Predicting the movements of permanently installed electrodes on an active landslide using time-lapse geoelectrical resistivity data only

If electrodes move during geoelectrical resistivity monitoring and their new positions are not incorporated in the inversion, then the resulting tomographic images exhibit artefacts that can obscure genuine time-lapse resistivity changes in the subsurface. The effects of electrode movements on time-lapse resistivity tomography are investigated using a simple analytical model and real data. The correspondence between the model and the data is sufficiently good to be able to predict the effects of electrode movements with reasonable accuracy. For the linear electrode arrays and 2D inversions under consideration, the data are much more sensitive to longitudinal than transverse or vertical movements. Consequently the model can be used to invert the longitudinal offsets of the electrodes from their known baseline positions using only the time-lapse ratios of the apparent resistivity data. The example datasets are taken from a permanently installed electrode array on an active lobe of a landslide. Using two sets with different levels of noise and subsurface resistivity changes, it is found that the electrode positions can be recovered to an accuracy of 4 % of the baseline electrode spacing. This is sufficient to correct the artefacts in the resistivity images, and provides for the possibility of monitoring the movement of the landslide and its internal hydraulic processes simultaneously using electrical resistivity tomography only

A bioavailable cathepsin S nitrile inhibitor abrogates tumor development

BACKGROUND: Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models. METHODS: Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K(i) values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors. RESULTS: We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis. CONCLUSIONS: In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-016-0513-7) contains supplementary material, which is available to authorized users

The HIV-1 Vpu Viroporin Inhibitor BIT225 Does Not Affect Vpu-Mediated Tetherin Antagonism

Among its many roles, the HIV-1 accessory protein Vpu performs a viroporin function and also antagonizes the host cell restriction factor tetherin through its transmembrane domain. BIT225 is a small molecule inhibitor that specifically targets the Vpu viroporin function, which, in macrophages, resulted in late stage inhibition of virus release and decreased infectivity of released virus, a phenotype similar to tetherin-mediated restriction. Here, we investigated whether BIT225 might mediate its antiviral function, at least in part, via inhibition of Vpu-mediated tetherin antagonism. Using T-cell lines inducible for tetherin expression, we found that BIT225 does not exert its antiviral function by inhibiting Vpu-mediated tetherin downmodulation from the cell surface, the main site of action of tetherin activity. In addition, results from a bioluminescence resonance energy transfer (BRET) assay showed that the Vpu-tetherin interaction was not affected by BIT225. Our data provide support for the concept that tetherin antagonism and viroporin function are separable on the Vpu transmembrane and that viroporin function might be cell-type dependent. Further, this work contributes to the characterization of BIT225 as an inhibitor that specifically targets the viroporin function of Vpu

First results from the Very Small Array -- I. Observational methods

The Very Small Array (VSA) is a synthesis telescope designed to image faint structures in the cosmic microwave background on degree and sub-degree angular scales. The VSA has key differences from other CMB interferometers with the result that different systematic errors are expected. We have tested the operation of the VSA with a variety of blank-field and calibrator observations and cross-checked its calibration scale against independent measurements. We find that systematic effects can be suppressed below the thermal noise level in long observations; the overall calibration accuracy of the flux density scale is 3.5 percent and is limited by the external absolute calibration scale.Comment: 9 pages, 10 figures, MNRAS in press (Minor revisions

Partnership, ownership and control: the impact of corporate governance on employment relations

Prevailing patterns of dispersed share ownership and rules of corporate governance for UK listed companies appear to constrain the ability of managers to make credible, long-term commitments to employees of the kind needed to foster effective labour-management partnerships. We present case study evidence which suggests that such partnerships can nevertheless emerge where product market conditions and the regulatory environment favour a stakeholder orientation. Proactive and mature partnerships may also be sustained where the board takes a strategic approach to mediating between the claims of different stakeholder groups, institutional investors are prepared to take a long-term view of their holdings, and strong and independent trade unions are in a position to facilitate organisational change

Galaxy redshift surveys selected by neutral hydrogen using FAST

We discuss the possibility of performing a substantial spectroscopic galaxy redshift survey selected via the 21cm emission from neutral hydrogen using the Five-hundred metre Aperture Spherical Telescope (FAST) to be built in China. We consider issues related to the estimation of the source counts and optimizations of the survey, and discuss the constraints on cosmological models that such a survey could provide. We find that a survey taking around two years could detect ~10^7 galaxies with an average redshift of ~0.15 making the survey complementary to those already carried out at optical wavelengths. These conservative estimates have used the z=0 HI mass function and have ignored the possibility of evolution. The results could be used to constrain Gamma = (Omega_m h) to 5 per cent and the spectral index, n_s, to 7 per cent independent of cosmic microwave background data. If we also use simulated power spectra from the Planck satellite, we can constrain w to be within 5 per cent of -1.Comment: 13 pages, 15 figures, Accepted by MNRAS, minor correction

SUMOylation of synaptic and synapse-associated proteins:An update

SUMOylation is a post‐translational modification that regulates protein signalling and complex formation by adjusting the conformation or protein–protein interactions of the substrate protein. There is a compelling and rapidly expanding body of evidence that, in addition to SUMOylation of nuclear proteins, SUMOylation of extranuclear proteins contributes to the control of neuronal development, neuronal stress responses and synaptic transmission and plasticity. In this brief review we provide an update of recent developments in the identification of synaptic and synapse‐associated SUMO target proteins and discuss the cell biological and functional implications of these discoveries. [Image: see text

CMB observations from the CBI and VSA: A comparison of coincident maps and parameter estimation methods

We present coincident observations of the Cosmic Microwave Background (CMB) from the Very Small Array (VSA) and Cosmic Background Imager (CBI) telescopes. The consistency of the full datasets is tested in the map plane and the Fourier plane, prior to the usual compression of CMB data into flat bandpowers. Of the three mosaics observed by each group, two are found to be in excellent agreement. In the third mosaic, there is a 2 sigma discrepancy between the correlation of the data and the level expected from Monte Carlo simulations. This is shown to be consistent with increased phase calibration errors on VSA data during summer observations. We also consider the parameter estimation method of each group. The key difference is the use of the variance window function in place of the bandpower window function, an approximation used by the VSA group. A re-evaluation of the VSA parameter estimates, using bandpower windows, shows that the two methods yield consistent results.Comment: 10 pages, 6 figures. Final version. Accepted for publication in MNRA

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies