Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

Objective Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis. Methods OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain. Results Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone. Conclusions This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes

Mathematical stories: Why do more boys than girls choose to study mathematics at AS-level in England?

Copyright @ 2005 Taylor & FrancisIn this paper I address the question: How is it that people come to choose mathematics and in what ways is this process gendered? I draw on the findings of a qualitative research study involving interviews with 43 young people all studying mathematics in post-compulsory education in England. Working within a post-structuralist framework, I argue that gender is a project and one that is achieved in interaction with others. Through a detailed reading of Toni and Claudia’s stories I explore the tensions for young women who are engaging in mathematics, something that is discursively inscribed as masculine, while (understandably) being invested in producing themselves as female. I conclude by arguing that seeing ‘doing mathematics’ as ‘doing masculinity’ is a productive way of understanding why mathematics is so male dominated and by looking at the implications of this understanding for gender and mathematics reform work.This work is funded by the ESR

Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a threat to human health worldwide. Although progress has been made, mechanisms of CA-MRSA pathogenesis are poorly understood and a comprehensive analysis of CA-MRSA exoproteins has not been conducted. To address that deficiency, we used proteomics to identify exoproteins made by MW2 (USA400) and LAC (USA300) during growth in vitro. Two hundred and fifty unique exoproteins were identified by 2-dimensional gel electrophoresis coupled with automated direct infusion-tandem mass spectrometry (ADI-MS/MS) analysis. Eleven known virulence-related exoproteins differed in abundance between the strains, including alpha-haemolysin (Hla), collagen adhesin (Cna), staphylokinase (Sak), coagulase (Coa), lipase (Lip), enterotoxin C3 (Sec3), enterotoxin Q (Seq), V8 protease (SspA) and cysteine protease (SspB). Mice infected with MW2 or LAC produced antibodies specific for known or putative virulence factors, such as autolysin (Atl), Cna, Ear, ferritin (Ftn), Lip, 1-phosphatidylinositol phosphodiesterase (Plc), Sak, Sec3 and SspB, indicating the exoproteins are made during infection in vivo. We used confocal microscopy to demonstrate aureolysin (Aur), Hla, SspA and SspB are produced following phagocytosis by human neutrophils, thereby linking exoprotein production in vitro with that during host–pathogen interaction. We conclude that the exoproteins identified herein likely account in part for the success of CA-MRSA as a human pathogen

At identical isowork rates, ageing influences cardiorespiratory adaptations in COPD out-patients

SummaryPurposeTo determine the extent to which younger COPD patients improve their cardiorespiratory function during exercise in comparison with older COPD patients, as a result of exercise training.MethodsThirty-nine COPD patients underwent an exercise program. They were divided into two groups: a younger group (57.2±1.0 years, n=18 patients) and an older group (68.8±0.6 years, n=21 patients). Forced expiratory volume in 1s was lower than 55% of the predicted value for all patients.ResultsAfter training, V˙O2 symptom-limited significantly improved by 10.3% and 8.4% for the younger and older COPD patients, respectively (P<0.05). Peak power significantly improved by 25.2% and 17.8% in the younger and older groups, respectively (P<0.05) with a greater improvement for the younger group (P<0.05). At submaximal exercise, ventilation and heart rate significantly decreased after training in the younger COPD patients (P<0.05) with no significant modification in the older COPD patients.ConclusionsThe results suggest that all patients with COPD benefit from exercise rehabilitation at maximal exercise workload, however, according to their age, submaximal cardiorespiratory adaptations were greater in younger patients

Evidence of Combat in Triceratops

Background: The horns and frill of Triceratops and other ceratopsids (horned dinosaurs) are interpreted variously as display structures or as weapons against conspecifics and predators. Lesions (in the form of periosteal reactive bone, healing fractures, and alleged punctures) on Triceratops skulls have been used as anecdotal support of intraspecific combat similar to that in modern horned and antlered animals. If ceratopsids with different cranial morphologies used their horns in such combat, this should be reflected in the rates of lesion occurrence across the skull. Methodology/Principal Findings: We used a G-test of independence to compare incidence rates of lesions in Triceratops (which possesses two large brow horns and a smaller nasal horn) and the related ceratopsid Centrosaurus (with a large nasal horn and small brow horns), for the nasal, jugal, squamosal, and parietal bones of the skull. The two taxa differ significantly in the occurrence of lesions on the squamosal bone of the frill (P = 0.002), but not in other cranial bones (P.0.20). Conclusions/Significance: This pattern is consistent with Triceratops using its horns in combat and the frill being adapted as a protective structure for this taxon. Lower pathology rates in Centrosaurus may indicate visual rather than physical use o

Crystal Structure of 2′,3′-Di-O-Acetyl-5′-Deoxy-5-Fluorocytidine with N–H···(O,F) Proton Donor Bifurcated and (C,N)–H···O Bifurcated Acceptor Dual Three-Center Hydrogen Bond Configurations

The title compound, C13H16O6N3F, features a central furan ring containing four carbon atom chiral centers with a 4-amino-5-fluoro-2-oxopyrimidine group, two acetyl groups and a methyl group bonded at the 2,3,4,5 positions, each in an absolute R configuration (2R,3R,4R,5R). It crystallizes in the monoclinic space group C2 with unit cell parameters a = 14.5341(3), b = 7.26230(10), c = 16.2197(3) Å, β = 116.607(2)°, Z = 4. An extensive array of intra and inter molecular hydrogen bond interactions dominate crystal packing in the unit cell highlighted by a relatively rare three-center proton-bifurcated donor N–H···(O,F) hydrogen bond interaction in cooperation with a second, (C,N)–H···O bifurcated acceptor three-center hydrogen bond in a supportive fashion. Additional weak Cg π-ring inter molecular interactions between a fluorine atom and the 4-amino-5-fluoro-2-oxopyrimidine ring in concert with multiple donor and acceptor hydrogen bonds significantly influence the bond distances, bond angles and torsion angles of the deoxy-5-fluorocytidine group. Comparison to a MOPAC computational calculation provides support to these observations

Drama, performance and touch in the medieval convent and beyond

In this analysis we explore the sensory performances of the performer, rather than the spectator, in medieval convent drama, particularly the tactile experiences of clothing, props, wigs, and beards worn by female performers presenting male and female characters

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission

SLC4A10 is a plasma-membrane bound transporter which utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of cerebrospinal fluid. Using next generation sequencing on samples from five unrelated families encompassing ten affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and typically severe intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorders including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioral abnormalities including delayed habituation and alterations in the 2-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggests an important role of SLC4A10 in the production of the cerebrospinal fluid. However, it is notable that despite diverse roles of the cerebrospinal fluid in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel characteristic neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties

The Relationship Between GPS Sampling Interval and Estimated Daily Travel Distances in Chacma Baboons (Papio ursinus)

Modern studies of animal movement use the Global Positioning System (GPS) to estimate animals’ distance traveled. The temporal resolution of GPS fixes recorded should match those of the behavior of interest; otherwise estimates are likely to be inappropriate. Here, we investigate how different GPS sampling intervals affect estimated daily travel distances for wild chacma baboons (Papio ursinus). By subsampling GPS data collected at one fix per second for 143 daily travel distances (12 baboons over 11–12 days), we found that less frequent GPS fixes result in smaller estimated travel distances. Moving from a GPS frequency of one fix every second to one fix every 30 s resulted in a 33% reduction in estimated daily travel distance, while using hourly GPS fixes resulted in a 66% reduction. We then use the relationship we find between estimated travel distance and GPS sampling interval to recalculate published baboon daily travel distances and find that accounting for the predicted effect of sampling interval does not affect conclusions of previous comparative analyses. However, if short-interval or continuous GPS data—which are becoming more common in studies of primate movement ecology—are compared with historical (longer interval) GPS data in future work, controlling for sampling interval is necessary

Diet rapidly and reproducibly alters the human gut microbiome

Long-term diet influences the structure and activity of the trillions of microorganisms residing in the human gut1–5, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here, we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila, and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale, and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals2, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi, and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids, and the outgrowth of microorganisms capable of triggering inflammatory bowel disease6. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles