IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury

Anomalies of ac driven solitary waves with internal modes: Nonparametric resonances induced by parametric forces

We study the dynamics of kinks in the $\phi^4$ model subjected to a parametric ac force, both with and without damping, as a paradigm of solitary waves with internal modes. By using a collective coordinate approach, we find that the parametric force has a non-parametric effect on the kink motion. Specifically, we find that the internal mode leads to a resonance for frequencies of the parametric driving close to its own frequency, in which case the energy of the system grows as well as the width of the kink. These predictions of the collective coordinate theory are verified by numerical simulations of the full partial differential equation. We finally compare this kind of resonance with that obtained for non-parametric ac forces and conclude that the effect of ac drivings on solitary waves with internal modes is exactly the opposite of their character in the partial differential equation.Comment: To appear in Phys Rev

Solidification behavior of intensively sheared hypoeutectic Al-Si alloy liquid

The official published version of this article can be found at the link below.The effect of the processing temperature on the microstructural and mechanical properties of Al-Si (hypoeutectic) alloy solidified from intensively sheared liquid metal has been investigated systematically. Intensive shearing gives a significant refinement in grain size and intermetallic particle size. It also is observed that the morphology of intermetallics, defect bands, and microscopic defects in high-pressure die cast components are affected by intensive shearing the liquid metal. We attempt to discuss the possible mechanism for these effects.Funded by the EPSRC

Light Gluinos and the Parton Structure of the Nucleon

We study the effects of light gluinos with mass below about 1 GeV on the nucleon parton densities and the running of alpha_(S). It is shown that from the available high-statistics DIS data no lower bound on the gluino mass can be derived. Also in the new kinematical region accessible at HERA the influence of such light gluinos on structure f unctions is found to be very small and difficult to detect. For use in more direct searches involving final state signatures we present a radiative estimate of the gluino distribution in the nucleon.Comment: 23 pages, LateX, 8 figures, MPI-PhT/94-22, LMU-3/9

Heavy-quark mass dependence in global PDF analyses and 3- and 4-flavour parton distributions

We study the sensitivity of our recent MSTW 2008 NLO and NNLO PDF analyses to the values of the charm- and bottom-quark masses, and we provide additional public PDF sets for a wide range of these heavy-quark masses. We quantify the impact of varying m_c and m_b on the cross sections for W, Z and Higgs production at the Tevatron and the LHC. We generate 3- and 4-flavour versions of the (5-flavour) MSTW 2008 PDFs by evolving the input PDFs and alpha_S determined from fits in the 5-flavour scheme, including the eigenvector PDF sets necessary for calculation of PDF uncertainties. As an example of their use, we study the difference in the Z total cross sections at the Tevatron and LHC in the 4- and 5-flavour schemes. Significant differences are found, illustrating the need to resum large logarithms in Q^2/m_b^2 by using the 5-flavour scheme. The 4-flavour scheme is still necessary, however, if cuts are imposed on associated (massive) b-quarks, as is the case for the experimental measurement of Z b bbar production and similar processes.Comment: 40 pages, 11 figures. Grids can be found at http://projects.hepforge.org/mstwpdf/ and in LHAPDF V5.8.4. v2: version published in EPJ

Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder

Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population. © 2017 Elsevier Inc

Mapping reviews, scoping reviews, and evidence and gap maps (EGMs): the same but different— the “Big Picture” review family

Scoping reviews, mapping reviews, and evidence and gap maps are evidence synthesis methodologies that address broad research questions, aiming to describe a bigger picture rather than address a specific question about intervention effectiveness. They are being increasingly used to support a range of purposes including guiding research priorities and decision making. There is however a confusing array of terminology used to describe these different approaches. In this commentary, we aim to describe where there are differences in terminology and where this equates to differences in meaning. We demonstrate the different theoretical routes that underpin these differences. We suggest ways in which the approaches of scoping and mapping reviews may differ in order to guide consistency in reporting and method. We propose that mapping and scoping reviews and evidence and gap maps have similarities that unite them as a group but also have unique differences. Understanding these similarities and differences is important for informing the development of methods used to undertake and report these types of evidence synthesis

Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitize MRSA to β-lactam antibiotics

The purine-derived signaling molecules c-di-AMP and (p)ppGpp control mecA/PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with de novo purine synthesis (pur operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a nupG mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including nupG and hpt. Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in nupG or deoD2 mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. IMPORTANCE The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens

Specific Heat Study of the Magnetic Superconductor HoNi2B2C

The complex magnetic transitions and superconductivity of HoNi2B2C were studied via the dependence of the heat capacity on temperature and in-plane field angle. We provide an extended, comprehensive magnetic phase diagram for B // [100] and B // [110] based on the thermodynamic measurements. Three magnetic transitions and the superconducting transition were clearly observed. The 5.2 K transition (T_{N}) shows a hysteresis with temperature, indicating the first order nature of the transition at B=0 T. The 6 K transition (T_{M}), namely the onset of the long-range ordering, displays a dramatic in-plane anisotropy: T_{M} increases with increasing magnetic field for B // [100] while it decreases with increasing field for B // [110]. The anomalous anisotropy in T_{M} indicates that the transition is related to the a-axis spiral structure. The 5.5 K transition (T^{*}) shows similar behavior to the 5.2 K transition, i.e., a small in-plane anisotropy and scaling with Ising model. This last transition is ascribed to the change from a^{*} dominant phase to c^{*} dominant phase.Comment: 9 pages, 11 figure