Role of muscle spindle feedback in regulating muscle activity strength during walking at different speed in mice

Terrestrial animals increase their walking speed by increasing the activity of the extensor muscles. However, the mechanism underlying this speed dependent amplitude modulation is achieved remain obscure. Previous studies have shown that group Ib afferent feedback from Golgi tendon organs that signal force is one of the major regulators of the strength of muscle activity during walking in cats and humans. In contrast, the contribution of group Ia/II afferent feedback from muscle spindle stretch receptors which signal angular displacement of leg joints is unclear. Some studies indicate that group II afferent feedback may be important for amplitude regulation in humans, but the role of muscle spindle feedback in regulation of muscle activity strength in quadrupedal animals is very poorly understood. To examine the role of feedback from muscle spindles, we combined in vivo electrophysiology and motion analysis with mouse genetics and gene delivery with adeno associated virus. We provide evidence that proprioceptive sensory feedback from muscle spindles is important for the regulation of the muscle activity strength and speed dependent amplitude modulation. Furthermore, our data suggest that feedback from the muscle spindles of the ankle extensor muscles, the triceps surae, are the main source for this mechanism. In contrast, muscle spindle feedback from the knee extensor muscles, the quadriceps femoris, has no influence on speed dependent amplitude modulation. We provide evidence that proprioceptive feedback from ankle extensor muscles is critical for regulating muscle activity strength as gait speed increases

Healthcare Resource Utilization Among Patients in England with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Database Analysis

Introduction Systemic sclerosis-associated interstitial lung disease (SSc-ILD) places a substantial burden on patients and healthcare systems. The objectives of this study were to describe clinical characteristics and assess healthcare resource utilization and costs of patients with SSc-ILD in England, compared with patients with non-pulmonary organ involvement related to SSc (SSc-OOI). Methods This population-based retrospective study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Data were extracted from medical records dated January 1, 2005 to March 31, 2016. Patients with SSc were identified and placed in subgroups based on organ involvement: SSc-ILD, SSc-OOI, and both (SSc-ILD-OOI). Patients with SSc-ILD-OOI were included in both the SSc-ILD and SSc-OOI subgroups. All-cause healthcare costs, excluding medication costs, were calculated to 2016 British pounds sterling (£). Results This study included 675 patients with SSc: 174 (26%) had neither ILD nor other organ involvement (OOI); 127 (19%) had SSc-ILD; 477 (71%) had SSc-OOI; 103 (15%) had SSc-ILD-OOI. Age-weighted median [interquartile range (IQR)] annual healthcare costs per patient were: £1496 (£664–£2817) in SSc only; £6375 (£3451–£15,041) in SSc-ILD; £4084 (£1454–£10,105) in SSc-OOI; £6632 (£4023–£17,009) in SSc-ILD-OOI. In multivariate analysis, older age at diagnosis, diagnosis of anemia, and number of comorbid diseases were associated with higher yearly healthcare costs. Conclusion The annual healthcare cost for patients with SSc-ILD is substantial, and higher than that of patients with SSc-OOI or SSc only. These results quantify the economic burden of SSc-ILD in a real-world setting, and highlight the need for treatment of this disease

Stable Isotope Phosphate Labelling of Diverse Metabolites is Enabled by a Family of O-18-Phosphoramidites**

A family of 18O2-phosphoramidites facilitates synthetic access on gram-scale to various isotopically pure 18O-labelled phosphate products, like nucleotides, inositol phosphates, polyphosphates, and DNA. The utility of these 18O-natural products is underlined in the assignment of various metabolites from biological matrices using capillary electrophoresis electrospray ionisation triple quadrupole mass spectrometry. Stable isotope labelling is state-of-the-art in quantitative mass spectrometry, yet often accessing the required standards is cumbersome and very expensive. Here, a unifying synthetic concept for 18O-labelled phosphates is presented, based on a family of modified 18O2-phosphoramidite reagents. This toolbox offers access to major classes of biologically highly relevant phosphorylated metabolites as their isotopologues including nucleotides, inositol phosphates, -pyrophosphates, and inorganic polyphosphates. 18O-enrichment ratios >95 % and good yields are obtained consistently in gram-scale reactions, while enabling late-stage labelling. We demonstrate the utility of the 18O-labelled inositol phosphates and pyrophosphates by assignment of these metabolites from different biological matrices. We demonstrate that phosphate neutral loss is negligible in an analytical setup employing capillary electrophoresis electrospray ionisation triple quadrupole mass spectrometry

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene x environment interaction approach

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes

Datatrust: Or, the political quest for numerical evidence and the epistemologies of Big Data

Recently, there has been renewed interest in so-called evidence-based policy making. Enticed by the grand promises of Big Data, public officials seem increasingly inclined to experiment with more data-driven forms of governance. But while the rise of Big Data and related consequences has been a major issue of concern across different disciplines, attempts to develop a better understanding of the phenomenon's historical foundations have been rare. This short commentary addresses this gap by situating the current push for numerical evidence within a broader socio-political context, demonstrating how the epistemological claims of Big Data science intersect with specific forms of trust, truth, and objectivity. We conclude by arguing that regulators' faith in numbers can be attributed to a distinct political culture, a representative democracy undermined by pervasive public distrust and uncertainty

Star forming dwarf galaxies

Star forming dwarf galaxies (SFDGs) have a high gas content and low metallicities, reminiscent of the basic entities in hierarchical galaxy formation scenarios. In the young universe they probably also played a major role in the cosmic reionization. Their abundant presence in the local volume and their youthful character make them ideal objects for detailed studies of the initial stellar mass function (IMF), fundamental star formation processes and its feedback to the interstellar medium. Occasionally we witness SFDGs involved in extreme starbursts, giving rise to strongly elevated production of super star clusters and global superwinds, mechanisms yet to be explored in more detail. SFDGs is the initial state of all dwarf galaxies and the relation to the environment provides us with a key to how different types of dwarf galaxies are emerging. In this review we will put the emphasis on the exotic starburst phase, as it seems less important for present day galaxy evolution but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon, September 2010, Springer Verlag, in pres

“You Might Belong in Gryffindor”: Children’s Courage and Its Relationships to Anxiety Symptoms, Big Five Personality Traits, and Sex Roles

This study describes a first exploration of the construct of courage in youths. Children aged 8–13 years were invited to report on the most courageous action that they had ever performed during their life. In addition, the Courage Measure for Children (CM-C) was construed as an index of children’s level of personal courage, and this scale was administered in two samples of school children (Ns being 168 and 159) along with a number of other questionnaires. Results indicated that children were familiar with the concept of courage as more than 70% reported to have carried out a courageous action during their life. In addition, self-reported courage as indexed by the CM-C was positively correlated with scores on a vignette measure of courage, parent ratings of children’s courage, extraversion, openness/intellect, and a masculine sex role, whereas a negative correlation was observed with anxiety symptoms. The implications of these findings and potential directions for future research are briefly discussed

Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

We have investigated the antiproliferative action towards CC531 colon adenocarcinoma cells of target cell-specific immunoliposomes containing the amphiphilic dipalmitoyl derivative of 5-fluorodeoxyuridine (FUdR-dP). FUdR-dP incorporated in immunoliposomes caused a 13-fold stronger inhibition of CC531 cell growth in vitro, during a 72-h treatment, than FUdR-dP in liposomes without antibody, demonstrating that the prodrug is efficiently hydrolysed to yield the active drug, FUdR, intracellularly. The intracellular release of active FUdR was confirmed by determining the fate of H-3-labelled immunoliposomal FUdR-dP. Treatments shorter than 72 h with FUdR-dP in immunoliposomes resulted in anti-tumour activities comparable to, or even higher than, that of free FUdR. The shorter treatments reflect more closely the in vivo situation and illustrate the potential advantage of the use of immunoliposomes over non-targeted liposomal FUdR-dP or free FUdR. Association of tumour cell-specific immunoliposomes with CC531 cells was up to tenfold higher than that of liposomes without antibody or with irrelevant IgG coupled, demonstrating a specific interaction between liposomes and target cells which causes an efficient intracellular delivery of the drug. Since biochemical evidence indicates a lack of internalization or degradation of the liposomes as such; we postulate that entry of the drug most likely involves the direct transfer of the prodrug from the immunoliposome to the cell membrane during its antigen-specific interaction with the cells. followed by hydrolysis of FUdR-dP leading to relatively high intracellular FUdR-levels. In conclusion, we describe a targeted liposomal formulation for the anticancer drug FUdR, which is able to deliver the active drug to colon carcinoma cells with high efficiency, without the need for the cells to internalize the liposomes as such

Influence of ground surface characteristics on the mean radiant temperature in urban areas

The effect of variations in land cover on mean radiant surface temperature (Tmrt) is explored through a simple scheme developed within the radiation model SOLWEIG. Outgoing longwave radiation is parameterised using surface temperature observations on a grass and an asphalt surface, whereas outgoing shortwave radiation is modelled through variations in albedo for the different surfaces. The influence of surface materials on Tmrt is small compared to the effects of shadowing. Nevertheless, altering ground surface materials could contribute to a reduction on Tmrt to reduce the radiant load during heat-wave episodes in locations where shadowing is not an option. Evaluation of the new scheme suggests that despite its simplicity it can simulate the outgoing fluxes well, especially during sunny conditions. However, it underestimates at night and in shadowed locations. One grass surface used to develop the parameterisation, with very different characteristics compared to an evaluation grass site, caused Tmrt to be underestimated. The implications of using high resolution (e.g. 15 minutes) temporal forcing data under partly cloudy conditions are demonstrated even for fairly proximal sites

Diffuse Gamma Rays: Galactic and Extragalactic Diffuse Emission

"Diffuse" gamma rays consist of several components: truly diffuse emission from the interstellar medium, the extragalactic background, whose origin is not firmly established yet, and the contribution from unresolved and faint Galactic point sources. One approach to unravel these components is to study the diffuse emission from the interstellar medium, which traces the interactions of high energy particles with interstellar gas and radiation fields. Because of its origin such emission is potentially able to reveal much about the sources and propagation of cosmic rays. The extragalactic background, if reliably determined, can be used in cosmological and blazar studies. Studying the derived "average" spectrum of faint Galactic sources may be able to give a clue to the nature of the emitting objects.Comment: 32 pages, 28 figures, kapproc.cls. Chapter to the book "Cosmic Gamma-Ray Sources," to be published by Kluwer ASSL Series, Edited by K. S. Cheng and G. E. Romero. More details can be found at http://www.gamma.mpe-garching.mpg.de/~aws/aws.htm