Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells

Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.

Vector summed sine wave tailored waveforms for dipolar excitation of ions in Paul trap mass spectrometers

A simple method to generate time domain tailored waveforms for excitation of ion axial amplitude in Paul trap mass spectrometers is described. The method is based on vector summation of sine waves followed by time domain sampling to obtain the discrete time domain data. A smoothing technique based on the time domain Kaiser window is then applied to the data so as to minimize the frequency domain Gibb's oscillations. The dynamic range of the time domain signal is controlled by phase modulation and time extension of the time domain waveform. Copyright (C) 1999 John Wiley & Sons, Ltd.

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve `health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.

Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication

Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication(1,2). To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data(3). Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.

?The Lord did give me a particular honour to make [me] a peacemaker? : Howel Harris, John Wesley and Methodist infighting, 1739-1750

Jones, David, '?The Lord did give me a particular honour to make [me] a peacemaker?: Howel Harris, John Wesley and Methodist infighting, 1739-1750', Bulletin of the John Rylands, University Library of Manchester (2003) 85(2-3) pp.73-88 RAE2008

Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.

Paul Karl Feyerabend Las proyecciones de la proliferación teórica en la relación ciencia-metafísica

La doctrina de la Proliferación teórica de Paul Karl Feyerabend ha sido interpretada por sus especialistas como un intento de salvaguardar el ideal del progreso científico. Aunque tales estudios hacen justicia, en parte, a la intencionalidad de nuestro filósofo no explicitan la crítica fundamental que implica para Feyerabend el pluralismo teórico. La proliferación teórica constituye en sí misma una reductio ad absurdum de los distintos intentos del positivismo lógico y del racionalismo crítico por definir la ciencia a expensas de lo metafísico. Este artículo presenta la proliferación teórica como una reivindicación del papel positivo que ocupa la metafísica en el quehacer científico. Se consigna la defensa que hace Feyerabend de la metafísica en cuanto que ésta constituye la posibilidad de superar el conservadurismo conceptual, aumentar de contenido empírico de la ciencia y recuperar el valor descriptivo de las teorías científicas.

No Evidence that Extended Tracts of Homozygosity are Associated with Alzheimer’s Disease.

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.

Epistolarum Familiarium Liber Unus in The Complete Works of John Milton: Volume XI (672pp.)

This edition of Milton’s Epistolarum Familiarium Liber Unus and of his Uncollected Letters, will appear as 672 pp. of The Complete Works of John Milton Volume XI, eds. Gordon Campbell and Edward Jones (Oxford University Press, forthcoming 2016). A diplomatic Latin text and a new facing English translation are complemented by a detailed Introduction and commentary that situate Milton’s Latin letters in relation to the classical, pedagogical and essentially humanist contexts at the heart of their composition. Now the art of epistolography advocated and exemplified by Cicero and Quintilian and embraced by Renaissance pedagogical manuals is read through a humanist filter whereby, via the precedent (and very title) of Epistolae Familiares, the Miltonic Liber is shown to engage with a neo-Latin re-invention of the classical epistola that had come to birth in quattrocento Italy in the letters of Petrarch and his contemporaries. At the same time the Epistolae are seen as offering fresh insight into Milton’s views on education, philology, his relations with Italian literati, his blindness, the poetic dimension of his Latin prose, and especially his verbal ingenuity as the ‘words’ of Latin ‘Letters’ become a self-conscious showcasing of etymological punning on the ‘letters’ of Latin ‘words’. The edition also announces several new discoveries, most notably its uncovering and collation of a manuscript of Henry Oldenburg’s transcription (in his Liber Epistolaris held in Royal Society, London) of Milton’s Ep. Fam. 25 (to Richard Jones). Oldenburg’s transcription (from the original sent to his pupil Jones) is an important find, given the loss of all but two of the manuscripts of Milton’s original Latin letters included in the 1674 volume. The edition also presents new evidence in regard to Milton’s relationships with the Italian philologist Benedetto Buonmattei, the Greek humanist Leonard Philaras, the radical pastor Jean Labadie (and the French church of London), and the elusive Peter Heimbach.