Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these. We incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced nitric oxide reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit

Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts

Background Late-stage breast cancer preferentially metastasises to bone; despite advances in targeted therapies, this condition remains incurable. The lack of clinically relevant models for studying breast cancer metastasis to a human bone microenvironment has stunted the development of effective treatments for this condition. To address this problem, we have developed humanised mouse models in which breast cancer patient-derived xenografts (PDXs) metastasise to human bone implants with low variability and high frequency. Methods To model the human bone environment, bone discs from femoral heads of patients undergoing hip replacement surgery were implanted subcutaneously into NOD/SCID mice. For metastasis studies, 7 patient-derived xenograft tumours (PDX: BB3RC32, ER+ PR+ HER2−; BB2RC08, ER+ PR+ ER2−; BB6RC37, ER− PR− HER2− and BB6RC39, ER+ PR+ HER2+), MDA-MB-231-luc2, T47D-luc2 or MCF7-Luc2 cells were injected into the 4th mammary ducts and metastases monitored by luciferase imaging and confirmed on histological sections. Bone integrity, viability and vascularisation were assessed by uCT, calcein uptake and histomorphometry. Expression profiling of genes/proteins during different stages of metastasis were assessed by whole genome Affymetrix array, real-time PCR and immunohistochemistry. Importance of IL-1 was confirmed following anakinra treatment. Results Implantation of femoral bone provided a metabolically active, human-specific site for tumour cells to metastasise to. After 4 weeks, bone implants were re-vascularised and demonstrated active bone remodelling (as evidenced by the presence of osteoclasts, osteoblasts and calcein uptake). Restricting bone implants to the use of subchondral bone and introduction of cancer cells via intraductal injection maximised metastasis to human bone implants. MDA-MB-231 cells specifically metastasised to human bone (70% metastases) whereas T47D, MCF7, BB3RC32, BB2RC08, and BB6RC37 cells metastasised to both human bone and mouse bones. Importantly, human bone was the preferred metastatic site especially from ER+ PDX (100% metastasis human bone compared with 20–75% to mouse bone), whereas ER-ve PDX developed metastases in 20% of human and 20% of mouse bone. Breast cancer cells underwent a series of molecular changes as they progressed from primary tumours to bone metastasis including altered expression of IL-1B, IL-1R1, S100A4, CTSK, SPP1 and RANK. Inhibiting IL-1B signalling significantly reduced bone metastasis. Conclusions Our reliable and clinically relevant humanised mouse models provide significant advancements in modelling of breast cancer bone metastasis

Attachment Styles Within the Coach-Athlete Dyad: Preliminary Investigation and Assessment Development

The present preliminary study aimed to develop and examine the psychometric properties of a new sport-specific self-report instrument designed to assess athletes’ and coaches’ attachment styles. The development and initial validation comprised three main phases. In Phase 1, a pool of items was generated based on pre-existing self-report attachment instruments, modified to reflect a coach and an athlete’s style of attachment. In Phase 2, the content validity of the items was assessed by a panel of experts. A final scale was developed and administered to 405 coaches and 298 athletes (N = 703 participants). In Phase 3, confirmatory factor analysis of the obtained data was conducted to determine the final items of the Coach-Athlete Attachment Scale (CAAS). Confirmatory factor analysis revealed acceptable goodness of fit indexes for a 3-first order factor model as well as a 2-first order factor model for both the athlete and the coach data, respectively. A secure attachment style positively predicted relationship satisfaction, while an insecure attachment style was a negative predictor of relationship satisfaction. The CAAS revealed initial psychometric properties of content, factorial, and predictive validity, as well as reliability

Spacetime Coarse Grainings in the Decoherent Histories Approach to Quantum Theory

We investigate the possibility of assigning consistent probabilities to sets of histories characterized by whether they enter a particular subspace of the Hilbert space of a closed system during a given time interval. In particular we investigate the case that this subspace is a region of the configuration space. This corresponds to a particular class of coarse grainings of spacetime regions. We consider the arrival time problem and the problem of time in reparametrization invariant theories as for example in canonical quantum gravity. Decoherence conditions and probabilities for those application are derived. The resulting decoherence condition does not depend on the explicit form of the restricted propagator that was problematic for generalizations such as application in quantum cosmology. Closely related is the problem of tunnelling time as well as the quantum Zeno effect. Some interpretational comments conclude, and we discuss the applicability of this formalism to deal with the arrival time problem.Comment: 23 pages, Few changes and added references in v

Cerebrovascular endothelial cells form transient Notch‐dependent cystic structures in zebrafish

We identify a novel endothelial membrane behaviour in transgenic zebrafish. Cerebral blood vessels extrude large transient spherical structures that persist for an average of 23 min before regressing into the parent vessel. We term these structures “kugeln”, after the German for sphere. Kugeln are only observed arising from the cerebral vessels and are present as late as 28 days post fertilization. Kugeln do not communicate with the vessel lumen and can form in the absence of blood flow. They contain little or no cytoplasm, but the majority are highly positive for nitric oxide reactivity. Kugeln do not interact with brain lymphatic endothelial cells (BLECs) and can form in their absence, nor do they perform a scavenging role or interact with macrophages. Inhibition of actin polymerization, Myosin II, or Notch signalling reduces kugel formation, while inhibition of VEGF or Wnt dysregulation (either inhibition or activation) increases kugel formation. Kugeln represent a novel Notch‐dependent NO‐containing endothelial organelle restricted to the cerebral vessels, of currently unknown function

Inequalities in health and community-oriented social work: lessons from Cuba?

Social justice is, as the World Health Organization Commission on Social Determinants of Health (WHO CSDH, 2008) reminds us, ‘a matter of life and death’. While the stark differences in mortality rates and life expectancy between rich and poor countries might be the most obvious example of this, it is also true that ‘Within countries, the differences in life chances are dramatic and are seen in all countries – even the richest’ (WHO CSDH, 2008: 26). As the Commission demonstrates, the roots of these inequities lie in social conditions, suggesting an important role for social work in this area. Unfortunately, the Commission says very little about the type of social work that might be appropriate: nevertheless, the report does provide fresh impetus to the debate about what social workers might contribute to tackling health inequalities. In this article, we suggest that a community-oriented approach to social work is required. In making a case for this, we review the progress of the government’s drive to reduce inequalities in England,1 arguing that this has, thus far, been largely unsuccessful because it has primarily been pursued through health-care services, while addressing the wider (social) determinants of health has been a secondary consideration. In contrast, we offer the example of Cuban community-oriented social work (COSW) which has helped maintain population health at a level that stands comparison with much wealthier nations, despite the hardships and inequalities which followed economic collapse in the 1990s. In many ways the Cuban situation is unusual, perhaps unique, so we are not arguing that Cuban social work methods can be readily transferred. Rather, we suggest that, in the neglected field of tackling health inequalities, social workers can learn from the general approach taken in Cuba. To establish the context of this discussion, we begin by defining key concepts: COSW itself, health inequalities and inequity, the health gap and the health gradient

UHECR as Decay Products of Heavy Relics? The Lifetime Problem

The essential features underlying the top-down scenarii for UHECR are discussed, namely, the stability (or lifetime) imposed to the heavy objects (particles) whatever they be: topological and non-topological solitons, X-particles, cosmic defects, microscopic black-holes, fundamental strings. We provide an unified formula for the quantum decay rate of all these objects as well as the particle decays in the standard model. The key point in the top-down scenarii is the necessity to adjust the lifetime of the heavy object to the age of the universe. This ad-hoc requirement needs a very high dimensional operator to govern its decay and/or an extremely small coupling constant. The natural lifetimes of such heavy objects are, however, microscopic times associated to the GUT energy scale (sim 10^{-28} sec. or shorter). It is at this energy scale (by the end of inflation) where they could have been abundantly formed in the early universe and it seems natural that they decayed shortly after being formed.Comment: 11 pages, LaTex, no figures, updated versio

Measurements of long-range near-side angular correlations in sNN=5\sqrt{s_{\text{NN}}}=5TeV proton-lead collisions in the forward region

Two-particle angular correlations are studied in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of $\sqrt{s_{\text{NN}}}=5$TeV, collected with the LHCb detector at the LHC. The analysis is based on data recorded in two beam configurations, in which either the direction of the proton or that of the lead ion is analysed. The correlations are measured in the laboratory system as a function of relative pseudorapidity, $\Delta\eta$, and relative azimuthal angle, $\Delta\phi$, for events in different classes of event activity and for different bins of particle transverse momentum. In high-activity events a long-range correlation on the near side, $\Delta\phi \approx 0$, is observed in the pseudorapidity range $2.0<\eta<4.9$. This measurement of long-range correlations on the near side in proton-lead collisions extends previous observations into the forward region up to $\eta=4.9$. The correlation increases with growing event activity and is found to be more pronounced in the direction of the lead beam. However, the correlation in the direction of the lead and proton beams are found to be compatible when comparing events with similar absolute activity in the direction analysed.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-040.htm

Study of the production of Λb0\Lambda_b^0 and B‾0\overline{B}^0 hadrons in pppp collisions and first measurement of the Λb0→J/ψpK−\Lambda_b^0\rightarrow J/\psi pK^- branching fraction

The product of the $\Lambda_b^0$ ($\overline{B}^0$) differential production cross-section and the branching fraction of the decay $\Lambda_b^0\rightarrow J/\psi pK^-$ ($\overline{B}^0\rightarrow J/\psi\overline{K}^*(892)^0$) is measured as a function of the beauty hadron transverse momentum, $p_{\rm T}$, and rapidity, $y$. The kinematic region of the measurements is $p_{\rm T}<20~{\rm GeV}/c$ and $2.0<y<4.5$. The measurements use a data sample corresponding to an integrated luminosity of $3~{\rm fb}^{-1}$ collected by the LHCb detector in $pp$ collisions at centre-of-mass energies $\sqrt{s}=7~{\rm TeV}$ in 2011 and $\sqrt{s}=8~{\rm TeV}$ in 2012. Based on previous LHCb results of the fragmentation fraction ratio, $f_{\Lambda_B^0}/f_d$, the branching fraction of the decay $\Lambda_b^0\rightarrow J/\psi pK^-$ is measured to be \begin{equation*} \mathcal{B}(\Lambda_b^0\rightarrow J/\psi pK^-)= (3.17\pm0.04\pm0.07\pm0.34^{+0.45}_{-0.28})\times10^{-4}, \end{equation*} where the first uncertainty is statistical, the second is systematic, the third is due to the uncertainty on the branching fraction of the decay $\overline{B}^0\rightarrow J/\psi\overline{K}^*(892)^0$, and the fourth is due to the knowledge of $f_{\Lambda_b^0}/f_d$. The sum of the asymmetries in the production and decay between $\Lambda_b^0$ and $\overline{\Lambda}_b^0$ is also measured as a function of $p_{\rm T}$ and $y$. The previously published branching fraction of $\Lambda_b^0\rightarrow J/\psi p\pi^-$, relative to that of $\Lambda_b^0\rightarrow J/\psi pK^-$, is updated. The branching fractions of $\Lambda_b^0\rightarrow P_c^+(\rightarrow J/\psi p)K^-$ are determined.Comment: 29 pages, 19figures. All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-032.htm

BB flavour tagging using charm decays at the LHCb experiment

An algorithm is described for tagging the flavour content at production of neutral $B$ mesons in the LHCb experiment. The algorithm exploits the correlation of the flavour of a $B$ meson with the charge of a reconstructed secondary charm hadron from the decay of the other $b$ hadron produced in the proton-proton collision. Charm hadron candidates are identified in a number of fully or partially reconstructed Cabibbo-favoured decay modes. The algorithm is calibrated on the self-tagged decay modes $B^+ \to J/\psi \, K^+$ and $B^0 \to J/\psi \, K^{*0}$ using $3.0\mathrm{\,fb}^{-1}$ of data collected by the LHCb experiment at $pp$ centre-of-mass energies of $7\mathrm{\,TeV}$ and $8\mathrm{\,TeV}$. Its tagging power on these samples of $B \to J/\psi \, X$ decays is $(0.30 \pm 0.01 \pm 0.01) \%$.Comment: All figures and tables, along with any supplementary material and additional information, are available at http://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-027.htm