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Find video protocols related to scientific articles indexed in Pubmed.
Patients receiving anti-TNF therapies experience clinically important improvements in RA-related fatigue: results from the British Society of Rheumatology Biologics Register for Rheumatoid Arthritis.
Rheumatology (Oxford)
PUBLISHED: 10-15-2014
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Pro-inflammatory cytokines such as TNF-? are important in the pathogenesis of fatigue in conditions such as RA. This study aimed to determine whether fatigue improved in a cohort of RA patients with clinically relevant fatigue commencing anti-TNF-? therapy and, if so, to identify predictors of improvement.
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Differentiating the Frontal Presentation of Alzheimer's Disease with FDG-PET.
J. Alzheimers Dis.
PUBLISHED: 09-28-2014
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Background: Alzheimer's disease (AD) can present with behavioral changes with this syndrome described as frontal variant AD (FvAD). Excess frontal pathology may explain this presentation. Neuroimaging with fluoro-deoxy-glucose positron emission tomography (FDG- PET) can be used to examine the effects of pathology in FvAD. Methods: We administered an assessment scale for frontal behavioral impairment, the Frontal Behavioral Inventory (FBI), to 53 patients with AD. Scores in the top quartile were defined as FvAD. FDG- PET was analyzed in 8 frontal regions. Results: The Z (SD) score for metabolism was significantly higher (indicating greater hypometabolism) in the FvAD group than the remaining AD group for combined left and right orbitofrontal regions (2.64 (SD 0.99) versus 2.11 (1.22), p < 0.03)) and combined left and right medial frontal regions (2.38 (0.63) versus 1.82 (0.88) p < 0.003) but insignificantly different in combined lateral frontal and superior frontal regions. Statistical parametric mapping revealed these frontal regions to be the only brain regions with significantly different metabolism between the FvAD and the remainder of the AD groups. Conclusions: Medial and orbital frontal hypometabolism is greater in AD patients presenting with more frontal/behavioral features, likely reflecting a greater pathological load in these brain regions in FvAD patients. These frontal regions may be more linked to behavioral features than other frontal brain regions.
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Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction.
Arthritis Res. Ther.
PUBLISHED: 08-30-2014
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IntroductionActivation of the inflammasome has been implicated in the pathology of various auto-inflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.MethodsAntigen-induced arthritis (AIA) was established in IL-10KO mice and wild type controls. Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies explored the regulation of inflammasome components. These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays.ResultsIn AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores. Here, focal bone erosions were associated with increased tartrate resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1ß. When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components. Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1. In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis.ConclusionThese data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.
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The cloud and other new computational methods to improve molecular modelling.
Expert Opin Drug Discov
PUBLISHED: 08-22-2014
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Industrial, as well as academic, drug discovery efforts are usually supported by computational modelling techniques. Many of these techniques, such as virtual high-throughput docking, pharmacophore-based screening of conformer databases and molecular dynamics simulations, are computationally very demanding. Depending on the parallelisation strategy applicable to the respective method, recent technologies based on central processing units, for example, cloud and grid computing, or graphics processing units (GPUs), can be employed to accelerate their execution times considerably. This allows the molecular modeller to look at larger data sets, or to use more accurate methods.
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Adaptive functional diversification of lysozyme in insectivorous bats.
Mol. Biol. Evol.
PUBLISHED: 08-18-2014
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The role of gene duplication in generating new genes and novel functions is well recognized and is exemplified by the digestion-related protein lysozyme. In ruminants, duplicated chicken-type lysozymes facilitate the degradation of symbiotic bacteria in the foregut. Chicken-type lysozyme has also been reported to show chitinase-like activity, yet no study has examined the molecular evolution of lysozymes in species that specialize on eating insects. Insectivorous bats number over 900 species, and lysozyme expression in the mouths of some of these species is associated with the ingestion of insect cuticle, suggesting a chitinase role. Here, we show that chicken-type lysozyme has undergone multiple duplication events in a major family of insect-eating bats (Vespertilionidae) and that new duplicates have undergone molecular adaptation. Examination of duplicates from two insectivorous bats-Pipistrellus abramus and Scotophilus kuhlii-indicated that the new copy was highly expressed in the tongue, whereas the other one was less tissue-specific. Functional assays applied to pipistrelle lysozymes confirmed that, of the two copies, the tongue duplicate was more efficient at breaking down glycol chitin, a chitin derivative. These results suggest that the evolution of lysozymes in vespertilionid bats has likely been driven in part by natural selection for insectivory.
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WIP is necessary for matrix invasion by breast cancer cells.
Eur. J. Cell Biol.
PUBLISHED: 08-07-2014
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Actin filament assembly and reorganisation during cell migration and invasion into extracellular matrices is a well-documented phenomenon. Among actin-binding proteins regulating its polymerisation, the members of the WASP (Wiskott Aldrich Syndrome Protein) family are generally thought to play the most significant role in supporting cell invasiveness. In situ, cytosolic N-WASP (neural WASP) is associated with a partner protein termed WIP (WASP Interacting Protein) that is bound to the N-terminal domain of N-WASP. Despite much effort, rather little is known about the role of WIP in regulating N-WASP and consequent actin-filament assembly. Even less is known about the function of WIP within the specialised cell adhesion and attachment structures known as podosomes and invadopodia. In particular, whilst the interaction of WIP with known participants in the development and maturation of invadopodia such as N-WASP, the Arp2/3 complex and cortactin has been described, little is known concerning the direct contribution of WIP to invadopodia and its potential role as a regulator of cancer cell invasion. In this report, we use 2D and 3D culture systems to describe the role played by WIP in modulating the morphology and invasiveness of metastatic breast cancer cells in vitro, as well as its effect on the process of mesenchymal-epithelial transition (MET) seen in these cells. We demonstrate that WIP is necessary for invadopodium formation and matrix degradation by basal breast cancer cells, but not sufficient to induce invasiveness in luminal cells.
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Where does New Zealand stand on permitting research on human embryos?
N. Z. Med. J.
PUBLISHED: 08-01-2014
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In many respects New Zealand has responded to the assisted reproductive technologies (ARTs) as positively as many comparable societies, such as Australia and the UK. Consequently, in vitro fertilisation (IVF) and pre-implantation genetic diagnosis (PGD) are widely available, as is non-commercial surrogacy utilising IVF. These developments have been made possible by the Human Assisted Reproductive Technology (HART) Act 2004, overseen by its two committees, the Advisory Committee on Assisted Reproductive Technology (ACART) and the Ethics Committee (ECART). However, New Zealand stands apart from many of these other societies by the lack of permission for scientists to conduct research using human embryos. There is no doubt this reflects strongly held viewpoints on the part of some that embryos should be protected and not exploited. Legitimate as this stance is, the resulting situation is problematic when IVF is already designated as an established procedure. This is because the development of IVF involved embryo research, and continuing improvements in procedures depend upon ongoing embryo research. While prohibition of research on human embryos gives the impression of protecting embryos, it fails to do this and also fails to enhance the health and wellbeing of children born using IVF. This situation will not be rectified until research is allowed on human embryos.
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Normative data for the Hospital Anxiety and Depression Scale.
Qual Life Res
PUBLISHED: 07-17-2014
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The Hospital Anxiety and Depression Scale (HADS) is widely used in both research and clinical contexts. However, UK normative data from HADS remain limited. In our recent review of the literature, only six reports from four studies were identified as reporting UK normative data and all had limitations. The aim of our study was to use a large population-based dataset to address this.
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Interleukin-6 in renal disease and therapy.
Nephrol. Dial. Transplant.
PUBLISHED: 07-12-2014
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Interleukin (IL)-6 has become a major target for clinical intervention in various autoimmune conditions. Here, drugs including the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab emphasize the clinical importance of IL-6 in driving disease and poor patient outcomes. During the course of this review, we will outline the biology surrounding IL-6 and discuss the impact of IL-6 in renal disease and the clinical complications associated with renal replacement therapies and transplantation. We will also consider the merit of IL-6 measurement as a prognostic indicator and provide a clinical perspective on IL-6-blocking therapies in renal disease.
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Ectopic lymphoid-like structures in infection, cancer and autoimmunity.
Nat. Rev. Immunol.
PUBLISHED: 06-20-2014
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Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
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Neural correlates of fatigue in granulomatosis with polyangiitis: a functional magnetic resonance imaging study.
Rheumatology (Oxford)
PUBLISHED: 06-13-2014
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The aim of this study was to investigate the neurophysiological effects of fatigue among patients with granulomatosis with polyangiitis (GPA).
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The effect of an internet option and single-sided printing format to increase the response rate to a population-based study: a randomized controlled trial.
BMC Med Res Methodol
PUBLISHED: 05-21-2014
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Paper questionnaires are a common means to collect self-reported information in population-based epidemiological studies. Over the past decades, the response rates to epidemiological studies have been decreasing which can affect the selection process of eligible subjects and lead to non-response bias. Hence, research into strategies to increase questionnaire response rates is crucial. The aim of this study was therefore to explore the effectiveness of single-sided questionnaires and an internet option for response in increasing response rates to a population-based study.
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OB-RL silencing inhibits the thermoregulatory ability of Great Roundleaf Bats (Hipposideros armiger).
Gen. Comp. Endocrinol.
PUBLISHED: 04-22-2014
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Previous studies have shown that the hormone Leptin has an important role in mammalian heterothermy by regulating metabolism and food intake via lipolysis, as well as adaptive evolution of Leptin in heterothermic bats driven by selected pressure. However, the mechanism of Leptin in heterothermic regulation in mammals is unknown. By combining previous results, we speculated that the Leptin signaling pathway mediated by OB-RL (Leptin receptor long form) in the hypothalamus is important. OB-RL is one of the products of db gene and mainly distributed in the hypothalamus. In this study, we used OB-RL as a molecular marker, combining with the RNA interference technology and physiological/molecular analyses with Hipposideros armiger (a hibernating bat species) as an animal model, to explore the mechanism of Leptin in heterothermic regulation. Our data showed that all of four anti-OB-RL shRNA lentivirus significantly inhibited OB-RL expression (>90%), and the interference efficiency of PSC1742 lentivirus reached the highest value. In situ hybridization proved that PSC1742 lentivirus significantly decreased the OB-RL expression in the hypothalamus, especially in the ventromedial hypothalamic nucleus (VHM, 86.6%). Physiological analysis demonstrated that the thermoregulatory ability of bats (e.g., reducing core body temperature and heart rate) was significantly depressed after OB-RL silencing in the hypothalamus, and animals could not enter torpor state. Our study for the first time proved that the knock-down of OB-RL expression in hypothalamus inhibits heterothermic regulation of bats, and also provided the clues for further analyzing the mechanism of Leptin in the heterothermic regulation of mammals.
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Current evidence of anti-tumor necrosis factor ? treatment efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach of individual drugs.
Arthritis Care Res (Hoboken)
PUBLISHED: 04-18-2014
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To summarize evidence regarding the effectiveness of anti-tumor necrosis factor ? (anti-TNF?) treatments in childhood autoimmune chronic uveitis (ACU), refractory to previous disease-modifying antirheumatic drugs (DMARDs).
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HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.
Nat. Genet.
PUBLISHED: 03-17-2014
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Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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The bacterial microbiota of Stolotermes ruficeps (Stolotermitidae), a phylogenetically basal termite endemic to New Zealand.
FEMS Microbiol. Ecol.
PUBLISHED: 02-26-2014
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Stolotermes ruficeps is a widespread, primitive, lower termite occupying dead and decaying wood of many tree species in New Zealand's temperate forests. We identified core bacterial taxa involved in gut processes through combined DNA- and RNA (cDNA)-based pyrosequencing analysis of the 16S nucleotide sequence from five S. ruficeps colonies. Most family and many genus-level taxa were common to S. ruficeps colonies despite being sampled from different tree species. Major taxa identified were Spirochaetaceae, Elusimicrobiaceae and Porphyromonadaceae. Others less well known in termite guts were Synergistaceae, Desulfobacteraceae, Rhodocyclaceae, Lachnospiraceae and Ruminococcaceae. Synergistaceae, Lachnospiraceae and Spirochaetaceae were well represented in the RNA data set, indicating a high-protein synthesis potential. Using 130 800 sequences from nine S. ruficeps DNA and RNA data sets, we estimated a high level of bacterial richness (4024 phylotypes at 3% genetic distance). Very few abundant phylotypes were site-specific; almost all (95%) abundant phylotypes, representing 97% of data set sequences, were detected in at least two S. ruficeps colonies. This study of a little-researched phylogenetically basal termite identifies core bacteria taxa. These findings will extend inventories of termite gut microbiota and contribute to the understanding of the specificity of termite gut microbiota.
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The prevalence of fibromyalgia in the general population - a comparison of the American College of Rheumatology 1990, 2010 and modified 2010 classification criteria.
PUBLISHED: 02-12-2014
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Background The ACR 1990 fibromyalgia classification criteria are based on widespread pain and tenderness. In 2010 new criteria were proposed, focusing more on multiple symptoms and these, latterly, were modified to require only self-report. The current study aimed to determine the population prevalence of fibromyalgia, and to compare differences in prevalence, using the alternative criteria. Methods A cross-sectional survey was conducted. Questionnaires, including items on pain, symptoms, and rheumatological diagnoses, were mailed to 4600 adults in northeast Scotland. Participants with chronic widespread pain, or who met the modified 2010 criteria, plus a sub-sample of other participants were invited to a research clinic. Attendees completed an additional questionnaire, and a rheumatological examination, and were classified according to the ACR 1990, 2010 and modified 2010 criteria. The prevalence of each was calculated, weighting back to the target population by age, sex and area of residence. Results Of 1604 questionnaire participants, 269 were invited and 104 (39%) attended the research clinic, of whom 32 (31%) met ?1 of the fibromyalgia criteria. The prevalence of fibromyalgia using the 1990, 2010 and modified 2010 criteria was 1.7% (95%CI: 0.7-2.8%); 1.2% (0.3-2.1%); and 5.4% (4.7-6.1%), respectively. The female/male ratio was 13.7 to 4.8 and 2.3, respectively. Conclusion Fibromyalgia prevalence varies with the different classification criteria - specifically, prevalence is higher, and a greater proportion of men are identified, with the modified 2010 criteria, compared to those requiring clinician input. This has important implications for the use of the new criteria both in research and in clinical practice. © 2014 American College of Rheumatology.
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Does switching anti-TNF? biologic agents represent an effective option in childhood chronic uveitis: the evidence from a systematic review and meta-analysis approach.
Semin. Arthritis Rheum.
PUBLISHED: 02-10-2014
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To summarize the evidence regarding the effectiveness of switching to a second anti-TNF? treatment in children with autoimmune chronic uveitis (ACU), refractory to the first course of anti-TNF? treatment.
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Maintained physical activity and physiotherapy in the management of distal upper limb pain - a protocol for a randomised controlled trial (the arm pain trial).
BMC Musculoskelet Disord
PUBLISHED: 02-10-2014
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Distal upper limb pain (pain affecting the elbow, forearm, wrist, or hand) can be non-specific, or can arise from specific musculoskeletal disorders. It is clinically important and costly, the best approach to clinical management is unclear. Physiotherapy is the standard treatment and, while awaiting treatment, advice is often given to rest and avoid strenuous activities, but there is no evidence base to support these strategies. This paper describes the protocol of a randomised controlled trial to determine, among patients awaiting physiotherapy for distal arm pain, (a) whether advice to remain active and maintain usual activities results in a long-term reduction in arm pain and disability, compared with advice to rest; and (b) whether immediate physiotherapy results in a long-term reduction in arm pain and disability, compared with physiotherapy delivered after a seven week waiting list period.
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Markers for work disability in anti-neutrophil cytoplasmic antibody-associated vasculitis.
Rheumatology (Oxford)
PUBLISHED: 01-31-2014
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ANCA-associated vasculitis (AAV) commonly affects those of working age. Since survival rates have been transformed by immunotherapeutics, the measurement of other outcomes has become increasingly relevant. Work disability is an important outcome for both patient and society that has yet to be fully evaluated in AAV. We aimed to assess employment status in AAV patients and identify putative predictors of their work disability.
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Fitting and handling dose response data.
J. Comput. Aided Mol. Des.
PUBLISHED: 01-28-2014
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The half maximal response of any compound in a biological system is a fundamental measure of the compound's potency whether the activity of the compound is beneficial or detrimental. As such, the estimation of this response as an Ec50 or an Ic50 results in a value that has fundamental significance in the determination of the potential of a compound. A collection of these values provide an invaluable data framework for understanding structure-activity relationships and computational method development and benchmarking. Therefore, understanding the errors and reproducibility issues associated with Ic50 determinations is essential for their robust calculation. This paper will discuss the practical approaches to the use of the Levenberg-Marquardt minimization method to fit dose response data and evaluate the resultant data in a statistically rigorous way.
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Integrin linked kinase (ILK) regulates podosome maturation and stability in dendritic cells.
Int. J. Biochem. Cell Biol.
PUBLISHED: 01-28-2014
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Podosomes are integrin-based adhesions fundamental for stabilisation of the leading lamellae in migrating dendritic cells (DCs) and for extracellular matrix (ECM) degradation. We have previously shown that soluble factors and chemokines such as SDF 1-a trigger podosome initiation whereas integrin ligands promote podosome maturation and stability in DCs. The exact intracellular signalling pathways that regulate the sequential organisation of podosomal components in response to extracellular cues remain largely undetermined. The Wiskott Aldrich Syndrome Protein (WASP) mediates actin polymerisation and the initial recruitment of integrins and associated proteins in a circular configuration surrounding the core of filamentous actin (F-actin) during podosome initiation. We have now identified integrin linked kinase (ILK) surrounding the podosomal actin core. We report that DC polarisation in response to chemokines and the assembly of actin cores during podosome initiation require PI3K-dependent clustering of the Wiskott Aldrich Syndrome Protein (WASP) in puncta independently of ILK. ILK is essential for the clustering of integrins and associated proteins leading to podosome maturation and stability that are required for degradation of the subjacent extracellular matrix and the invasive motility of DCs across connective tissue barriers. We conclude that WASP regulates DCs polarisation for migration and initiation of actin polymerisation downstream of PI3K in nascent podosomes. Subsequently, ILK mediates the accumulation of integrin-associated proteins during podosome maturation and stability for efficient degradation of the subjacent ECM during the invasive migration of DCs.
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Interleukin-6 signaling drives fibrosis in unresolved inflammation.
Immunity
PUBLISHED: 01-09-2014
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Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-? (IFN-?), STAT1, or RAG-1. Here, IFN-? and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.
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Second generation sequencing and morphological faecal analysis reveal unexpected foraging behaviour by Myotis nattereri (Chiroptera, Vespertilionidae) in winter.
Front. Zool.
PUBLISHED: 01-01-2014
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Temperate winters produce extreme energetic challenges for small insectivorous mammals. Some bat species inhabiting locations with mild temperate winters forage during brief inter-torpor normothermic periods of activity. However, the winter diet of bats in mild temperate locations is studied infrequently. Although microscopic analyses of faeces have traditionally been used to characterise bat diet, recently the coupling of PCR with second generation sequencing has offered the potential to further advance our understanding of animal dietary composition and foraging behaviour by allowing identification of a much greater proportion of prey items often with increased taxonomic resolution. We used morphological analysis and Illumina-based second generation sequencing to study the winter diet of Natterer's bat (Myotis nattereri) and compared the results obtained from these two approaches. For the first time, we demonstrate the applicability of the Illumina MiSeq platform as a data generation source for bat dietary analyses.
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Relaxed evolution in the tyrosine aminotransferase gene tat in old world fruit bats (chiroptera: pteropodidae).
PLoS ONE
PUBLISHED: 01-01-2014
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Frugivorous and nectarivorous bats fuel their metabolism mostly by using carbohydrates and allocate the restricted amounts of ingested proteins mainly for anabolic protein syntheses rather than for catabolic energy production. Thus, it is possible that genes involved in protein (amino acid) catabolism may have undergone relaxed evolution in these fruit- and nectar-eating bats. The tyrosine aminotransferase (TAT, encoded by the Tat gene) is the rate-limiting enzyme in the tyrosine catabolic pathway. To test whether the Tat gene has undergone relaxed evolution in the fruit- and nectar-eating bats, we obtained the Tat coding region from 20 bat species including four Old World fruit bats (Pteropodidae) and two New World fruit bats (Phyllostomidae). Phylogenetic reconstructions revealed a gene tree in which all echolocating bats (including the New World fruit bats) formed a monophyletic group. The phylogenetic conflict appears to stem from accelerated TAT protein sequence evolution in the Old World fruit bats. Our molecular evolutionary analyses confirmed a change in the selection pressure acting on Tat, which was likely caused by a relaxation of the evolutionary constraints on the Tat gene in the Old World fruit bats. Hepatic TAT activity assays showed that TAT activities in species of the Old World fruit bats are significantly lower than those of insectivorous bats and omnivorous mice, which was not caused by a change in TAT protein levels in the liver. Our study provides unambiguous evidence that the Tat gene has undergone relaxed evolution in the Old World fruit bats in response to changes in their metabolism due to the evolution of their special diet.
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Determinants and patterns of reproductive success in the greater horseshoe bat during a population recovery.
PLoS ONE
PUBLISHED: 01-01-2014
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An individual's reproductive success will depend on traits that increase access to mates, as well as the number of mates available. In most well-studied mammals, males are the larger sex, and body size often increases success in intra-sexual contests and thus paternity. In comparison, the determinants of male success in species with reversed sexual size dimorphism (RSD) are less well understood. Greater horseshoe bats (Rhinolophus ferrumequinum) exhibit RSD and females appear to exert mate choice when they visit and copulate with males in their underground territories. Here we assessed putative determinants of reproductive success in a colony of greater horseshoe bats during a 19-year period of rapid population growth. We genotyped 1080 bats with up to 40 microsatellite loci and assigned maternity to 99.5% of pups, and paternity to 76.8% of pups. We found that in spite of RSD, paternity success correlated positively with male size, and, consistent with our previous findings, also with age. Female reproductive success, which has not previously been studied in this population, was also age-related and correlated positively with individual heterozygosity, but not with body size. Remarkable male reproductive skew was detected that initially increased steadily with population size, possibly coinciding with the saturation of suitable territories, but then levelled off suggesting an upper limit to a male's number of partners. Our results illustrate that RSD can occur alongside intense male sexual competition, that male breeding success is density-dependent, and that male and female greater horseshoe bats are subject to different selective pressures.
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Vinculin binding angle in podosomes revealed by high resolution microscopy.
PLoS ONE
PUBLISHED: 01-01-2014
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Podosomes are highly dynamic actin-rich adhesive structures formed predominantly by cells of the monocytic lineage, which degrade the extracellular matrix. They consist of a core of F-actin and actin-regulating proteins, surrounded by a ring of adhesion-associated proteins such as vinculin. We have characterised the structure of podosomes in macrophages, particularly the structure of the ring, using three super-resolution fluorescence microscopy techniques: stimulated emission depletion microscopy, structured illumination microscopy and localisation microscopy. Rather than being round, as previously assumed, we found the vinculin ring to be created from relatively straight strands of vinculin, resulting in a distinctly polygonal shape. The strands bind preferentially at angles between 116° and 135°. Furthermore, adjacent vinculin strands are observed nucleating at the corners of the podosomes, suggesting a mechanism for podosome growth.
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The importance of invertebrates when considering the impacts of anthropogenic noise.
Proc. Biol. Sci.
PUBLISHED: 12-17-2013
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Anthropogenic noise is now recognized as a major global pollutant. Rapidly burgeoning research has identified impacts on individual behaviour and physiology through to community disruption. To date, however, there has been an almost exclusive focus on vertebrates. Not only does their central role in food webs and in fulfilling ecosystem services make imperative our understanding of how invertebrates are impacted by all aspects of environmental change, but also many of their inherent characteristics provide opportunities to overcome common issues with the current anthropogenic noise literature. Here, we begin by explaining why invertebrates are likely to be affected by anthropogenic noise, briefly reviewing their capacity for hearing and providing evidence that they are capable of evolutionary adaptation and behavioural plasticity in response to natural noise sources. We then discuss the importance of quantifying accurately and fully both auditory ability and noise content, emphasizing considerations of direct relevance to how invertebrates detect sounds. We showcase how studying invertebrates can help with the behavioural bias in the literature, the difficulties in drawing strong, ecologically valid conclusions and the need for studies on fitness impacts. Finally, we suggest avenues of future research using invertebrates that would advance our understanding of the impact of anthropogenic noise.
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Global prevalence of ankylosing spondylitis.
Rheumatology (Oxford)
PUBLISHED: 12-09-2013
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Objectives. For effective health care provision, knowledge of disease prevalence is paramount. There has been no systematic endeavour to establish continent-based AS estimates, however, prevalence is thought to vary by country and background HLA-B27 prevalence. This study aimed to estimate AS prevalence worldwide and to calculate the expected number of cases.Methods. A systematic literature search was conducted. Prevalence data were extracted and used to calculate the mean prevalence by continent and the expected number of cases based on country-specific prevalence (or, if missing, the prevalence from neighbouring countries). A second estimate was made using the prevalence from countries with similar HLA-B27 prevalences if a country-specific prevalence estimate was not available.Results. The mean AS prevalence per 10 000 (from 36 eligible studies) was 23.8 in Europe, 16.7 in Asia, 31.9 in North America, 10.2 in Latin America and 7.4 in Africa. Additional estimates, weighted by study size, were calculated as 18.6, 18.0 and 12.2 for Europe, Asia and Latin America, respectively. There were sufficient studies to estimate the number of cases in Europe and Asia, calculated to be 1.30-1.56 million and 4.63-4.98 million, respectively.Conclusion. This study represents the first systematic attempt to collate estimates of AS prevalence into a single continent-based estimate. In addition, the number of expected cases in Europe and Asia was estimated. Through reviewing the current literature, it is apparent that the continuing conduct of epidemiological studies of AS prevalence is of great importance, particularly as diagnostic capabilities improve and with the recent development of the criteria for axial SpA.
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Early changes in scores of chronic damage on transplant kidney protocol biopsies reflect donor characteristics, but not future graft function.
Clin Transplant
PUBLISHED: 08-27-2013
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The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single-center cohort, we examined the relationship between donor-, recipient-, and transplantation-associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2-3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0-8) and 2-3 months post-transplant (median 8% IQR:4-15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post-transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes.
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Creating the best workplace on earth.
Harv Bus Rev
PUBLISHED: 08-01-2013
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No organization can fulfill every hope and desire of its employees, so it helps to know which matter most to people. Goffee and Jones have identified the six most essential imperatives for creating an ideal work environment. Their insights come from surveys and interviews of hundreds of executives from all over the world. Few organizations embody all six attributes of the dream organization, many are difficult to achieve, and some even conflict with one another. But they nonetheless stand as an agenda for executives who wish to create the most productive, most rewarding workplace imaginable. Agenda 1. Let people be themselves. 2. Unleash the flow of information. 3. Magnify peoples strengths. 4. Stand for more than shareholder value. 5. Show how the daily work makes sense. 6. Have rules people can believe in. This list contains no surprises, but implementing the elements is no easy task. Almost all of them require leaders to carefully balance competing interests and to reallocate their time and attention. Companies like Arup, LVMH, Waitrose, and even McDonalds are doing it to varying degrees. Your challenge is to match-and then to exceed-what they have managed to accomplish.
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First knockdown gene expression in bat (Hipposideros armiger) brain mediated by lentivirus.
Mol. Biotechnol.
PUBLISHED: 07-03-2013
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Lentivirus-mediated RNA interference (RNAi) is a potent experimental tool for investigating gene functions in vitro and in vivo. It has advantages that transgenic technology lacks. However, in vivo applications are difficult to apply in the central nervous system of non-model organisms due to the lack of a standard brain atlas and genetic information. Here, we report the development of an in vivo gene delivery system used in bat brain tissue for the first time, based on lentivirus (LV) vectors expressing short hairpin RNA (shRNA) targeting Hipposideros armiger forkhead box P2 (FoxP2). In vitro transfection into HEK 293T cell with the vector bearing the cassettes encoding FoxP2 shRNA verified the knockdown efficiency. Pseudovirus particles were administered via stereotactic intracerebral microinjection into the anterior cingulate cortex of H. armiger. FoxP2 is of major interest because of its role in sensorimotor coordination and probably in echolocation. Subsequent in situ hybridization validated the in vivo silencing of the target gene. This report demonstrates that LV-mediated expression of RNAi could achieve effective gene silencing in bats, a non-model organism, and will assist in elucidating the functions of bat genes.
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Age-related increase in electromyography burst activity in males and females.
J Aging Res
PUBLISHED: 06-16-2013
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The rapid advancement of electromyography (EMG) technology facilitates measurement of muscle activity outside the laboratory during daily life. The purpose of this study was to determine whether bursts in EMG recorded over a typical 8-hour day differed between young and old males and females. Muscle activity was recorded from biceps brachii, triceps brachii, vastus lateralis, and biceps femoris of 16 young and 15 old adults using portable surface EMG. Old muscles were active 16-27% of the time compared to 5-9% in young muscles. The number of bursts was greater in old than young adults and in females compared to males. Burst percentage and mean amplitude were greater in the flexor muscles compared with the extensor muscles. The greater burst activity in old adults coupled with the unique activity patterns across muscles in males and females provides further understanding of how changes in neuromuscular activity effects age-related functional decline between the sexes.
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Explaining fatigue in ANCA-associated vasculitis.
Rheumatology (Oxford)
PUBLISHED: 06-04-2013
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To identify the determinants of fatigue among patients with ANCA-associated vasculitis (AAV).
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Imaging cells at the nanoscale.
Int. J. Biochem. Cell Biol.
PUBLISHED: 05-09-2013
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Recently developed super-resolution techniques in optical microscopy have pushed the length scale at which cellular structure can be observed down to tens of nanometres. A wide array of methods have been described that fall under the umbrella term of super-resolution microscopy and each of these methods has different requirements for acquisition speed, experimental complexity, fluorophore requirements and post-processing of data. For example, experimental complexity can be decreased by using a standard widefield microscope for acquisition, but this requires substantial processing of the data to extract the super-resolution information. These powerful techniques are bringing new insights into the nanoscale structure of sub-cellular assemblies such as podosomes, which are an ideal system to observe with super-resolution microscopy as the structures are relatively thin and they form and dissociate over a period of several minutes. Here we discuss the major classes of super-resolution microscopy techniques, and demonstrate their relative performance by imaging podosomes.
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LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-? production by repressing ?-catenin activation in dendritic cells.
PLoS Pathog.
PUBLISHED: 05-01-2013
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Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2-/- mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear ?-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2-/- DCs. Accordingly, Lat2-/- DCs directed reduced Th1 polarization in vitro and Lat2-/- mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-? production in vivo/ex vivo. Thus our data define a novel link between LAB and ?-catenin nuclear accumulation in DCs that facilitates IFN-? responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-? response for pathogen clearance.
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Integrin-Matrix Clusters Form Podosome-like Adhesions in the Absence of Traction Forces.
Cell Rep
PUBLISHED: 04-26-2013
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Matrix-activated integrins can form different adhesion structures. We report that nontransformed fibroblasts develop podosome-like adhesions when spread on fluid Arg-Gly-Asp peptide (RGD)-lipid surfaces, whereas they habitually form focal adhesions on rigid RGD glass surfaces. Similar to classic macrophage podosomes, the podosome-like adhesions are protrusive and characterized by doughnut-shaped RGD rings that surround characteristic core components including F-actin, N-WASP, and Arp2/Arp3. Furthermore, there are 18 podosome markers in these adhesions, though they lack matrix metalloproteinases that characterize invadopodia and podosomes of Src-transformed cells. When nontransformed cells develop force on integrin-RGD clusters by pulling RGD lipids to prefabricated rigid barriers (metal lines spaced by 1-2 ?m), these podosomes fail to form and instead form focal adhesions. The formation of podosomes on fluid surfaces is mediated by local activation of phosphoinositide 3-kinase (PI3K) and the production of phosphatidylinositol-(3,4,5)-triphosphate (PIP3) in a FAK/PYK2-dependent manner. Enrichment of PIP3 precedes N-WASP activation and the recruitment of RhoA-GAP ARAP3. We propose that adhesion structures can be modulated by traction force development and that production of PIP3 stimulates podosome formation and subsequent RhoA downregulation in the absence of traction force.
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Phylogeography and postglacial recolonization of Europe by Rhinolophus hipposideros: evidence from multiple genetic markers.
Mol. Ecol.
PUBLISHED: 04-23-2013
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The demographic history of Rhinolophus hipposideros (lesser horseshoe bat) was reconstructed across its European, North African and Middle-Eastern distribution prior to, during and following the most recent glaciations by generating and analysing a multimarker data set. This data set consisted of an X-linked nuclear intron (Bgn; 543 bp), mitochondrial DNA (cytb-tRNA-control region; 1630 bp) and eight variable microsatellite loci for up to 373 individuals from 86 localities. Using this data set of diverse markers, it was possible to determine the species demography at three temporal stages. Nuclear intron data revealed early colonization into Europe from the east, which pre-dates the Quaternary glaciations. The mtDNA data supported multiple glacial refugia across the Mediterranean, the largest of which were found in the Ibero-Maghreb region and an eastern location (Anatolia/Middle East)-that were used by R. hipposideros during the most recent glacial cycles. Finally, microsatellites provided the most recent information on these species movements since the Last Glacial Maximum and suggested that lineages that had diverged into glacial refugia, such as in the Ibero-Maghreb region, have remained isolated. These findings should be used to inform future conservation management strategies for R. hipposideros and show the power of using a multimarker data set for phylogeographic studies.
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Fatigue-related brain white matter changes in granulomatosis with polyangiitis.
Rheumatology (Oxford)
PUBLISHED: 04-12-2013
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To determine the association between brain white matter (WM) damage and persistent fatigue among patients with granulomatosis with polyangiitis (GPA).
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Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for ?-amyloid imaging in aging and dementia.
J. Nucl. Med.
PUBLISHED: 04-10-2013
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(11)C-Pittsburgh compound-B ((11)C-PiB) is the benchmark radiotracer for imaging of ?-amyloid (A?) plaque in Alzheimer disease (AD). (18)F-labeled A? tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new (18)F-labeled A? tracer, (18)F-AZD4694 (recently renamed NAV4694), with (11)C-PiB in the same subjects.
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Mitigating the effect of development on bats in England with derogation licensing.
Conserv. Biol.
PUBLISHED: 04-05-2013
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The Convention on Biological Diversity has catalyzed worldwide awareness of threats to biological diversity and stimulated global conservation strategies. These have led to national and international legislation and have generated debate about the most effective conservation actions. Under the EU Habitats Directive, all member states are obliged to establish a system for strict protection of species listed in Annex IV(a), which includes all bats. In England, this obligation has resulted in legislation that allows for derogation from strict protection under license, provided activities are undertaken to mitigate any potential negative effects on bat numbers. We used an evidence-based approach to assess the cost-effectiveness of mitigation strategies and the English bat-derogation licensing process as a whole. We analyzed data from 389 bat derogation licenses issued in England from 2003 to 2005 relating to 1776 roosts and 15 species to determine the nature and extent of development and mitigation activities and their effects on bats. Overall the effects of licensed activities on roosts were negative. Despite the level of protection afforded to bats, the majority (68%) of roosts for which derogation licenses were issued were destroyed. There were species-specific differences in the probability of roosts being destroyed, and impacts on roosts did not reflect a species conservation status. Information provided by licensees was inadequate and inconsistent. Most licensees (67%) failed to submit postdevelopment reports, and postdevelopment monitoring was conducted at only 19% of sites. Despite a minimum of £4.13 million spent on mitigation structures for bats from 2003 to 2005, it was unclear whether the licensing process meets EU obligations. On the basis of our results, we believe there is a need to overhaul the licensing process, to establish a comprehensive, standardized postdevelopment monitoring system, and to demonstrate that mitigation is commensurate with Britains legal obligations. Mitigando el Efecto del Desarrollo sobre los Murciélagos en Inglaterra con Licencias de Derogación.
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The shaping of genetic variation in edge-of-range populations under past and future climate change.
Ecol. Lett.
PUBLISHED: 04-04-2013
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With rates of climate change exceeding the rate at which many species are able to shift their range or adapt, it is important to understand how future changes are likely to affect biodiversity at all levels of organisation. Understanding past responses and extent of niche conservatism in climatic tolerance can help predict future consequences. We use an integrated approach to determine the genetic consequences of past and future climate changes on a bat species, Plecotus austriacus. Glacial refugia predicted by palaeo-modelling match those identified from analyses of extant genetic diversity and model-based inference of demographic history. Former refugial populations currently contain disproportionately high genetic diversity, but niche conservatism, shifts in suitable areas and barriers to migration mean that these hotspots of genetic diversity are under threat from future climate change. Evidence of population decline despite recent northward migration highlights the need to conserve leading-edge populations for spearheading future range shifts.
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Daily electromyography in females with Parkinsons disease: a potential indicator of frailty.
Arch Gerontol Geriatr
PUBLISHED: 03-26-2013
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Females with Parkinsons disease (PD) are at increased risk for frailty, yet are often excluded from frailty studies. Daily electromyography (EMG) recordings of muscle activity can dissociate stages of frailty and indicate functional decline in non-neurological conditions. The purpose of this investigation was to determine whether muscle activity can be used to identify frailty phenotypes in females with PD. EMG during a typical 6.5-h day was examined in biceps brachii, triceps brachii, vastus lateralis and biceps femoris on less-affected PD side. Muscle activity was quantified through burst (>2% maximum exertion, >0.1s) and gap characteristics (<1% maximum exertion, >0.1s). Differences across frailty phenotype (nonfrail, prefrail, frail) and muscle (biceps brachii, BB; triceps brachii, TB; vastus lateralis, VL; biceps femoris, BF) were evaluated with a 2-way repeated measure ANOVA for each burst/gap characteristic. Thirteen right-handed females (mean=67 ± 8 years) were classified as nonfrail (n = 4), prefrail (n = 6), and frail (n = 3) according to the Cardiovascular Health Study frailty index (CHSfi). Frail females had 73% decreased gaps and 48% increased burst duration compared with nonfrail. Decreased gaps may be interpreted as reduced muscle recovery time, which may result in earlier onset fatigue and eventually culminating in frailty. Longer burst durations suggest more muscle activity is required to initiate movement leading to slower movement time in frail females with PD. This is the first study to use EMG to dissociate frailty phenotypes in females with PD during routine daily activities and provides insight into how PD-associated motor declines contributes to frailty and functional decline.
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Sensory biology: listening in the dark for echoes from silent and stationary prey.
Curr. Biol.
PUBLISHED: 03-23-2013
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New research shows how bats use echolocation unexpectedly to detect silent and stationary prey in darkness. Bats may use acoustic search images to identify potential prey when prey-generated noises, visual and olfactory cues are absent.
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Parkinsons disease and sex-related differences in electromyography during daily life.
J Electromyogr Kinesiol
PUBLISHED: 03-18-2013
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Daily bilateral electromyography (EMG) recordings reveal muscle activation patterns implicated in asymmetric Parkinsons disease (PD)-related functional decline. Also, daily EMG recordings reveal sex-differences in muscle activity that give rise to unique PD presentation in males and females.
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Testing times: do new prenatal tests signal the end of Down syndrome?
N. Z. Med. J.
PUBLISHED: 03-12-2013
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Since 2010, prenatal screening for Down syndrome (DS) has been offered to all pregnant women in New Zealand. The programme has been criticised by several groups, on claims that screening is eugenic and discriminatory towards those with DS. Recently, tests have been developed that may one day prove more efficient than current screening methods. They are an example of Non-Invasive Prenatal Diagnosis (NIPD), which enables diagnosis earlier in pregnancy with less risk of complications. If the current programme raises objections, what threats does this new and seemingly more attractive technology pose to the DS community? We argue that NIPD is simply an extension of current screening methods, raising similar ethical concerns. Presently, the programme shows little evidence of eugenics, demonstrated by moderate uptake rates and varying attitudes towards disability. We do not regard the offer of screening to be threatening, as women choose whether or not to be screened depending on their own personal circumstances. One day, prenatal testing may result in fewer people with DS; but past and present trends indicate these individuals will continue to be supported, irrespective of group size. Care and respect for the disabled will remain essential, regardless of a womans decision over her pregnancy.
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Nox2 is required for macrophage chemotaxis towards CSF-1.
PLoS ONE
PUBLISHED: 02-01-2013
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Macrophage migration and infiltration is an important first step in many pathophysiological processes, in particular inflammatory diseases. Redox modulation of the migratory signalling processes has been reported in endothelial cells, vascular smooth muscle cells and fibroblasts. However the redox modulation of the migratory process in macrophages and in particular that from the NADPH oxidase-2 (Nox2) dependent ROS has not been established. To investigate the potential role of Nox2 in the migratory response of macrophages, bone marrow derived macrophages were obtained from WT and NOX2 knockout mice (Nox2KO) and subjected to CSF-1 stimulation. We report here that loss of Nox2 expression in BMM resulted in a significant reduction in the CSF-1 induced spreading response suggesting that Nox2 can modulate cytoskeletal events. Moreover, Nox2KO BMMs were deficient in cellular displacement in the presence of CSF-1. More significantly, when challenged with a gradient of CSF-1, Nox2KO BMMs showed a complete loss of chemotaxis accompanied by a reduction in cell migration speed and directional migration persistence. These results point to a specific role for Nox2KO downstream of CSF-1 during the BMM migratory response. Indeed, we have further found that Nox2KO BMMs display a significant reduction in the levels of ERK1/2 phosphorylation following stimulation with CSF-1.Thus Nox2 is important in BMM cellular motion to CSF-1 stimulation and necessary for their directed migration towards a CSF-1 gradient, highlighting Nox2 dependent signalling as a potential anti-inflammatory target.
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The characterisation and determinants of quality of life in ANCA associated vasculitis.
Ann. Rheum. Dis.
PUBLISHED: 01-25-2013
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To contextualise and identify the determinants of poor health related quality of life (QOL) among patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV).
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Limk2 mediates semaphorin signalling in cortical interneurons migrating through the subpallium.
Biol Open
PUBLISHED: 01-17-2013
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En route to the neocortex, interneurons migrate around and avoid the developing striatum. This is due to the chemorepulsive cues of class 3 semaphorins (Sema3A and Sema3F) acting through neuropilin and plexin co-receptors expressed in interneurons. In a recent genetic screen aimed at identifying novel components that may play a role in interneuron migration, we identified LIM-kinase 2 (Limk2), a kinase previously shown to be involved in cell movement and in Sema7A-PlexinC1 signalling. Here we show that Limk2 is differentially expressed in interneurons, with a higher expression in the subpallium compared to cortex, suggesting it may play a role in their migration through the subpallium. Chemotactic assays, carried out with small interfering RNAs (siRNAs), revealed that Limk2-siRNA transfected interneurons are less responsive to Sema3A, but respond to Sema3F. Lack of responsiveness to Sema3A resulted in their aberrant invasion of the developing striatum, as demonstrated in brain slice preparations and in in utero electroporated mouse embryos with the same siRNAs. Our results reveal a previously unknown role for Limk2 in interneuron migration and Sema3A signalling.
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High throughput phenotypic analysis of Mycobacterium tuberculosis and Mycobacterium bovis strains metabolism using biolog phenotype microarrays.
PLoS ONE
PUBLISHED: 01-10-2013
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Tuberculosis is a major human and animal disease of major importance worldwide. Genetically, the closely related strains within the Mycobacterium tuberculosis complex which cause disease are well-characterized but there is an urgent need better to understand their phenotypes. To search rapidly for metabolic differences, a working method using Biolog Phenotype MicroArray analysis was developed. Of 380 substrates surveyed, 71 permitted tetrazolium dye reduction, the readout over 7 days in the method. By looking for ?5-fold differences in dye reduction, 12 substrates differentiated M. tuberculosis H37Rv and Mycobacterium bovis AF2122/97. H37Rv and a Beijing strain of M. tuberculosis could also be distinguished in this way, as could field strains of M. bovis; even pairs of strains within one spoligotype could be distinguished by 2 to 3 substrates. Cluster analysis gave three clear groups: H37Rv, Beijing, and all the M. bovis strains. The substrates used agreed well with prior knowledge, though an unexpected finding that AF2122/97 gave greater dye reduction than H37Rv with hexoses was investigated further, in culture flasks, revealing that hexoses and Tween 80 were synergistic for growth and used simultaneously rather than in a diauxic fashion. Potential new substrates for growth media were revealed, too, most promisingly N-acetyl glucosamine. Osmotic and pH arrays divided the mycobacteria into two groups with different salt tolerance, though in contrast to the substrate arrays the groups did not entirely correlate with taxonomic differences. More interestingly, these arrays suggested differences between the amines used by the M. tuberculosis complex and enteric bacteria in acid tolerance, with some hydrophobic amino acids being highly effective. In contrast, ?-aminobutyrate, used in the enteric bacteria, had no effect in the mycobacteria. This study proved principle that Phenotype MicroArrays can be used with slow-growing pathogenic mycobacteria and already has generated interesting data worthy of further investigation.
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Alternative population sampling frames produced important differences in estimates of association: a case-control study of vasculitis.
J Clin Epidemiol
PUBLISHED: 01-10-2013
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A common population sampling frame in countries with universal health care is health service registers. We have evaluated the use of such a register, in the United Kingdom, against a commercially available database claiming large population coverage, an alternative that offers ease of access and flexibility of use.
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Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane.
Blood
PUBLISHED: 01-10-2013
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Megakaryocytes give rise to platelets via extension of proplatelet arms, which are released through the vascular sinusoids into the bloodstream. Megakaryocytes and their precursors undergo varying interactions with the extracellular environment in the bone marrow during their maturation and positioning in the vascular niche. We demonstrate that podosomes are abundant in primary murine megakaryocytes adherent on multiple extracellular matrix substrates, including native basement membrane. Megakaryocyte podosome lifetime and density, but not podosome size, are dependent on the type of matrix, with podosome lifetime dramatically increased on collagen fibers compared with fibrinogen. Podosome stability and dynamics depend on actin cytoskeletal dynamics but not matrix metalloproteases. However, podosomes degrade matrix and appear to be important for megakaryocytes to extend protrusions across a native basement membrane. We thus demonstrate for the first time a fundamental requirement for podosomes in megakaryocyte process extension across a basement membrane, and our results suggest that podosomes may have a role in proplatelet arm extension or penetration of basement membrane.
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Environmental risk factors in systemic sclerosis.
Curr Opin Rheumatol
PUBLISHED: 01-05-2013
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Environmental risk factors have been implicated in the pathogenesis of systemic sclerosis (SSc). Recent evidence further supports this relationship and constitutes the focus of this review article.
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Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol.
Transplant Res
PUBLISHED: 01-04-2013
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Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown.
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WIP regulates persistence of cell migration and ruffle formation in both mesenchymal and amoeboid modes of motility.
PLoS ONE
PUBLISHED: 01-01-2013
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The spatial distribution of signals downstream from receptor tyrosine kinases (RTKs) or G-protein coupled receptors (GPCR) regulates fundamental cellular processes that control cell migration and growth. Both pathways rely significantly on actin cytoskeleton reorganization mediated by nucleation-promoting factors such as the WASP-(Wiskott-Aldrich Syndrome Protein) family. WIP (WASP Interacting Protein) is essential for the formation of a class of polarised actin microdomain, namely dorsal ruffles, downstream of the RTK for PDGF (platelet-derived growth factor) but the underlying mechanism is poorly understood. Using lentivirally-reconstituted WIP-deficient murine fibroblasts we define the requirement for WIP interaction with N-WASP (neural WASP) and Nck for efficient dorsal ruffle formation and of WIP-Nck binding for fibroblast chemotaxis towards PDGF-AA. The formation of both circular dorsal ruffles in PDGF-AA-stimulated primary fibroblasts and lamellipodia in CXCL13-treated B lymphocytes are also compromised by WIP-deficiency. We provide data to show that a WIP-Nck signalling complex interacts with RTK to promote polarised actin remodelling in fibroblasts and provide the first evidence for WIP involvement in the control of migratory persistence in both mesenchymal (fibroblast) and amoeboid (B lymphocytes) motility.
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Independent losses of visual perception genes Gja10 and Rbp3 in echolocating bats (order: chiroptera).
PLoS ONE
PUBLISHED: 01-01-2013
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A trade-off between the sensory modalities of vision and hearing is likely to have occurred in echolocating bats as the sophisticated mechanism of laryngeal echolocation requires considerable neural processing and has reduced the reliance of echolocating bats on vision for perceiving the environment. If such a trade-off exists, it is reasonable to hypothesize that some genes involved in visual function may have undergone relaxed selection or even functional loss in echolocating bats. The Gap junction protein, alpha 10 (Gja10, encoded by Gja10 gene) is expressed abundantly in mammal retinal horizontal cells and plays an important role in horizontal cell coupling. The interphotoreceptor retinoid-binding protein (Irbp, encoded by the Rbp3 gene) is mainly expressed in interphotoreceptor matrix and is known to be critical for normal functioning of the visual cycle. We sequenced Gja10 and Rbp3 genes in a taxonomically wide range of bats with divergent auditory characteristics (35 and 18 species for Gja10 and Rbp3, respectively). Both genes have became pseudogenes in species from the families Hipposideridae and Rhinolophidae that emit constant frequency echolocation calls with Doppler shift compensation at high-duty-cycles (the most sophisticated form of biosonar known), and in some bat species that emit echolocation calls at low-duty-cycles. Our study thus provides further evidence for the hypothesis that a trade-off occurs at the genetic level between vision and echolocation in bats.
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From the ultrasonic to the infrared: molecular evolution and the sensory biology of bats.
Front Physiol
PUBLISHED: 01-01-2013
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Great advances have been made recently in understanding the genetic basis of the sensory biology of bats. Research has focused on the molecular evolution of candidate sensory genes, genes with known functions [e.g., olfactory receptor (OR) genes] and genes identified from mutations associated with sensory deficits (e.g., blindness and deafness). For example, the FoxP2 gene, underpinning vocal behavior and sensorimotor coordination, has undergone diversification in bats, while several genes associated with audition show parallel amino acid substitutions in unrelated lineages of echolocating bats and, in some cases, in echolocating dolphins, representing a classic case of convergent molecular evolution. Vision genes encoding the photopigments rhodopsin and the long-wave sensitive opsin are functional in bats, while that encoding the short-wave sensitive opsin has lost functionality in rhinolophoid bats using high-duty cycle laryngeal echolocation, suggesting a sensory trade-off between investment in vision and echolocation. In terms of olfaction, bats appear to have a distinctive OR repertoire compared with other mammals, and a gene involved in signal transduction in the vomeronasal system has become non-functional in most bat species. Bitter taste receptors appear to have undergone a "birth-and death" evolution involving extensive gene duplication and loss, unlike genes coding for sweet and umami tastes that show conservation across most lineages but loss in vampire bats. Common vampire bats have also undergone adaptations for thermoperception, via alternative splicing resulting in the evolution of a novel heat-sensitive channel. The future for understanding the molecular basis of sensory biology is promising, with great potential for comparative genomic analyses, studies on gene regulation and expression, exploration of the role of alternative splicing in the generation of proteomic diversity, and linking genetic mechanisms to behavioral consequences.
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Adaptive evolution of the myo6 gene in old world fruit bats (family: pteropodidae).
PLoS ONE
PUBLISHED: 01-01-2013
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Myosin VI (encoded by the Myo6 gene) is highly expressed in the inner and outer hair cells of the ear, retina, and polarized epithelial cells such as kidney proximal tubule cells and intestinal enterocytes. The Myo6 gene is thought to be involved in a wide range of physiological functions such as hearing, vision, and clathrin-mediated endocytosis. Bats (Chiroptera) represent one of the most fascinating mammal groups for molecular evolutionary studies of the Myo6 gene. A diversity of specialized adaptations occur among different bat lineages, such as echolocation and associated high-frequency hearing in laryngeal echolocating bats, large eyes and a strong dependence on vision in Old World fruit bats (Pteropodidae), and specialized high-carbohydrate but low-nitrogen diets in both Old World and New World fruit bats (Phyllostomidae). To investigate what role(s) the Myo6 gene might fulfill in bats, we sequenced the coding region of the Myo6 gene in 15 bat species and used molecular evolutionary analyses to detect evidence of positive selection in different bat lineages. We also conducted real-time PCR assays to explore the expression levels of Myo6 in a range of tissues from three representative bat species. Molecular evolutionary analyses revealed that the Myo6 gene, which was widely considered as a hearing gene, has undergone adaptive evolution in the Old World fruit bats which lack laryngeal echolocation and associated high-frequency hearing. Real-time PCR showed the highest expression level of the Myo6 gene in the kidney among ten tissues examined in three bat species, indicating an important role for this gene in kidney function. We suggest that Myo6 has undergone adaptive evolution in Old World fruit bats in relation to receptor-mediated endocytosis for the preservation of protein and essential nutrients.
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Tyrosine phosphorylation of WASP promotes calpain-mediated podosome disassembly.
Haematologica
PUBLISHED: 12-01-2011
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Podosomes are actin-based adhesions involved in migration of cells that have to cross tissue boundaries such as myeloid cells. The Wiskott Aldrich Syndrome Protein regulates de novo actin polymerization during podosome formation and it is cleaved by the protease calpain during podosome disassembly. The mechanisms that may induce the Wiskott Aldrich Syndrome Protein cleavage by calpain remain undetermined. We now report that in myeloid cells, tyrosine phosphorylation of the Wiskott Aldrich Syndrome Protein-tyrosine291 (Human)/tyrosine293 (mouse) not only enhances Wiskott Aldrich Syndrome Protein-mediated actin polymerization but also promotes its calpain-dependent degradation during podosome disassembly. We also show that activation of the Wiskott Aldrich Syndrome Protein leading to podosome formation occurs independently of tyrosine phosphorylation in spleen-derived dendritic cells. We conclude that tyrosine phosphorylation of the Wiskott Aldrich Syndrome Protein integrates dynamics of actin and cell adhesion proteins during podosome disassembly required for mobilization of myeloid cells during the immune response.
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Phylogeny of Chaetothyriaceae in northern Thailand including three new species.
Mycologia
PUBLISHED: 11-28-2011
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In a recent study unusual taxa of epiphyllous ascomycota belonging to Chaetothyriaceae (Eurotiomycetes) were collected in northern Thailand. This family is poorly understood due to morphological confusion and lack of phylogenetic studies. This paper deals with three new species, Ceramothyrium thailandicum, Chaetothyrium brischofiacola and Phaeosaccardinula ficus, which are fully described and illustrated. A DNA sequence analyses of LSU and ITS rDNA genes shows that the new species cluster in the Chaetothyriaceae. This paper adds six sequences for Chaetothyriaceae to GenBank, providing much needed data for the family.
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A comparison of the relationship of 14 performance-based measures with frailty in older women.
Appl Physiol Nutr Metab
PUBLISHED: 11-23-2011
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The purpose of this study was to determine which performance measures of physical function are most closely related to frailty and whether physical function is different across levels of frailty. Fifty-three community-dwelling Greek women (63-100 years) participated in this study. Participants were divided into 3 tertiles based on level of frailty as calculated from a frailty index (FI): lowest FI group (<0.19 FI), intermediate FI group (0.19-0.36 FI), and highest FI group (>0.36 FI). Performance measures tested were handgrip and knee extension muscle strength and fatigue, upper and lower body muscular endurance, walking performance, agility, and dynamic balance. The greatest proportion of variance in the FI was explained by combining all performance-based measures of physical function. The performance measures that were most closely related to frailty yet different across levels of frailty were ambulatory mobility, lower body muscular endurance, and nondominant handgrip strength. Walking at a preferred pace had the strongest relationship to frailty rather than walking at maximal pace. Grip strength of the nondominant hand had a stronger correlation with frailty compared with the dominant hand. The FI was a better predictor of physical function than chronological age. The decline in physical function accelerated after the intermediate FI tertile. Definitions of frailty need to combine performance-based measures that can identify impairments in various domains of physical function. The assessment protocols of these measures are important.
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Capnodiaceae.
Fungal Divers.
PUBLISHED: 11-16-2011
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In this paper we revisit the Capnodiaceae with notes on selected genera. Type specimens of the ascomycetous genera Aithaloderma, Anopeltis, Callebaea, Capnodaria, Echinothecium, Phragmocapnias and Scorias were re-examined, described and illustrated. Leptoxyphium is anamorphic Capnodiaceae and Polychaeton is a legitimate and earlier name for Capnodium, but in order to maintain nomenclatural stability we propose that the teleomorphic name should be conisdered for the approved lists of names currently in preparation for fungi. Notes are provided on the ascomycetous genus Scoriadopsis. However, we were unable to locate the type of this genus during the time frame of this study. The ascomycetous genera Aithaloderma, Ceramoclasteropsis, Hyaloscolecostroma and Trichomerium are excluded from Capnodiaceae on the basis of having ascostromata and trans-septate hyaline ascospores and should be accommodated in Chaetothyriaceae. Callebaea is excluded as the ascomata are thyriothecia and the genus is placed in Micropeltidaceae. Echinothecium is excluded as synonym of Sphaerellothecium and is transferred to Mycosphaerellaceae. The type specimen of Capnophaeum is lost and this should be considered as a doubtful genus. The coelomycetous Microxiphium is polyphyletic, while the status of Fumiglobus, Polychaetella and Tripospermum is unclear. Fourteen new collections of sooty moulds made in Thailand were isolated and sequenced. The nuclear large and small rDNA was partially sequenced and compared in a phylogeny used to build a more complete understanding of the relationships of genera in Capnodiaceae. Four new species are described and illustrated, while Phragmocapnias and Scorias are epitypified with fresh collections.
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Bayesian localization microscopy reveals nanoscale podosome dynamics.
Nat. Methods
PUBLISHED: 11-02-2011
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We describe a localization microscopy analysis method that is able to extract results in live cells using standard fluorescent proteins and xenon arc lamp illumination. Our Bayesian analysis of the blinking and bleaching (3B analysis) method models the entire dataset simultaneously as being generated by a number of fluorophores that may or may not be emitting light at any given time. The resulting technique allows many overlapping fluorophores in each frame and unifies the analysis of the localization from blinking and bleaching events. By modeling the entire dataset, we were able to use each reappearance of a fluorophore to improve the localization accuracy. The high performance of this technique allowed us to reveal the nanoscale dynamics of podosome formation and dissociation throughout an entire cell with a resolution of 50 nm on a 4-s timescale.
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Renal function in type 1 diabetics one year after successful pancreas transplantation.
Clin Transplant
PUBLISHED: 10-18-2011
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The effect of pancreas transplantation on renal function remains a matter of debate. The purpose of this retrospective, single-unit study is a preliminary analysis of renal function one?yr after pancreas transplant (pancreas alone [PTA] or pancreas after kidney [PAK]). Fifty-nine patients were included. Serum creatinine and estimated glomerular filtration rate (eGFR) levels were compared three, six, and 12?months post-transplantation for the whole sample and separately for PTA and PAK and high (>45?mL/min/1.73?m(2)) and low (?45?mL/min/1.73?m(2)) pre-transplant eGFR subgroups. Overall, eGFR did not change significantly (p?=?0.228) at the end of the first year post-transplant, with patients of low initial eGFR presenting a more prominent trend toward stable or improved levels. In the PAK subgroup, eGFR was significantly improved (p?=?0.035). High eGFR subgroup demonstrated no significant deterioration in renal function, while patients with low initial eGFR had significantly higher levels 3 (p?=?0.012) and six?months (p?=?0.009) post-transplant. Our study shows that renal function did not deteriorate significantly one?yr after pancreas transplant (PTA or PAK), even in patients with substantial pre-existing renal dysfunction. Evaluation at a wider scale and identification of risk factors for potential deterioration are challenges for future research.
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Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor.
J. Biol. Chem.
PUBLISHED: 10-11-2011
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IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.
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Risk analysis for deterioration of renal function after pancreas alone transplant.
Clin Transplant
PUBLISHED: 10-10-2011
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The risk of progression to renal replacement after pancreas transplant alone (PTA) is a concern in patients with pre-transplant estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m(2). This is a retrospective, single-center risk analysis of potential factors affecting renal function after PTA. Twenty-four patients, transplanted over a three-yr period, with functioning pancreatic grafts at the studys end point were included. High tacrolimus levels (> 12 mg/dL) at six months post-transplant was the only independent risk factor identifying a substantial decline in native renal function by Cox regression analysis (HR = 14.300, CI = 1.271-160.907, p = 0.031). The presence of severe pre-transplant proteinuria (urine Pr/Cr ? 100 mg/mmol) marginally failed to reach significance (p = 0.056). Low eGFR levels alone (? 45 and ? 40 mL/min/1.73 m(2)) at the time of transplant did not correlate with substantial decline in renal function. Our data suggest that PTA is a justifiable therapy for patients with hypoglycemia unawareness or other life-threatening diabetic complications, even in those with borderline renal function, provided that they do not suffer from severe proteinuria and appropriate monitoring and tailoring of immunosuppression is ensured.
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The relationship between body mass index across the life course and knee pain in adulthood: results from the 1958 birth cohort study.
Rheumatology (Oxford)
PUBLISHED: 10-08-2011
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To determine whether a high BMI in childhood or early adulthood has a long-term influence on the likelihood of knee pain.
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Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense.
Mol. Ther.
PUBLISHED: 10-04-2011
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Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) promise specific correction of disease-causing gene expression. Therapeutic implementation, however, has been forestalled by poor delivery to the appropriate tissue, cell type, and subcellular compartment. Topical administration is considered to circumvent these issues. The availability of inhalation devices and unmet medical need in lung disease has focused efforts in this tissue. We report the development of a novel cell sorting method for quantitative, cell type-specific analysis of siRNA, and locked nucleic acid (LNA) ASO uptake and efficacy after intratracheal (i.t.) administration in mice. Through fluorescent dye labeling, we compare the utility of this approach to whole animal and whole tissue analysis, and examine the extent of tissue distribution. We detail rapid systemic access and renal clearance for both therapeutic classes and lack of efficacy at the protein level in lung macrophages, epithelia, or other cell types. We nevertheless observe efficient redirection of i.t. administered phosphorothioate (PS) LNA ASO to the liver and kidney leading to targeted gene knockdown. These data suggest delivery remains a key obstacle to topically administered, naked oligonucleotide efficacy in the lung and introduce inhalation as a potentially viable alternative to injection for antisense administration to the liver and kidneys.
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A comparison of physical activity (PA) assessment tools across levels of frailty.
Arch Gerontol Geriatr
PUBLISHED: 09-28-2011
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Determine which PA assessment tools are most closely related to frailty and whether PA is different across levels of frailty.
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