Mitochondrial decay in aging

AbstractSeveral mitochondrial functions decline with age. The contributing factors include, the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging

Interactions of asbestos-activated macrophages with an experimental fibrosarcoma

Supernatants from in vivo asbestos-activated macrophages failed to show any cytostatic activity against a syngeneic fibrosarcoma cell line in vitro. UICC chrysotile-induced peritoneal exudate cells also failed to demonstrate any growth inhibitory effect on the same cells in Winn assays of tumor growth. Mixing UICC crocidolite with inoculated tumor cells resulted in a dose-dependent inhibition of tumor growth; this could, however, be explained by a direct cytostatic effect on the tumor cells of high doses of crocidolite, which was observed in vitro

Electronic inhomogeneity and Ag:Sb imbalance of Ag1−yPb18Sb1+zTe20 high-performance thermoelectrics elucidated by 125Te and 207Pb NMR

Using magic-angle spinning 125Te and 207Pb NMR, we have discovered the presence of two phases of approximately tenfold different free-electron concentration, n, in high-performance thermoelectrics Ag1−yPb18Sb1+zTe20 (“LAST-18”), proven by pairs of Knight-shifted NMR peaks and biexponential spin-lattice relaxation. The ratio of the phases is typically 2:1 with n ≈ 2 × 1019 cm−3 and 0.2 × 1019 cm−3, respectively, determined from the spin-lattice relaxation times. 125Te NMR spectra show that both phases contain similar concentrations of Sb. The low-n component is assigned to Ag-rich regions with Ag-Sb pairing (but not AgSbTe2), the dominant high-n component to PbTe:Sb resulting from the excess of Sb relative to Ag. The electronic inhomogeneity observed here must be considered in the search for a better understanding of high performance thermoelectric materials

Nonlinear transport of Bose-Einstein condensates through mesoscopic waveguides

We study the coherent flow of interacting Bose-condensed atoms in mesoscopic waveguide geometries. Analytical and numerical methods, based on the mean-field description of the condensate, are developed to study both stationary as well as time-dependent propagation processes. We apply these methods to the propagation of a condensate through an atomic quantum dot in a waveguide, discuss the nonlinear transmission spectrum and show that resonant transport is generally suppressed due to an interaction-induced bistability phenomenon. Finally, we establish a link between the nonlinear features of the transmission spectrum and the self-consistent quasi-bound states of the quantum dot.Comment: 23 pages, 16 figure

Consistency Conditions for Fundamentally Discrete Theories

The dynamics of physical theories is usually described by differential equations. Difference equations then appear mainly as an approximation which can be used for a numerical analysis. As such, they have to fulfill certain conditions to ensure that the numerical solutions can reliably be used as approximations to solutions of the differential equation. There are, however, also systems where a difference equation is deemed to be fundamental, mainly in the context of quantum gravity. Since difference equations in general are harder to solve analytically than differential equations, it can be helpful to introduce an approximating differential equation as a continuum approximation. In this paper implications of this change in view point are analyzed to derive the conditions that the difference equation should satisfy. The difference equation in such a situation cannot be chosen freely but must be derived from a fundamental theory. Thus, the conditions for a discrete formulation can be translated into conditions for acceptable quantizations. In the main example, loop quantum cosmology, we show that the conditions are restrictive and serve as a selection criterion among possible quantization choices.Comment: 33 page

The feasibility of using citizens to segment anatomy from medical images: Accuracy and motivation

This is the final version. Available from Public Library of Science via the DOI in this record.Data cannot be shared publicly because participants did not consent for their data to be made publicly available, however, consent was granted to make the data available to researchers for use in related studies. Further information about the data and details of how to request access are available from the University of Exeter's institutional repository at: https://doi.org/10.24378/exe.1703.The development of automatic methods for segmenting anatomy from medical images is an important goal for many medical and healthcare research areas. Datasets that can be used to train and test computer algorithms, however, are often small due to the difficulties in obtaining experts to segment enough examples. Citizen science provides a potential solution to this problem but the feasibility of using the public to identify and segment anatomy in a medical image has not been investigated. Our study therefore aimed to explore the feasibility, in terms of performance and motivation, of using citizens for such purposes. Public involvement was woven into the study design and evaluation. Twenty-nine citizens were recruited and, after brief training, asked to segment the spine from a dataset of 150 magnetic resonance images. Participants segmented as many images as they could within three one-hour sessions. Their accuracy was evaluated by comparing them, as individuals and as a combined consensus, to the segmentations of three experts. Questionnaires and a focus group were used to determine the citizens’ motivation for taking part and their experience of the study. Citizen segmentation accuracy, in terms of agreement with the expert consensus segmentation, varied considerably between individual citizens. The citizen consensus, however, was close to the expert consensus, indicating that when pooled, citizens may be able to replace or supplement experts for generating large image datasets. Personal interest and a desire to help were the two most common reasons for taking part in the study.Wellcome Trus

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations