2,214 research outputs found
Multi-dimensional TOF-SIMS analysis for effective profiling of disease-related ions from the tissue surface
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) emerges as a promising tool to identify the ions (small molecules) indicative of disease states from the surface of patient tissues. In TOF-SIMS analysis, an enhanced ionization of surface molecules is critical to increase the number of detected ions. Several methods have been developed to enhance ionization capability. However, how these methods improve identification of disease-related ions has not been systematically explored. Here, we present a multi-dimensional SIMS (MD-SIMS) that combines conventional TOF-SIMS and metal-assisted SIMS (MetA-SIMS). Using this approach, we analyzed cancer and adjacent normal tissues first by TOF-SIMS and subsequently by MetA-SIMS. In total, TOF- and MetA-SIMS detected 632 and 959 ions, respectively. Among them, 426 were commonly detected by both methods, while 206 and 533 were detected uniquely by TOF- and MetA-SIMS, respectively. Of the 426 commonly detected ions, 250 increased in their intensities by MetA-SIMS, whereas 176 decreased. The integrated analysis of the ions detected by the two methods resulted in an increased number of discriminatory ions leading to an enhanced separation between cancer and normal tissues. Therefore, the results show that MD-SIMS can be a useful approach to provide a comprehensive list of discriminatory ions indicative of disease states.1178Ysciescopu
In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia
To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.The PhDstudentships of S. V. M., T. B. and T. G. C. were funded by EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1) and the Centre for Neurotechnology (EP/L016737/1). Wethank Javier Cudeiro Blanco for his support and the Facility for Imaging by Light Microscopy (FILM) at Imperial College London funded by the Wellcome Trust (grant 104931/ZS/14/Z) and BBSRC (grant BB/L015129/1)
Altered cortical brain activity in end stage liver disease assessed by multi-channel near-infrared spectroscopy: associations with delirium
A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes
Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties
Higgs production as a probe of anomalous top couplings
The LHC may be currently seeing the first hints of the Higgs boson. The
dominant production mode for the Higgs at the LHC involves a top-quark loop. An
accurate measurement of Higgs production cross-sections and decay widths can
thus be used to obtain limits on anomalous top couplings. We find that such an
exercise could potentially yield constraints that are stronger than those
derived from low-energy observables as well as direct bounds expected from the
top pair-production process.Comment: Version published in JHE
Search for Higgs bosons of the Universal Extra Dimensions at the Large Hadron Collider
The Higgs sector of the Universal Extra Dimensions (UED) has a rather
involved setup. With one extra space dimension, the main ingredients to the
construct are the higher Kaluza-Klein (KK) excitations of the Standard Model
Higgs boson and the fifth components of the gauge fields which on
compactification appear as scalar degrees of freedom and can mix with the
former thus leading to physical KK-Higgs states of the scenario. In this work,
we explore in detail the phenomenology of such a Higgs sector of the UED with
the Large Hadron Collider (LHC) in focus. We work out relevant decay branching
fractions involving the KK-Higgs excitations. Possible production modes of the
KK-Higgs bosons are then discussed with an emphasis on their associated
production with the third generation KK-quarks and that under the cascade
decays of strongly interacting UED excitations which turn out to be the only
phenomenologically significant modes. It is pointed out that the collider
searches of such Higgs bosons face generic hardship due to soft end-products
which result from severe degeneracies in the masses of the involved excitations
in the minimal version of the UED (MUED). Generic implications of either
observing some or all of the KK-Higgs bosons at the LHC are discussed.Comment: 25 pages, 9 figures and 1 tabl
Spatio-temporal Models of Lymphangiogenesis in Wound Healing
Several studies suggest that one possible cause of impaired wound healing is
failed or insufficient lymphangiogenesis, that is the formation of new
lymphatic capillaries. Although many mathematical models have been developed to
describe the formation of blood capillaries (angiogenesis), very few have been
proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a
markedly different process from angiogenesis, occurring at different times and
in response to different chemical stimuli. Two main hypotheses have been
proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the
edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic
endothelial cells first pool in the wound region following the lymph flow and
then, once sufficiently populated, start to form a network. Here we present two
PDE models describing lymphangiogenesis according to these two different
hypotheses. Further, we include the effect of advection due to interstitial
flow and lymph flow coming from open capillaries. The variables represent
different cell densities and growth factor concentrations, and where possible
the parameters are estimated from biological data. The models are then solved
numerically and the results are compared with the available biological
literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total
Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms
Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3β²-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability
Neutralino dark matter in mSUGRA/CMSSM with a 125 GeV light Higgs scalar
The minimal supergravity (mSUGRA or CMSSM) model is an oft-used framework for
exhibiting the properties of neutralino (WIMP) cold dark matter (CDM). However,
the recent evidence from Atlas and CMS on a light Higgs scalar with mass
m_h\simeq 125 GeV highly constrains the superparticle mass spectrum, which in
turn constrains the neutralino annihilation mechanisms in the early universe.
We find that stau and stop co-annihilation mechanisms -- already highly
stressed by the latest Atlas/CMS results on SUSY searches -- are nearly
eliminated if indeed the light Higgs scalar has mass m_h\simeq 125 GeV.
Furthermore, neutralino annihilation via the A-resonance is essentially ruled
out in mSUGRA so that it is exceedingly difficult to generate
thermally-produced neutralino-only dark matter at the measured abundance. The
remaining possibility lies in the focus-point region which now moves out to
m_0\sim 10-20 TeV range due to the required large trilinear soft SUSY breaking
term A_0. The remaining HB/FP region is more fine-tuned than before owing to
the typically large top squark masses. We present updated direct and indirect
detection rates for neutralino dark matter, and show that ton scale noble
liquid detectors will either discover mixed higgsino CDM or essentially rule
out thermally-produced neutralino-only CDM in the mSUGRA model.Comment: 17 pages including 9 .eps figure
Predictors of neurological outcomes after successful extracorporeal cardiopulmonary resuscitation
- β¦