High resolution neurochemical gold staining method for myelin in peripheral and central nervous system at the light- and electron-microscopic level

Myelin is a multilamellar membrane structure primarily composed of lipids and myelin proteins essential for proper neuronal function. Since myelin is a target structure involved in many pathophysiological conditions such as metabolic, viral, and autoimmune diseases and genetic myelin disorders, a reliable myelin detection technique is required that is equally suitable for light- and electron-microscopic analysis. Here, we report that single myelinated fibers are specifically stained by the gold phosphate complex, Black gold, which stains myelin in the brain, spinal cord, and peripheral nerve fibers in a reliable manner. Electron-microscopic and morphometric analyses have revealed that gold particles are equally distributed in the inner, compact, and outer myelin layers. In contrast to Luxol fast blue, the gold dye stains proteinase-sensitive myelin structures, indicating its selective labeling of myelin-specific proteins. Aiming at defining the target of gold staining, we performed staining in several mouse myelin mutants. Gold complex distribution and myelin staining in MBP−/−/shiverer mouse mutants was comparable with that seen in wild-type mice but revealed a more clustered Black gold distribution. This gold staining method thus provides a sensitive and specific high-resolution marker for both central and peripheral myelin sheaths; it also allows the quantitative analysis of myelinated fibers at the light- and electron-microscopic level suitable for investigations of myelin and axonal disorder

Motor deficits and recovery in rats with unilateral spinal cord hemisection mimic the Brown-Séquard syndrome

Cervical incomplete spinal cord injuries often lead to severe and persistent impairments of sensorimotor functions and are clinically the most frequent type of spinal cord injury. Understanding the motor impairments and the possible functional recovery of upper and lower extremities is of great importance. Animal models investigating motor dysfunction following cervical spinal cord injury are rare. We analysed the differential spontaneous recovery of fore- and hindlimb locomotion by detailed kinematic analysis in adult rats with unilateral C4/C5 hemisection, a lesion that leads to the Brown-Séquard syndrome in humans. The results showed disproportionately better performance of hindlimb compared with forelimb locomotion; hindlimb locomotion showed substantial recovery, whereas the ipsilesional forelimb remained in a very poor functional state. Such a differential motor recovery pattern is also known to occur in monkeys and in humans after similar spinal cord lesions. On the lesioned side, cortico-, rubro-, vestibulo- and reticulospinal tracts and the important modulatory serotonergic, dopaminergic and noradrenergic fibre systems were interrupted by the lesion. In an attempt to facilitate locomotion, different monoaminergic agonists were injected intrathecally. Injections of specific serotonergic and noradrenergic agonists in the chronic phase after the spinal cord lesion revealed remarkable, although mostly functionally negative, modulations of particular parameters of hindlimb locomotion. In contrast, forelimb locomotion was mostly unresponsive to these agonists. These results, therefore, show fundamental differences between fore- and hindlimb spinal motor circuitries and their functional dependence on remaining descending inputs and exogenous spinal excitation. Understanding these differences may help to develop future therapeutic strategies to improve upper and lower limb function in patients with incomplete cervical spinal cord injurie

Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets

Antibody delivery to the CNS remains a huge hurdle for the clinical application of antibodies targeting a CNS antigen. The blood-brain barrier and blood-CSF barrier restrict access of therapeutic antibodies to their CNS targets in a major way. The very high amounts of therapeutic antibodies that are administered systemically in recent clinical trials to reach CNS targets are barely viable cost-wise for broad, routine applications. Though global CNS delivery of antibodies can be achieved by intrathecal application, these procedures are invasive. A non-invasive method to bring antibodies into the CNS reliably and reproducibly remains an important unmet need in neurology. In the present study, we show that intranasal application of a mouse monoclonal antibody against the neurite growth-inhibiting and plasticity-restricting membrane protein Nogo-A leads to a rapid transfer of significant amounts of antibody to the brain and spinal cord in intact adult rats. Daily intranasal application for 2 wk of anti-Nogo-A antibody enhanced growth and compensatory sprouting of corticofugal projections and functional recovery in rats after large unilateral cortical strokes. These findings are a starting point for clinical translation for a less invasive route of application of therapeutic antibodies to CNS targets for many neurological indications

Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury

Înjured axons in mammalian peripheral nerves often regenerate successfully over long distances, in contrast to axons in the brain and spinal cord (CNS). Neurite growth-inhibitory proteins, including the recently cloned membrane protein Nogo-A, are enriched in the CNS, in particular in myelin. Nogo-A is not detectable in peripheral nerve myelin. Using regulated transgenic expression of Nogo-A in peripheral nerve Schwann cells, we show that axonal regeneration and functional recovery are impaired after a sciatic nerve crush. Nogo-A thus overrides the growth-permissive and -promoting effects of the lesioned peripheral nerve, demonstrating its in vivo potency as an inhibitor of axonal regeneration

On the puzzling plateau in the specific star formation rate at z=2-7

The observational indications for a constant specific star-formation rate (sSFR) in the redshift range z=2-7 are puzzling in the context of current galaxy-formation models. Despite the tentative nature of the data, their marked conflict with theory motivates a study of the possible implications. The plateau at sSFR ~ 2 Gyr^-1 is hard to reproduce because (a) its level is low compared to the cosmological specific accretion rate at z > 6, (b) it is higher than the latter at z ~ 2, (c) the natural correlation between SFR and stellar mass makes it difficult to manipulate their ratio, and (d) a low SFR at high z makes it hard to produce enough massive galaxies by z ~ 2. Using a flexible semi-analytic model, we explore ad-hoc modifications to the standard physical recipes trying to obey the puzzling observational constraints. Successful models involve non-trivial modifications, such as (a) a suppressed SFR at z > 4 in galaxies of all masses, by enhanced feedback or reduced SFR efficiency, following an initial active phase at z > 7, (b) a delayed gas consumption into stars, allowing the gas that was prohibited from forming stars or ejected at high z to form stars later in more massive galaxies, and (c) enhanced growth of massive galaxies, in terms of either faster assembly or more efficient starbursts in mergers, or by efficient star formation in massive haloes.Comment: 17 pages, 11 figures. MNRAS accepted. References added, small changes to text after referee report. Results and conclusions unchange

HerMES: dust attenuation and star formation activity in ultraviolet-selected samples from z 4 to 1.5

We study the link between observed ultraviolet (UV) luminosity, stellar mass and dust attenuation within rest-frame UV-selected samples at z ∼ 4, ∼ 3 and ∼1.5. We measure by stacking at 250, 350 and 500μm in the Herschel/Spectral and Photometric Imaging Receiver images from the Herschel Multi-Tiered Extragalactic Survey (HerMES) program the average infrared luminosity as a function of stellar mass and UV luminosity. We find that dust attenuation is mostly correlated with stellar mass. There is also a secondary dependence with UV luminosity: at a given UV luminosity, dust attenuation increases with stellar mass, while at a given stellar mass it decreases with UV luminosity. We provide new empirical recipes to correct for dust attenuation given the observed UV luminosity and the stellar mass. Our results also enable us to put new constraints on the average relation between star formation rate (SFR) and stellar mass at z ∼ 4, ∼3 and ∼1.5. The SFR–stellar mass relations are well described by power laws (SFR ∝ M 0.7∗), with the amplitudes being similar at z ∼ 4 and ∼3, and decreasing by a factor of 4 at z ∼ 1.5 at a given stellar mass. We further investigate the evolution with redshift of the specific SFR. Our results are in the upper range of previous measurements, in particular at z ∼ 3, and are consistent with a plateau at 3 < z < 4. Current model predictions (either analytic, semi-analytic or hydrodynamic) are inconsistent with these values, as they yield lower predictions than the observations in the redshift range we explore. We use these results to discuss the star formation histories of galaxies in the framework of the main sequence of star-forming galaxies. Our results suggest that galaxies at high redshift (2.5 < z < 4) stay around 1 Gyr on the main sequence. With decreasing redshift, this time increases such that z = 1 main-sequence galaxies with 10 8 < M ∗ /Mo < 10 10 stay on the main sequence until z = 0

Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability

The redshift evolution of the distribution of star formation among dark matter halos as seen in the infrared

Recent studies revealed a strong correlation between the star formation rate (SFR) and stellar mass of star-forming galaxies, the so-called star-forming main sequence. An empirical modeling approach (2-SFM) which distinguishes between the main sequence and rarer starburst galaxies is capable of reproducing most statistical properties of infrared galaxies. In this paper, we extend this approach by establishing a connection between stellar mass and halo mass with the technique of abundance matching. Based on a few, simple assumptions and a physically motivated formalism, our model successfully predicts the (cross-)power spectra of the cosmic infrared background (CIB), the cross-correlation between CIB and cosmic microwave background (CMB) lensing, and the correlation functions of bright, resolved infrared galaxies measured by Herschel, Planck, ACT and SPT. We use this model to infer the redshift distribution these observables, as well as the level of correlation between CIB-anisotropies at different wavelengths. We also predict that more than 90% of cosmic star formation activity occurs in halos with masses between 10^11.5 and 10^13.5 Msun. Taking into account subsequent mass growth of halos, this implies that the majority of stars were initially (at z>3) formed in the progenitors of clusters, then in groups at 0.5<z<3 and finally in Milky-Way-like halos at z<0.5. At all redshifts, the dominant contribution to the star formation rate density stems from halos of mass ~10^12 Msun, in which the instantaneous star formation efficiency is maximal (~70%). The strong redshift-evolution of SFR in the galaxies that dominate the CIB is thus plausibly driven by increased accretion from the cosmic web onto halos of this characteristic mass scale

Beyond Crowd Judgments: Data-driven Estimation of Market Value in Association Football

Association football is a popular sport, but it is also a big business. From a managerial perspective, the most important decisions that team managers make concern player transfers, so issues related to player valuation, especially the determination of transfer fees and market values, are of major concern. Market values can be understood as estimates of transfer fees—that is, prices that could be paid for a player on the football market—so they play an important role in transfer negotiations. These values have traditionally been estimated by football experts, but crowdsourcing has emerged as an increasingly popular approach to estimating market value. While researchers have found high correlations between crowdsourced market values and actual transfer fees, the process behind crowd judgments is not transparent, crowd estimates are not replicable, and they are updated infrequently because they require the participation of many users. Data analytics may thus provide a sound alternative or a complementary approach to crowd-based estimations of market value. Based on a unique data set that is comprised of 4217 players from the top five European leagues and a period of six playing seasons, we estimate players’ market values using multilevel regression analysis. The regression results suggest that data-driven estimates of market value can overcome several of the crowd’s practical limitations while producing comparably accurate numbers. Our results have important implications for football managers and scouts, as data analytics facilitates precise, objective, and reliable estimates of market value that can be updated at any time

Improved Models for Cosmic Infrared Background Anisotropies: New Constraints on the IR Galaxy Population

The power spectrum of cosmic infrared background (CIB) anisotropies is sensitive to the connection between star formation and dark matter halos over the entire cosmic star formation history. Here we develop a model that associates star-forming galaxies with dark matter halos and their subhalos. The model is based on a parameterized relation between the dust-processed infrared luminosity and (sub)halo mass. By adjusting 3 free parameters, we attempt to simultaneously fit the 4 frequency bands of the Planck measurement of the CIB anisotropy power spectrum. To fit the data, we find that the star-formation efficiency must peak on a halo mass scale of ~ 5x10^12 solar mass and the infrared luminosity per unit mass must increase rapidly with redshift. By comparing our predictions with a well-calibrated phenomenological model for shot noise, and with a direct observation of source counts, we show that the mean duty cycle of the underlying infrared sources must be near unity, indicating that the CIB is dominated by long-lived quiescent star formation, rather than intermittent short "star bursts". Despite the improved flexibility of our model, the best simultaneous fit to all four Planck channels remains relatively poor. We discuss possible further extensions to alleviate the remaining tension with the data. Our model presents a theoretical framework for a future joint analysis of both background anisotropy and source count measurements.Comment: 14 pages, 2 tables, 7 figures, submitted to MNRA