDA/European Medicines Agency (EMEA) label] group included both the CXCR4 (X4) samples and the dual and mixed CCR5/CXCR4 (R5/X4) samples. Compared with Trofile(TM) population PTTs, population GTTs showed a higher sensitivity (97%) and a higher negative predictive value (91%), but almost equal specificity and an equal positive predictive value. CONCLUSIONS: In line with recent reports from clinical trial data, our data support the use of population genotypic tropism testing as a tool for tropism determination before the start of maraviroc

Development of a SiPM Camera for a Schwarzschild-Couder Cherenkov Telescope for the Cherenkov Telescope Array

We present the development of a novel 11328 pixel silicon photomultiplier (SiPM) camera for use with a ground-based Cherenkov telescope with Schwarzschild-Couder optics as a possible medium-sized telescope for the Cherenkov Telescope Array (CTA). The finely pixelated camera samples air-shower images with more than twice the optical resolution of cameras that are used in current Cherenkov telescopes. Advantages of the higher resolution will be a better event reconstruction yielding improved background suppression and angular resolution of the reconstructed gamma-ray events, which is crucial in morphology studies of, for example, Galactic particle accelerators and the search for gamma-ray halos around extragalactic sources. Packing such a large number of pixels into an area of only half a square meter and having a fast readout directly attached to the back of the sensors is a challenging task. For the prototype camera development, SiPMs from Hamamatsu with through silicon via (TSV) technology are used. We give a status report of the camera design and highlight a number of technological advancements that made this development possible.Comment: 8 pages, 5 figures, In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

Metal-induced malformations in early Palaeozoic plankton are harbingers of mass extinction

Glacial episodes have been linked to Ordovician–Silurian extinction events, but cooling itself may not be solely responsible for these extinctions. Teratological (malformed) assemblages of fossil plankton that correlate precisely with the extinction events can help identify alternate drivers of extinction. Here we show that metal poisoning may have caused these aberrant morphologies during a late Silurian (Pridoli) event. Malformations coincide with a dramatic increase of metals (Fe, Mo, Pb, Mn and As) in the fossils and their host rocks. Metallic toxins are known to cause a teratological response in modern organisms, which is now routinely used as a proxy to assess oceanic metal contamination. Similarly, our study identifies metal-induced teratology as a deep-time, palaeobiological monitor of palaeo-ocean chemistry. The redox-sensitive character of enriched metals supports emerging ‘oceanic anoxic event’ models. Our data suggest that spreading anoxia and redox cycling of harmful metals was a contributing kill mechanism during these devastating Ordovician–Silurian palaeobiological events