Cone pigments in a North American marsupial, the opossum (Didelphis virginiana)

Only two of the four cone opsin gene families found in vertebrates are represented in contemporary eutherian and marsupial species. Recent genetic studies of two species of South American marsupial detected the presence of representatives from two of the classes of cone opsin genes and the structures of these genes predicted cone pigments with respective peaks in the ultraviolet and long-wavelength portions of the spectrum. The Virginia opossum (Didelphis virginiana), a profoundly nocturnal animal, is the only marsupial species found in North America. The prospects for cone-based vision in this species were examined through recordings of the electroretinogram (ERG), a commonly examined retinal response to photic stimulation. Recorded under flickering-light conditions that elicit signals from cone photoreceptors, the spectral sensitivity of the opossum eye is well accounted for by contributions from the presence of a single cone pigment having peak absorption at 561–562 nm. A series of additional experiments that employed various chromatic adaptation paradigms were conducted in a search for possible contributions from a second (short-wavelength sensitive) cone pigment. We found no evidence that such a mechanism contributes to the ERG in this marsupial

Persistence of contrasting traditions in cultural evolution: Unpredictable payoffs generate slower rates of cultural change

We report an experimental test of the hypothesis that contrasting traditions will persist for longer, maintaining cultural differences between otherwise similar groups, under conditions of uncertainty about payoffs from individual learning. We studied the persistence of two alternative, experimentally-introduced, task solutions in chains of human participants. In some chains, participants were led to believe that final payoffs would be difficult to predict for an innovative solution, and in others, participants were aware that their final payoff would be directly linked to their immediate solution. Although the difference between the conditions was illusory (only participants' impressions were manipulated, not actual payoffs) clear differences were found between the conditions. Consistent with predictions, in the chains that were less certain about final payoffs, the distinctive variants endured over several replacement "generations" of participants. In contrast, in the other chains, the influence of the experimentally-introduced solutions was rapidly diluted by participants' exploration of alternative approaches. The finding provides support for the notion that rates of cultural change are likely to be slower for behaviors for which the relationship between performance and payoff may be hard to predict

Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype

The type II PI 4-kinases enzymes synthesise the lipid phosphatidylinositol 4-phosphate (PI(4)P) which has been detected at the Golgi complex and endosomal compartments, and which recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear.We found that depletion of PI4KIIα and PI4KIIβ using siRNA led to actin remodelling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP).Depletion of PI4KII isoforms also differentially affected TGN pools of PI(4)P and post-TGN traffic. PI4KIIβ depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalisation of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7, but increased localisation with the exocytic Rab8. Depletion of PI4KIIβ was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIβ mRNA is associated with human cancers. This finding supports the cell data and suggests that PI4KIIβ may be a clinically significant suppressor of invasion. We propose that PI4KIIβ synthesises a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia

Ethnic differences in diabetes, cardiovascular risk factors and health care: the Amsterdam Health Survey of 2004

The prevalence of diabetes in inhabitants of Amsterdam (18 years and older) is 4%. The prevalence of diabetes is three times higher among Turkish people and four times higher among Moroccans in comparison to Dutch people. Turkish diabetes patients have a higher mean body mass index compared to Dutch diabetes patients, but Turkish and Moroccan diabetes patients are admitted to hospital less often than Dutch diabetes patients. It is important for policy makers to know the differences in disease prevalence and health care use between ethnic groups, considering the expected rise in the proportion of immigrants. These results formed contributions to this report that was brought out by the National Institute for Public Health and the Environment and in cooperation with the Amsterdam Health Monitor of the Amsterdam Health Service. Forty-three percent of the 4042 invited Amsterdam inhabitants participated in the study in 2004. Ethnic differences in health and health care use were analyzed for the age group of 18-70 years, standardized for age and gender. Turkish and Moroccan people without diabetes differed from Dutch people without diabetes on many counts. For example, Turkish and Moroccan people were more often overweight and had higher mean blood glucose levels. They visited their general practitioners more often and experienced their own health as being moderate or poor on a more frequent basis. Turkish people without diabetes experienced more serious cardiac problems than Dutch people. The prevalence of cardiovascular risk factors in diabetes patients was high among all ethnic groups. In general, cardiovascular risk factors were more frequent in Turkish diabetes patients, and to a lesser extent in Moroccan diabetes patients, compared to Dutch diabetes patients. Treatment of cardiovascular risk factors in diabetes patients is important for the prevention of or delay in cardiovascular complications.De prevalentie van diabetes bij inwoners van Amsterdam (18 jaar en ouder) wordt geschat op vier procent. Turken en Marokkanen hebben respectievelijk driemaal en viermaal vaker diabetes vergeleken met Nederlanders. Turkse diabeten zijn gemiddeld zwaarder dan Nederlandse diabeten. Turkse en Marokkaanse diabeten worden echter minder vaak opgenomen in een ziekenhuis dan Nederlandse diabeten. Een beschrijving van etniciteitverschillen in het voorkomen van ziekten en zorggebruik is van belang voor het beleid omdat immigranten een steeds groter deel van de bevolking zullen gaan uitmaken. De Amsterdamse Gezondheidsmonitor 2004 is uitgevoerd door de GGD Amsterdam in samenwerking met het RIVM. Drieenveertig procent van 4042 uitgenodigde Amsterdammers (18 jaar en ouder) heeft aan het onderzoek meegedaan. Etnische verschillen in gezondheid en zorg werden geanalyseerd voor de leeftijd 18-70 jaar, gestandaardiseerd naar leeftijd en geslacht. Turken en Marokkanen zonder diabetes verschilden op bijna alle uitkomsten van Nederlanders zonder diabetes. Turken en Marokkanen waren bijvoorbeeld gemiddeld zwaarder dan Nederlanders en zij hadden hogere gemiddelde bloedglucosewaarden. Zij gingen vaker naar de huisarts en waren minder tevreden over de eigen gezondheid. Acht procent van de Turken zonder diabetes heeft ooit een ernstige hartaandoening gehad, dit is bijna viermaal zo vaak als bij Nederlanders zonder diabetes. Risicofactoren voor hart- en vaatziekten kwamen veel voor bij diabeten uit alle etnische groepen. Turkse diabeten, en in mindere mate Marokkaanse diabeten, hadden over het algemeen een ongunstiger risicoprofiel dan Nederlandse diabeten. Behandeling van het risicoprofiel van diabetespatienten is belangrijk om het optreden van complicaties te voorkomen of uit te stellen

Differences in the distribution of stroke subtypes in a UK black stroke population - final results from the South London Ethnicity and Stroke Study.

BACKGROUND: Stroke incidence is increased in Black individuals but the reasons for this are poorly understood. Exploring the differences in aetiological stroke subtypes, and the extent to which they are explained by conventional and novel risk factors, is an important step in elucidating the underlying mechanisms for this increased stroke risk. METHODS: Between 1999 and 2010, 1200 black and 1200 white stroke patients were prospectively recruited from a contiguous geographical area in South London in the UK. The Trial of Org 10172 (TOAST) classification was used to classify stroke subtype. Age- and sex-adjusted comparisons of socio-demographics, traditional vascular risk factors and stroke subtypes were performed between black and white stroke patients and between Black Caribbean and Black African stroke patients using age-, sex-, and social deprivation-adjusted univariable and multivariable logistic regression analyses. RESULTS: Black stroke patients were younger than white stroke patients (mean (SD) 65.1 (13.7) vs. 74.8 (13.7) years). There were significant differences in the distribution of stroke subtypes. Small vessel disease stroke was increased in black patients versus white patients (27 % vs. 12 %; OR, 2.74; 95 % CI, 2.19-3.44), whereas large vessel and cardioembolic stroke was less frequent in black patients (OR, 0.59; 95 % CI, 0.45-0.78 and OR, 0.61; 95 % CI, 0.50-0.74, respectively). These associations remained after controlling for traditional vascular risk factors and socio-demographics. Black Caribbean patients appeared to have an intermediate risk factor and stroke subtype profile between that found in Black African and white stroke patients. Cardioembolic stroke was more strongly associated with Black Caribbean ethnicity versus Black African ethnicity (OR, 1.48; 95 % CI, 1.04-2.10), whereas intracranial large vessel disease was less frequent in Black Caribbean patients versus Black African subjects (OR, 0.44; 95 % CI, 0.24-0.83). CONCLUSIONS: Clear differences exist in stroke subtype distribution between black and white stroke patients, with a marked increase in small vessel stroke. These could not be explained by differences in the assessed traditional risk factors. Possible explanations for these differences might include variations in genetic susceptibility, differing rates of control of vascular risk factors, or as yet undetermined environmental risk factors.This work was supported by a Stroke Association (UK) Programme Grant (PROG 3) (www.stroke.org.uk) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London (http://www.guysandstthomasbrc.nihr.ac.uk). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Loes Rutten-Jacobs was supported by a British Heart Foundation Immediate Research Fellowship (FS/15/61/31626) (www.bhf.org.uk). Hugh Markus is supported by an NIHR Senior Investigator award (www.nihr.ac.uk) and his work is supported by the NIHR Cambridge University Hospital Trusts Comprehensive BRC (www.cambridge-brc.org.uk)

Single-Molecule Super-Resolution Imaging of T-Cell Plasma Membrane CD4 Redistribution upon HIV-1 Binding

The first step of cellular entry for the human immunodeficiency virus type-1 (HIV-1) occurs through the binding of its envelope protein (Env) with the plasma membrane receptor CD4 and co-receptor CCR5 or CXCR4 on susceptible cells, primarily CD4+ T cells and macrophages. Although there is considerable knowledge of the molecular interactions between Env and host cell receptors that lead to successful fusion, the precise way in which HIV-1 receptors redistribute to sites of virus binding at the nanoscale remains unknown. Here, we quantitatively examine changes in the nanoscale organisation of CD4 on the surface of CD4+ T cells following HIV-1 binding. Using singlemolecule super-resolution imaging, we show that CD4 molecules are distributed mostly as either individual molecules or small clusters of up to 4 molecules. Following virus binding, we observe a local 3-to-10-fold increase in cluster diameter and molecule number for virus-associated CD4 clusters. Moreover, a similar but smaller magnitude reorganisation of CD4 was also observed with recombinant gp120. For one of the first times, our results quantify the nanoscale CD4 reorganisation triggered by HIV-1 on host CD4+ T cells. Our quantitative approach provides a robust methodology for characterising the nanoscale organisation of plasma membrane receptors in general with the potential to link spatial organisation to function

Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia.

BACKGROUND AND PURPOSE: Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. METHODS: This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. RESULTS: We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10-18 for MD and rs67827860; P=1.3×10-14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. CONCLUSIONS: Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder

IL-1RI (interleukin-1 receptor type I) signalling is essential for host defence and hemichannel activity during acute central nervous system bacterial infection

Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1) response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood–brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system) infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I) KO (knockout) animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared with WT (wild-type) animals. Loss of IL-1RI signalling also dampened the expression of select cytokines and chemokines, concomitant with significant reductions in neutrophil and macrophage infiltrates into the brain. In addition, the opening of astrocyte hemichannels during acute infection was shown to be dependent on IL-1RI activity. Collectively, these results demonstrate that IL-1RI signalling plays a pivotal role in the genesis of immune responses during the acute stage of brain abscess development through S. aureus containment, inflammatory mediator production, peripheral immune cell recruitment, and regulation of astrocyte hemichannel activity. Taken in the context of previous studies with MyD88 (myeloid differentiation primary response gene 88) and TLR2 (Toll-like receptor 2) KO animals, the current report advances our understanding of MyD88-dependent cascades and implicates IL-1RI signalling as a major antimicrobial effector pathway during acute brain-abscess formation

Graded Associations of Blood Lead and Urinary Cadmium Concentrations with Oxidative-Stress–Related Markers in the U.S. Population: Results from the Third National Health and Nutrition Examination Survey

Although oxidative stress has been proposed as a mechanism of lead and cadmium toxicity mostly based on in vitro experiments or animal studies, it is uncertain whether this mechanism is relevant in the pathogenesis of lead- or cadmium-related diseases in the general population with low environmental exposure to lead and cadmium. We examined associations of blood lead and urinary cadmium levels with oxidative stress markers of serum γ-glutamyltransferase (GGT), vitamin C, carotenoids, and vitamin E among 10,098 adult participants in the third U.S. National Health and Nutrition Examination Survey. After adjusting for race, sex, and age (plus serum total cholesterol in the case of serum carotenoids and vitamin E), blood lead and urinary cadmium levels both showed graded associations, positive with serum GGT and inverse with serum vitamin C, carotenoids, and vitamin E (p for trend < 0.01, respectively). These associations were consistently observed among most subgroups: non-Hispanic white, non-Hispanic black, men, women, all age groups, non-drinkers, drinkers, nonsmokers, ex-smokers, current smokers, and body mass index (< 25, 25–29.9, and ≥30). The strong association of blood lead and urinary cadmium levels with oxidative stress markers in this population suggests that oxidative stress should be considered in the pathogenesis of lead- and cadmium-related diseases even among people with low environmental exposure to lead and cadmium

Likelihood inference for exponential-trawl processes

Integer-valued trawl processes are a class of serially correlated, stationary and infinitely divisible processes that Ole E. Barndorff-Nielsen has been working on in recent years. In this Chapter, we provide the first analysis of likelihood inference for trawl processes by focusing on the so-called exponential-trawl process, which is also a continuous time hidden Markov process with countable state space. The core ideas include prediction decomposition, filtering and smoothing, complete-data analysis and EM algorithm. These can be easily scaled up to adapt to more general trawl processes but with increasing computation efforts.Comment: 29 pages, 6 figures, forthcoming in: "A Fascinating Journey through Probability, Statistics and Applications: In Honour of Ole E. Barndorff-Nielsen's 80th Birthday", Springer, New Yor