A formal proof of the Kepler conjecture

This article describes a formal proof of the Kepler conjecture on dense sphere packings in a combination of the HOL Light and Isabelle proof assistants. This paper constitutes the official published account of the now completed Flyspeck project

Selective targeting of microglia by quantum dots

<p>Abstract</p> <p>Background</p> <p>Microglia, the resident immune cells of the brain, have been implicated in brain injury and various neurological disorders. However, their precise roles in different pathophysiological situations remain enigmatic and may range from detrimental to protective. Targeting the delivery of biologically active compounds to microglia could help elucidate these roles and facilitate the therapeutic modulation of microglial functions in neurological diseases.</p> <p>Methods</p> <p>Here we employ primary cell cultures and stereotaxic injections into mouse brain to investigate the cell type specific localization of semiconductor quantum dots (QDs) in vitro and in vivo. Two potential receptors for QDs are identified using pharmacological inhibitors and neutralizing antibodies.</p> <p>Results</p> <p>In mixed primary cortical cultures, QDs were selectively taken up by microglia; this uptake was decreased by inhibitors of clathrin-dependent endocytosis, implicating the endosomal pathway as the major route of entry for QDs into microglia. Furthermore, inhibiting mannose receptors and macrophage scavenger receptors blocked the uptake of QDs by microglia, indicating that QD uptake occurs through microglia-specific receptor endocytosis. When injected into the brain, QDs were taken up primarily by microglia and with high efficiency. In primary cortical cultures, QDs conjugated to the toxin saporin depleted microglia in mixed primary cortical cultures, protecting neurons in these cultures against amyloid beta-induced neurotoxicity.</p> <p>Conclusions</p> <p>These findings demonstrate that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in brain and may allow for the selective delivery of therapeutic agents to these cells.</p

Direction-Selective Circuitry in Rat Retina Develops Independently of GABAergic, Cholinergic and Action Potential Activity

The ON-OFF direction selective ganglion cells (DSGCs) in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience

Enterovirus D68 in Viet Nam (2009-2015)

Background: Since 1962, enterovirus D68 (EV-D68) has been implicated in multiple outbreaks and sporadic cases of respiratory infection worldwide, especially in the USA and Europe with an increasing frequency between 2010 and 2014. We describe the detection, associated clinical features and molecular characterization of EV-D68 in central and southern Viet Nam between 2009 and 2015. Methods: Enterovirus/rhinovirus PCR positive respiratory or CSF samples taken from children and adults with respiratory/central nervous system infections in Viet Nam were tested by an EV-D68 specific PCR. The included samples were derived from 3 different observational studies conducted at referral hospitals across central and southern Viet Nam 2009 2015. Whole-genome sequencing was carried out using a MiSeq based approach. Phylogenetic reconstruction and estimation of evolutionary rate and recombination were carried out in BEAST and Recombination Detection Program, respectively. Results: EV-D68 was detected in 21/625 (3.4%) enterovirus/rhinovirus PCR positive respiratory samples but in none of the 15 CSF. All the EV-D68 patients were young children (age range: 11.8 – 24.5 months) and had moderate respiratory infections. Phylogenetic analysis suggested that the Vietnamese sequences clustered with those from Asian countries, of which 9 fell in the B1 clade, and the remaining sequence was identified within the A2 clade. One intra sub-clade recombination event was detected, representing the second reported recombination within EV-D68. The evolutionary rate of EV-D68 was estimated to be 5.12E -3 substitutions/site/year. Phylogenetic analysis indicated that the virus was imported into Viet Nam in 2008. Conclusions: We have demonstrated for the first time EV-D68 has been circulating at low levels in Viet Nam since 2008, associated with moderate acute respiratory infection in children. EV-D68 in Viet Nam is most closely related to Asian viruses, and clusters separately from recent US and European viruses that were suggested to be associated with acute flaccid paralysis

Adaptation of pineal expressed teleost exo-rod opsin to non-image forming photoreception through enhanced Meta II decay

Photoreception by vertebrates enables both image-forming vision and non-image-forming responses such as circadian photoentrainment. Over the recent years, distinct non-rod non-cone photopigments have been found to support circadian photoreception in diverse species. By allowing specialization to this sensory task a selective advantage is implied, but the nature of that specialization remains elusive. We have used the presence of distinct rod opsin genes specialized to either image-forming (retinal rod opsin) or non-image-forming (pineal exo-rod opsin) photoreception in ray-finned fish (Actinopterygii) to gain a unique insight into this problem. A comparison of biochemical features for these paralogous opsins in two model teleosts, Fugu pufferfish (Takifugu rubripes) and zebrafish (Danio rerio), reveals striking differences. While spectral sensitivity is largely unaltered by specialization to the pineal environment, in other aspects exo-rod opsins exhibit a behavior that is quite distinct from the cardinal features of the rod opsin family. While they display a similar thermal stability, they show a greater than tenfold reduction in the lifetime of the signaling active Meta II photoproduct. We show that these features reflect structural changes in retinal association domains of helices 3 and 5 but, interestingly, not at either of the two residues known to define these characteristics in cone opsins. Our findings suggest that the requirements of non-image-forming photoreception have lead exo-rod opsin to adopt a characteristic that seemingly favors efficient bleach recovery but not at the expense of absolute sensitivity

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Vegetarianism, bone loss, fracture and vitamin D: A longitudinal study in Asian vegans and non-vegans

Background/Objectives:The effect of vegan diet on bone loss has not been studied. The aim of this study was to examine the association between veganism and bone loss in postmenopausal women.Subjects/Methods:The study was designed as a prospective longitudinal investigation with 210 women, including 105 vegans and 105 omnivores. Femoral neck (FN) bone mineral density (BMD) was measured in 2008 and 2010 by dual-energy X-ray absorptiometry (Hologic QDR4500). The incidence of vertebral fracture was ascertained by X-ray report. Serum levels of C-terminal telopeptide of type I collagen (ΒCTX) and N-terminal propeptide of type I procollagen (PINP) were measured by Roche Elecsys assays. Serum concentration of 25-hydroxyvitamin D and parathyroid hormone were measured by electrochemiluminescence.Results:Among the 210 women who initially participated in the study in 2008, 181 women had completed the study and 29 women were lost to follow-up. The rate of loss in FN BMD was -1.91±3.45%/year in omnivores and -0.86±3.81%/year (P=0.08) in vegans. Lower body weight, higher intakes of animal protein and lipid, and corticosteroid use were associated with greater rate of bone loss. The 2-year incidence of fracture was 5.7% (n5/88) in vegans, which was not significantly different from omnivores (5.4%, n6/93). There were no significant differences in ΒCTX and PINP between vegans and omnivores. The prevalence of vitamin D insufficiency in vegans was higher than in omnivores (73% versus 46%; P=0.0003).Conclusions:Vegan diet did not have adverse effect on bone loss and fracture. Corticosteroid use and high intakes of animal protein and animal lipid were negatively associated with bone loss. © 2012 Macmillan Publishers Limited All rights reserved