On the Relation Between Receptive Field Structure and Stimulus Selectivity in the Tree Shrew Primary Visual Cortex

There are notable differences in functional properties of primary visual cortex (V1) neurons among mammalian species, particularly those concerning the occurrence of simple and complex cells and the generation of orientation selectivity. Here, we present quantitative data on receptive field (RF) structure, response modulation, and orientation tuning for single neurons in V1 of the tree shrew, a close relative of primates. We find that spatial RF subfield segregation, a criterion for identifying simple cells, was exceedingly small in the tree shrew V1. In contrast, many neurons exhibited elevated F1/F0 modulation that is often used as a simple cell marker. This apparent discrepancy can be explained by the robust stimulus polarity preference in tree shrew V1, which inflates F1/F0 ratio values. RF structure mapped with sparse-noise—which is spatially restricted and emphasizes thalamo-cortical feed-forward inputs—appeared unrelated to orientation selectivity. However, RF structure mapped using the Hartley subspace stimulus—which covers a large area of the visual field and recruits considerable intracortical processing—did predict orientation preference. Our findings reveal a number of striking similarities in V1 functional organization between tree shrews and primates, emphasizing the important role of intracortical recurrent processing in shaping V1 response properties in these specie

Aboriginal Status is a Prognostic Factor for Mortality among Antiretroviral Naive HIV-Positive Individuals First Initiating HAART

Background: Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and accessto treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicityand outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysisto determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasmaviral load response, CD4 cell response and time to all-cause mortality.Methods: A population-based analysis of a cohort of antiretroviral therapy naïve HIV-positive Aboriginal menand women 18 years or older in British Columbia, Canada. Participants were antiretroviral therapy naïve, initiatedtriple combination therapy between August 1, 1996 and September 30, 1999. Participants had to complete abaseline questionnaire as well as have at least two follow-up CD4 and HIV plasma viral load measures. Theprimary endpoints were CD4 and HIV plasma viral load response and all cause mortality. Cox proportionalhazards models were used to determine the association between Aboriginal status and CD4 cell response, HIVplasma viral load response and all-cause mortality while controlling for several confounder variables.Results: A total of 622 participants met the study criteria. Aboriginal status was significantly associated with noAIDS diagnosis at baseline (p = 0.0296), having protease inhibitor in the first therapy (p = 0.0209), lower baselineHIV plasma viral load (p < 0.001), less experienced HIV physicians (P = 0.0133), history of IDU (p < 0.001), notcompleting high school (p = 0.0046), and an income of less than $10,000 per year (p = 0.0115). Cox proportionalhazards models controlling for clinical characteristics found that Aboriginal status had an increased hazard ofmortality (HR = 3.12, 95% CI: 1.77–5.48) but did not with HIV plasma viral load response (HR = 1.15, 95% CI:0.89–1.48) or CD4 cell response (HR = 0.95, 95% CI: 0.73–1.23).Conclusion: Our study demonstrates that HIV-infected Aboriginal persons accessing HAART had similar HIVtreatment response as non-Aboriginal persons but have a shorter survival. This study highlights the need forcontinued research on medical interventions and behavioural changes among HIV-infected Aboriginal and othermarginalized populations

U-Pb SHRIMP zircon dating of Grenvillian metamorphism in Western Sierras Pampeanas (Argentina) : correlation with the Arequipa-Antofalla craton and constraints on the extent of the Precordillera Terrane

The Sierras Pampeanas of Argentina, the largest outcrop of pre-Andean crystalline basement in southern South America, resulted from plate interactions along the proto-Andean margin of Gondwana, from as early as Mesoproterozoic to Late Paleozoic times (e.g., Ramos, 2004, and references therein). Two discrete Paleozoic orogenic belts have been recognized: the Early Cambrian Pampean belt in the eastern sierras, and the Ordovician Famatinian belt, which partially overprints it to the west (e.g., Rapela et al., 1998). In the Western Sierras Pampeanas, Mesoproterozoic igneous rocks (ca. 1.0–1.2 Ga) have been recognized in the Sierra de Pie de Palo (Fig. 1) (McDonough et al., 1993 M.R. McDonough, V.A. Ramos, C.E. Isachsen, S.A. Bowring and G.I. Vujovich, Edades preliminares de circones del basamento de la Sierra de Pie de Palo, Sierras Pampeanas occidentales de San Juán: sus implicancias para el supercontinente proterozoico de Rodinia, 12° Cong. Geol. Argentino, Actas vol. 3 (1993), pp. 340–342.McDonough et al., 1993, Pankhurst and Rapela, 1998 and Vujovich et al., 2004) that are time-coincident with the Grenvillian orogeny of eastern and northeastern North America (e.g., Rivers, 1997 and Corrievau and van Breemen, 2000). These Grenvillian-age rocks have been considered to be the easternmost exposure of basement to the Precordillera Terrane, a supposed Laurentian continental block accreted to Gondwana during the Famatinian orogeny (Thomas and Astini, 2003, and references therein). However, the boundaries of this Grenvillian belt are still poorly defined, and its alleged allochthoneity has been challenged (Galindo et al., 2004). Moreover, most of the Grenvillian ages so far determined relate to igneous protoliths, and there is no conclusive evidence for a Grenvillian orogenic belt, other than inferred from petrographic evidence alone (Casquet et al., 2001). We provide here the first evidence, based on U–Pb SHRIMP zircon dating at Sierra de Maz, for a Grenville-age granulite facies metamorphism, leading to the conclusion that a continuous mobile belt existed throughout the proto-Andean margin of Gondwana in Grenvillian times

Inhibition of Activin/Myostatin signalling impairs mouse testis Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development

Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development

Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development

Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development.Peer reviewe

Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

von Willebrand disease (VWD) is the most common inherited human bleeding disorder and is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWF is a secreted glycoprotein that circulates as large multimers. While reduced VWF is associated with bleeding, elevations in overall level or multimer size are implicated in thrombosis. The zebrafish is a powerful genetic model in which the hemostatic system is well conserved with mammals. The ability of this organism to generate thousands of offspring and its optical transparency make it unique and complementary to mammalian models of hemostasis. Previously, partial clones of zebrafish vwf have been identified, and some functional conservation has been demonstrated. In this paper we clone the complete zebrafish vwf cDNA and show that there is conservation of domain structure. Recombinant zebrafish Vwf forms large multimers and pseudo-Weibel-Palade bodies (WPBs) in cell culture. Larval expression is in the pharyngeal arches, yolk sac, and intestinal epithelium. These results provide a foundation for continued study of zebrafish Vwf that may further our understanding of the mechanisms of VWD

Protein and molecular characterization of a clinically compliant amniotic fluid stem cell derived extracellular vesicle fraction capable of accelerating muscle regeneration through the enhancement of angiogenesis

The secretome of human amniotic fluid stem cells (AFSC) has great potential as a therapeutic agent in regenerative medicine. However it must be produced in a clinically compliant manner before it can be used in humans. Here we developed a means of producing a biologically active secretome from AFSCs that is free of all exogenous molecules. We demonstrate that the full secretome is capable of promoting stem cell proliferation, migration and protection of cells against senescence. Furthermore, it has significant anti-inflammatory properties. Most importantly we show that it promotes tissue regeneration in a model of muscle damage. We then demonstrate that the secretome contains extracellular vesicles (EV) that harbour much but not all the biological activity of the whole secretome. Proteomic characterisation of the EV and free secretome fraction show the presence of numerous molecules specific to each fraction that could be key regulators of tissue regeneration. Intriguingly we show that the EVs only contain miRNA and not mRNA. This suggests tissue regeneration in the host is mediated by the action of EVs modifying existing, rather than the imposition of new, signalling pathways. The EVs harbour significant anti-inflammatory activity as well as promoting angiogenesis; the latter may be the mechanistic explanation for their ability to promote muscle regeneration after cardiotoxin injury

Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling

Background One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit. Methods To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone. Results We show that muscle of Ercc1(Delta/-) progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.14 mm(3) in untreated mice, cortical bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.22 mm(3) in untreated mice). The onset of neurological abnormalities was delayed (by similar to 5 weeks) and their severity reduced, overall sustaining health without affecting lifespan. Conclusions This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.Peer reviewe

Enhanced exercise and regenerative capacity in a mouse model that violates size constraints of oxidative muscle fibres

A central tenet of skeletal muscle biology is the existence of an inverse relationship between the oxidative fibre capacity and its size. However, robustness of this relationship is unknown. We show that superimposition of Estrogen-related receptor gamma (Erry) on the myostatin (Mtn) mouse null background (Mtn(-/-)Err gamma(Tg/+)) results in hypertrophic muscle with a high oxidative capacity thus violating the inverse relationship between fibre size and oxidative capacity. We also examined the canonical view that oxidative muscle phenotype positively correlate with Satellite cell number, the resident stem cells of skeletal muscle. Surprisingly, hypertrophic fibres from Mtn(-/-)Err gamma(Tg/+) mouse showed satellite cell deficit which unexpectedly did not affect muscle regeneration. These observations 1) challenge the concept of a constraint between fibre size and oxidative capacity and 2) indicate the important role of the microcirculation in the regenerative capacity of a muscle even when satellite cell numbers are reduced.Peer reviewe

Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins

Abstract Background The mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair. Methods Here we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source. Results Here we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage. We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo. Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome. Conclusions Taken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation