A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

The Musicality of Non-Musicians: An Index for Assessing Musical Sophistication in the General Population

Musical skills and expertise vary greatly in Western societies. Individuals can differ in their repertoire of musical behaviours as well as in the level of skill they display for any single musical behaviour. The types of musical behaviours we refer to here are broad, ranging from performance on an instrument and listening expertise, to the ability to employ music in functional settings or to communicate about music. In this paper, we first describe the concept of ‘musical sophistication’ which can be used to describe the multi-faceted nature of musical expertise. Next, we develop a novel measurement instrument, the Goldsmiths Musical Sophistication Index (Gold-MSI) to assess self-reported musical skills and behaviours on multiple dimensions in the general population using a large Internet sample (n = 147,636). Thirdly, we report results from several lab studies, demonstrating that the Gold-MSI possesses good psychometric properties, and that self-reported musical sophistication is associated with performance on two listening tasks. Finally, we identify occupation, occupational status, age, gender, and wealth as the main socio-demographic factors associated with musical sophistication. Results are discussed in terms of theoretical accounts of implicit and statistical music learning and with regard to social conditions of sophisticated musical engagement

IMG/VR: A database of cultured and uncultured DNA viruses and retroviruses

Viruses represent the most abundant life forms on the planet. Recent experimental and computational improvements have led to a dramatic increase in the number of viral genome sequences identified primarily from metagenomic samples. As a result of the expanding catalog of metagenomic viral sequences, there exists a need for a comprehensive computational platform integrating all these sequences with associated metadata and analytical tools. Here we present IMG/VR (https://img.jgi.doe.gov/vr/), the largest publicly available database of 3908 isolate reference DNA viruses with 264 413 computationally identified viral contigs from >6000 ecologically diverse metagenomic samples. Approximately half of the viral contigs are grouped into genetically distinct quasi-species clusters. Microbial hosts are predicted for 20 000 viral sequences, revealing nine microbial phyla previously unreported to be infected by viruses. Viral sequences can be queried using a variety of associated metadata, including habitat type and geographic location of the samples, or taxonomic classification according to hallmark viral genes. IMG/VR has a user-friendly interface that allows users to interrogate all integrated data and interact by comparingwith external sequences, thus serving as an essential resource in the viral genomics community

Millennial physical events and the end-Permian mass mortality in the western Palaeotethys: timing and primary causes.

This chapter focuses on the nature and pattern of four transgressive–regressive depositional cycles (C1–C4) across the Permian–Triassic Boundary (PTB) in the Dolomites, on their timing and on the possible causal relationships with four massmortality events (E0–E3), which, considered together, constitute the end-Permian extinction event in the western Palaeotethys. The duration of the investigated interval is ca. 200 ky; the duration of each cycle ranged from less than 20 ky to ca. 100 ky; and the magnitude of the sea level changes ranged from 5 to 15 m. Each mass-mortality event affecting the shallow marine environments of the western Palaeotethys corresponds with a regressive phase lasting a few millennia. The oldest mortality event (E0) at the top of Cycle 1 (i.e., the top of the Ostracod Unit) in the Southern Alps is aligned with the regressive Bed 24e of the Meishan D section in the eastern Palaeotethys; it is usually considered the actual end-Permian extinction event. The same cooling/fall-stand has been identified in various sites along the shallow-marine Gondwana margin. In the Southern Alps, E0 is mostly masked by stressed conditions typical of the regional carbonate tidal flat. During the following transgression and high-stand periods of Cycle 2 (i.e., Bulla Member), the shallow marine environment became re-populated by ca. 200 species referred to ca. 30 genera. At the top of Cycle 2, the sea level fell 10 m or less in a few millennia; it started the most devastating mass-mortality event (E1) in the Southern Alps. This mortality event lasted less than 20 millennia; it continued briefly during the trangressive phase of the following Cycle 3—which brackets the Bellerophon-Werfen formational boundary (BWB). This interval, aligned with Beds 26–27a at Meishan in the eastern Palaeotethys, was deposited in a deeper and distal environment. About 90% of the marine skeletal biomass disappeared at the end of E1. The acme of mortality event, E1, corresponded with a submarine chemical-corrosion event, followed locally by subaerial exposure and pedogenesis. The mass-mortality event on land slightly predates—or is nearly coeval—with the mass-mortality event in shallow marine environments. The intensity of submarine corrosion became almost imperceptible at the foreshore–offshore boundary. The sea level rose ca. 15 m during Cycle 3 when the shallow marine environment, mostly over-saturated in carbonate but punctuated by short periods of vadose or submarine dissolution, transgressed rapidly more than 40km inland over the corroded bedrock, depositing oolite shoals and microbialite. The subsequent mortality events E2 and E3 are obviously of less intensity. E2, ca. 20 ky after E1, corresponds to a regressive interval associated with the first appearance of Hindeodus parvus (i.e., the Permian–Triassic Boundary). It seems to be the acme of colonisation of the shallow sea floor by cyanobacteria (stromatolites). E3, ca. 10 ky after the Permian–Triassic Boundary, corresponds to the last occurrence of Permian-type red algae in the Dolomites area. Whereas the end of E3 is gradual in the shoreface, it appears to have been abrupt in the lower foreshore, probably because of general conditions of less-ventilated and suboxic conditions. We hypothesise that a few local palaeo-environmental factors (e.g., distance of stressing factors from the source area, the pattern of atmospheric and marine palaeocurrents, and reduction of the shallow coastal area due to retreat of the coastline) concurred to modulate the intensity and duration of mortality events in space and time. Data suggest that increased warming was of primary importance in controlling the mortality tail but doesn’t allow us to confirm or deny other local or general concurrent causes, such as up-welling of anoxic oceanic waters from the Palaeotethys. We interpret the cause of the mass-mortality events in the Dolomites area as having been a composite “top-down” mechanism with acid-rain events devastating the Permian-type life on continental and, subsequently, in shallow marine environments during millennial periods of cooling and regression of the Bellerophon sea. The ultimate causal factor was, very probably, large atmospheric perturbations connected with volcanism. Most of the sparse surviving biota disappeared immediately after the beginning of the following transgression—because of rapid global warming produced by greenhouse conditions, with only minor, repeated, episodes of acid rains. These stressed conditions contributed to inhibiting recovery of the long and efficient shallow-marine food chain. Because the magnitude of mass-mortality event E0 in the Dolomites and in much of the Gondwana margin is appreciably lower than the coeval one in Meishan, the first may have acted as refugia. Mass-mortality event E1 affected the shallow-marine western Palaeotethys for only a few millennia after E0. In the eastern Palaeotethys, coeval Beds 26–27a of Meishan were deposited from lower foreshore to marine shelf, lacking any clear record of anoxic conditions. It is the same for the coeval short-term parasequences in many sites along the Gondwana margin. We interpret the different magnitude of extinction on the shelves as due to different levels of temperature and excessive carbon dioxide (pCO2) in the seawater. The rapid demise of taxa (occurring concordantly with the diachronous major mortality events) caused local severing of food chains, mostly of small suspension feeders, resulting in the “Lilliput” faunas (sensu Twitchett 2005) of event E2 in the Dolomites. This aligns with Beds 27c–d at Meishan—these beds were deposited in the lower foreshore and marine shelf environments under suboxic to dysoxic bottom conditions. It seems unlikely that the disappearance of red algae in the western Palaeotethys was connected with dysoxic conditions; increased temperature seems a more likely factor. Doubtless a medley of different mechanisms, including rapid fluctuations in marine salinity, operated variously as regards time and space and produced the end-Permian extinction—occurring over a time span of less than 100 ky