Probing the reactivity of a 2,2′-bipyridyl-3,3′-bis-imine ligand by X-ray crystallography

The reactivity of a Schiff-base bis-imine ligand 3 is probed by X-ray diffraction studies. Its susceptibility to hydrolysis, oxidation and nucleophilic addition reactions is demonstrated by the isolation of the methanol adduct 4 and two diazapene heterocycles 5 and 6. This reactivity is also reflected in the molecular structures of two coordination complexes isolated by the reaction of 3 with MIJhfac)2 salts, to afford [Cu(5)-(hfac)(tfa)] (8) and [Zn(6)(hfac)2] (9)

Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells

© The Author(s) 2016. Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl-Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl-Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling

Environmental Heterogeneity Generates Fluctuating Selection on a Secondary Sexual Trait

SummaryIn any population in which resources are limiting, the allocation of resources toward increased reproductive success may generate costs to survival [1–8]. The relationship between a sexually selected trait and fitness will therefore represent a balance between its relative associations with fecundity versus viability [3, 6, 7]. Because the risk of mortality in a population is likely to be heavily determined by ecological conditions, survival costs may vary as a function of the prevailing environment [7]. As a result, for populations experiencing heterogeneous ecological conditions, there may not be a single optimal level of allocation toward reproduction versus survival [9]. Here, we show that early viability and fecundity selection act in opposing directions on a secondary sexual trait and that their relative magnitude depends upon ecological conditions, generating fluctuating selection. In a wild population of Soay sheep (Ovis aries), phenotypic and genetic associations between male horn growth and lifetime reproductive success were positive under good environmental conditions (because of increased breeding success) and negative under poor environmental conditions (because of reduced survival). In an unpredictable environment, high allocation to early horn growth is a gamble that will only pay off if ensuing conditions are favorable. Such fluctuating selection may play an important role in preventing the erosion of genetic variance in secondary sexual traits

Start‐ups' use of knowledge spillovers for product innovation: the influence of entrepreneurial ecosystems and virtual platforms

Data availability statement: The data is not available.Copyright © 2022 The Authors. Entrepreneurial ecosystems have been explored widely in entrepreneurship, management and social sciences literature. The Knowledge Spillover Theory of Entrepreneurship (KSTE) aims to uncover the effects of information on start- ups co- located in diverse locations, such as urban areas, science and technology parks, incubators, and accelerator programs. Extant research has focused on how entrepreneurs launch start- ups and develop patents over a 5– 10 years timespan from a regional perspective. However, studies into the devel-opment processes of start- ups and the creation of entrepreneurial ecosystems in physical and virtual environments in high- tech start- ups, are limited. As a result, this paper aims to identify the development processes undertaken by high- tech entrepreneurs at the individual level and evaluate the absorption and implementation of knowledge in physical and virtual clusters within entrepreneurial ecosystems. A multiple case study of 32 start- ups that have attended incubator and accelerator programs in London, United Kingdom, is presented. Semi- structured interviews were conducted with Chief Executive Officers (CEOs) and Founders of start- ups to propose the Model of Knowledge Spillovers and Entrepreneurial Ecosystems. The themes identified during interviews highlight the mechanisms employed by start- ups to capture tacit and explicit knowledge spillovers. Theoretically, the findings of this study contribute to the KSTE by questioning the flexibility of entrepreneurs to access knowledge without the limitation of geographical proximity to sources of knowledge. Practically, our findings provide entrepreneurs with proven mechanisms required to cap-ture tacit knowledge spillovers within entrepreneurial ecosystems and use virtual platforms to obtain explicit knowledge spillovers towards product innovation

Development of an internationally agreed minimal dataset for juvenile dermatomyositis (JDM) for clinical and research use

Background: Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory disorder associated with significant morbidity and mortality. International collaboration is necessary to better understand the pathogenesis of the disease, response to treatment and long-term outcome. To aid international collaboration, it is essential to have a core set of data that all researchers and clinicians collect in a standardised way for clinical purposes and for research. This should include demographic details, diagnostic data and measures of disease activity, investigations and treatment. Variables in existing clinical registries have been compared to produce a provisional data set for JDM. We now aim to develop this into a consensus-approved minimum core dataset, tested in a wider setting, with the objective of achieving international agreement. Methods/Design: A two-stage bespoke Delphi-process will engage the opinion of a large number of key stakeholders through Email distribution via established international paediatric rheumatology and myositis organisations. This, together with a formalised patient/parent participation process will help inform a consensus meeting of international experts that will utilise a nominal group technique (NGT). The resulting proposed minimal dataset will be tested for feasibility within existing database infrastructures. The developed minimal dataset will be sent to all internationally representative collaborators for final comment. The participants of the expert consensus group will be asked to draw together these comments, ratify and 'sign off' the final minimal dataset. Discussion: An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. The final approved minimum core dataset could be rapidly incorporated into national and international collaborative efforts, including existing prospective databases, and be available for use in randomised controlled trials and for treatment/protocol comparisons in cohort studies

Stringent neutron-star limits on large extra dimensions

Supernovae (SNe) are copious sources for Kaluza-Klein gravitons which are generic for theories with large extra dimensions. These massive particles are produced with average velocities ~0.5 c so that many of them are gravitationally retained by the SN core. Every neutron star thus has a halo of KK gravitons which decay into nu bar-nu, e^+e^- and gamma gamma on time scales \~10^9 years. The EGRET gamma-flux limits (E_gamma ~ 100 MeV) for nearby neutron stars constrain the fundamental scale for n=2 extra dimensions to M >500 TeV, and M>30 TeV for n=3. The upcoming GLAST satellite is a factor ~30 more sensitive and thus may detect KK decays, for example at the nearby neutron star RX J185635--3754. The requirement that neutron stars are not excessively heated by KK decays implies M>1700 TeV for n=2, and M>60 TeV for n=3.Comment: Minor changes, matches version to appear in PR

Radiative Efficiency and Content of Extragalactic Radio Sources: Toward a Universal Scaling Relation Between Jet Power and Radio Power

We present an analysis of the energetics and particle content of the lobes of 24 radio galaxies at the cores of cooling clusters. The radio lobes in these systems have created visible cavities in the surrounding hot, X-ray-emitting gas, which allow direct measurement of the mechanical jet power of radio sources over six decades of radio luminosity, independently of the radio properties themselves. Using these measurements, we examine the ratio between radio power and total jet power (the radiative efficiency). We find that jet (cavity) power increases with radio synchrotron power approximately as P_jet ~ (L_radio)^beta, where 0.35 < beta < 0.70 depending on the bandpass of measurement and state of the source. However, the scatter about these relations caused by variations in radiative efficiency spans more than four orders of magnitude. After accounting for variations in synchrotron break frequency (age), the scatter is reduced by ~ 50%, yielding the most accurate scaling relation available between the lobe bolometric radio power and the jet (cavity) power. We place limits on the magnetic field strengths and particle content of the radio lobes using a variety of X-ray constraints. We find that the lobe magnetic field strengths vary between a few to several tens of microgauss depending on the age and dynamical state of the lobes. If the cavities are maintained in pressure balance with their surroundings and are supported by internal fields and particles in equipartition, the ratio of energy in electrons to heavy particles (k) must vary widely from approximately unity to 4000, consistent with heavy (hadronic) jets.Comment: 20 pages, 11 figures. Accepted for publication in Ap