Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging

Superluminal motion of a relativistic jet in the neutron star merger GW170817

The binary neutron star merger GW170817 was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 41+/-3 Mpc. The radio and X-ray afterglows of GW170817 exhibited delayed onset, a gradual rise in the emission with time as t^0.8, a peak at about 150 days post-merger, followed by a relatively rapid decline. To date, various models have been proposed to explain the afterglow emission, including a choked-jet cocoon and a successful-jet cocoon (a.k.a. structured jet). However, the observational data have remained inconclusive as to whether GW170817 launched a successful relativistic jet. Here we show, through Very Long Baseline Interferometry, that the compact radio source associated with GW170817 exhibits superluminal motion between two epochs at 75 and 230 days post-merger. This measurement breaks the degeneracy between the models and indicates that, while the early-time radio emission was powered by a wider-angle outflow (cocoon), the late-time emission was most likely dominated by an energetic and narrowly-collimated jet, with an opening angle of <5 degrees, and observed from a viewing angle of about 20 degrees. The imaging of a collimated relativistic outflow emerging from GW170817 adds substantial weight to the growing evidence linking binary neutron star mergers and short gamma-ray bursts.Comment: 42 pages, 4 figures (main text), 2 figures (supplementary text), 2 tables. Referee and editor comments incorporate

Entorhinal Denervation Induces Homeostatic Synaptic Scaling of Excitatory Postsynapses of Dentate Granule Cells in Mouse Organotypic Slice Cultures

Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro

Determinants of Inapparent and Symptomatic Dengue Infection in a Prospective Study of Primary School Children in Kamphaeng Phet, Thailand

Dengue viruses are a major cause of illness and hospitalizations in tropical and subtropical regions of the world. Severe dengue illness can cause prolonged hospitalization and in some cases death in both children and adults. The majority of dengue infections however are inapparent, producing little clinical illness. Little is known about the epidemiology or factors that determine the incidence of inapparent infection. We describe in a study of school children in Northern Thailand the changing nature of symptomatic and inapparent dengue infection. We demonstrate that the proportion of inapparent dengue infection varies widely among schools during a year and within schools during subsequent years. Important factors that determine this variation are the amount of dengue infection in a given and previous year. Our findings provide an important insight in the virus-host interaction that determines dengue severity, how severe a dengue epidemic may be in a given year, and important clues on how a dengue vaccine may be effective

Site-Specific and Time-Dependent Activation of the Endocannabinoid System after Transection of Long-Range Projections

Background: After focal neuronal injury the endocannabinioid system becomes activated and protects or harms neurons depending on cannabinoid derivates and receptor subtypes. Endocannabinoids (eCBs) play a central role in controlling local responses and influencing neural plasticity and survival. However, little is known about the functional relevance of eCBs in long-range projection damage as observed in stroke or spinal cord injury (SCI). Methods: In rat organotypic entorhino-hippocampal slice cultures (OHSC) as a relevant and suitable model for investigating projection fibers in the CNS we performed perforant pathway transection (PPT) and subsequently analyzed the spatial and temporal dynamics of eCB levels. This approach allows proper distinction of responses in originating neurons (entorhinal cortex), areas of deafferentiation/anterograde axonal degeneration (dentate gyrus) and putative changes in more distant but synaptically connected subfields (cornu ammonis (CA) 1 region). Results: Using LC-MS/MS, we measured a strong increase in arachidonoylethanolamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels in the denervation zone (dentate gyrus) 24 hours post lesion (hpl), whereas entorhinal cortex and CA1 region exhibited little if any changes. NAPE-PLD, responsible for biosynthesis of eCBs, was increased early, whereas FAAH, a catabolizing enzyme, was up-regulated 48hpl. Conclusion: Neuronal damage as assessed by transection of long-range projections apparently provides a strong time-dependent and area-confined signal for de novo synthesis of eCB, presumably to restrict neuronal damage. The present data underlines the importance of activation of the eCB system in CNS pathologies and identifies a novel site-specific intrinsic regulation of eCBs after long-range projection damage

Contrasting Spatial Distribution and Risk Factors for Past Infection with Scrub Typhus and Murine Typhus in Vientiane City, Lao PDR

Scrub typhus and murine typhus are neglected but important treatable causes of fever, morbidity and mortality in South-East Asia. Epidemiological data suggests that scrub typhus would be more common in rural areas and murine typhus in urban areas but there are very few comparative data from places where both diseases occur, as is the case in Vientiane, the capital of the Lao PDR. We therefore determined the frequency of IgG antibody seropositivity against scrub typhus and murine typhus, as indices of prior exposure to these pathogens, in a randomly selected population of 2,002 adults living in different neighbourhoods in Vientiane. The overall prevalence of IgG against these two pathogens was ∼20%. However, within the city, the spatial distribution of IgG against these two diseases was radically different - past exposure to murine typhus being more frequent in urbanized areas while past exposure to scrub typhus more frequent in outlying areas. This study underscores the importance of ecological characteristics in improving the understanding of both scrub typhus and murine typhus transmission and epidemiology

The Predicted Secretome of the Plant Pathogenic Fungus Fusarium graminearum: A Refined Comparative Analysis

The fungus Fusarium graminearum forms an intimate association with the host species wheat whilst infecting the floral tissues at anthesis. During the prolonged latent period of infection, extracellular communication between live pathogen and host cells must occur, implying a role for secreted fungal proteins. The wheat cells in contact with fungal hyphae subsequently die and intracellular hyphal colonisation results in the development of visible disease symptoms. Since the original genome annotation analysis was done in 2007, which predicted the secretome using TargetP, the F. graminearum gene call has changed considerably through the combined efforts of the BROAD and MIPS institutes. As a result of the modifications to the genome and the recent findings that suggested a role for secreted proteins in virulence, the F. graminearum secretome was revisited. In the current study, a refined F. graminearum secretome was predicted by combining several bioinformatic approaches. This strategy increased the probability of identifying truly secreted proteins. A secretome of 574 proteins was predicted of which 99% was supported by transcriptional evidence. The function of the annotated and unannotated secreted proteins was explored. The potential role(s) of the annotated proteins including, putative enzymes, phytotoxins and antifungals are discussed. Characterisation of the unannotated proteins included the analysis of Pfam domains and features associated with known fungal effectors, for example, small size, cysteine-rich and containing internal amino acid repeats. A comprehensive comparative genomic analysis involving 57 fungal and oomycete genomes revealed that only a small number of the predicted F. graminearum secreted proteins can be considered to be either species or sequenced strain specific

The 2016 Feb 19 outburst of comet 67P/CG: an ESA Rosetta multi-instrument study

On 2016 Feb 19, nine Rosetta instruments serendipitously observed an outburst of gas and dust from the nucleus of comet 67P/Churyumov-Gerasimenko. Among these instruments were cameras and spectrometers ranging from UV over visible to microwave wavelengths, in situ gas, dust and plasma instruments, and one dust collector. At 09:40 a dust cloud developed at the edge of an image in the shadowed region of the nucleus. Over the next two hours the instruments recorded a signature of the outburst that significantly exceeded the background. The enhancement ranged from 50 per cent of the neutral gas density at Rosetta to factors >100 of the brightness of the coma near the nucleus. Dust related phenomena (dust counts or brightness due to illuminated dust) showed the strongest enhancements (factors >10). However, even the electron density at Rosetta increased by a factor 3 and consequently the spacecraft potential changed from ∼−16 V to −20 V during the outburst. A clear sequence of events was observed at the distance of Rosetta (34 km from the nucleus): within 15 min the Star Tracker camera detected fast particles (∼25 m s−1) while 100 μm radius particles were detected by the GIADA dust instrument ∼1 h later at a speed of 6 m s−1. The slowest were individual mm to cm sized grains observed by the OSIRIS cameras. Although the outburst originated just outside the FOV of the instruments, the source region and the magnitude of the outburst could be determined