Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations.

Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs within the tissue. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a single stem cell taking over the niche and producing progeny. We show: (1) that there is a significantly lower mtDNA mutation load in the mitotic epithelium of the gastrointestinal tract when compared to the smooth muscle in the same tissue in patients with the pathogenic m.3243A>G and m.8344A>G mutations; (2) that there is considerable variation seen in individual crypts, suggesting changes in the stem cell population; (3) that this lower mutation load is reflected in the absence of a defect in oxidative phosphorylation in the epithelium. This suggests that there is selection against inherited mtDNA mutations in the gastrointestinal stem cells that is in marked contrast to the somatic mtDNA mutations that accumulate with age in epithelial stem cells leading to a biochemical defect. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.Wellcome Trust. Grant Number: G096919 MRC ESRC EPSRC BBSRC Newcastle University Centre for Ageing and Vitalit

3D time series analysis of cell shape using Laplacian approaches

Background: Fundamental cellular processes such as cell movement, division or food uptake critically depend on cells being able to change shape. Fast acquisition of three-dimensional image time series has now become possible, but we lack efficient tools for analysing shape deformations in order to understand the real three-dimensional nature of shape changes. Results: We present a framework for 3D+time cell shape analysis. The main contribution is three-fold: First, we develop a fast, automatic random walker method for cell segmentation. Second, a novel topology fixing method is proposed to fix segmented binary volumes without spherical topology. Third, we show that algorithms used for each individual step of the analysis pipeline (cell segmentation, topology fixing, spherical parameterization, and shape representation) are closely related to the Laplacian operator. The framework is applied to the shape analysis of neutrophil cells. Conclusions: The method we propose for cell segmentation is faster than the traditional random walker method or the level set method, and performs better on 3D time-series of neutrophil cells, which are comparatively noisy as stacks have to be acquired fast enough to account for cell motion. Our method for topology fixing outperforms the tools provided by SPHARM-MAT and SPHARM-PDM in terms of their successful fixing rates. The different tasks in the presented pipeline for 3D+time shape analysis of cells can be solved using Laplacian approaches, opening the possibility of eventually combining individual steps in order to speed up computations

Impact of a hospice rapid response service on preferred place of death, and costs

Background: Many people with a terminal illness would prefer to die at home. A new palliative rapid response service (RRS) provided by a large hospice provider in South East England was evaluated (2010) to provide evidence of impact on achieving preferred place of death and costs. The RRS was delivered by a team of trained health care assistants and available 24/7. The purpose of this study was to (i) compare the characteristics of RRS users and non-users, (ii) explore differences in the proportions of users and non-users dying in the place of their choice, (iii) monitor the whole system service utilisation of users and non-users, and compare costs. Methods: All hospice patients who died with a preferred place of death recorded during an 18 month period were included. Data (demographic, preferences for place of death) were obtained from hospice records. Dying in preferred place was modelled using stepwise logistic regression analysis. Service use data (period between referral to hospice and death) were obtained from general practitioners, community providers, hospitals, social services, hospice, and costs calculated using validated national tariffs. Results: Of 688 patients referred to the hospice when the RRS was operational, 247 (35.9 %) used it. Higher proportions of RRS users than non-users lived in their own homes with a co-resident carer (40.3 % vs. 23.7 %); more non-users lived alone or in residential care (58.8 % vs. 76.3 %). Chances of dying in the preferred place were enhanced 2.1 times by being a RRS user, compared to a non-user, and 1.5 times by having a co-resident carer, compared to living at home alone or in a care home. Total service costs did not differ between users and non-users, except when referred to hospice very close to death (users had higher costs). Conclusions: Use of the RRS was associated with increased likelihood of dying in the preferred place. The RRS is cost neutral

Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions

Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error

The shadow knows: using shadows to investigate the structure of the pretransitional disk of HD 100453

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.We present GPI polarized intensity imagery of HD 100453 in Y-, J-, and K1 bands which reveals an inner gap ($9 - 18$ au), an outer disk ($18-39$ au) with two prominent spiral arms, and two azimuthally-localized dark features also present in SPHERE total intensity images (Wagner 2015). SED fitting further suggests the radial gap extends to $1$ au. The narrow, wedge-like shape of the dark features appears similar to predictions of shadows cast by a inner disk which is misaligned with respect to the outer disk. Using the Monte Carlo radiative transfer code HOCHUNCK3D (Whitney 2013), we construct a model of the disk which allows us to determine its physical properties in more detail. From the angular separation of the features we measure the difference in inclination between the disks 45$^{\circ}$, and their major axes, PA = 140$^{\circ}$ east of north for the outer disk and 100$^{\circ}$for the inner disk. We find an outer disk inclination of $25 \pm 10^{\circ}$ from face-on in broad agreement with the Wagner 2015 measurement of 34$^{\circ}$. SPHERE data in J- and H-bands indicate a reddish disk which points to HD 100453 evolving into a young debris disk.Based in part on data obtained at the Gemini Observatory via the time exchange program between Gemini and the Subaru Telescope (GS-2015A-C-1). The Gemini Observatory is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the National Research Council (Canada), CONICYT (Chile), Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina), and Ministério da Ciência, Tecnologia e Inovação (Brazil). M.T. is partly supported by JSPS KAKENHI 2680016. C.A.G. is supported under NASA Origins of Solar Systems Funding via NNG16PX39P. Y.H. is supported by Jet Propulsion Laboratory, California Institute of Technology under a contract from NASA. M.S. is supported by NASA Exoplanet Research Program NNX16AJ75G. J.K. acknowledges support from Philip Leverhulme Prize (PLP-2013-110, PI: Stefan Kraus). S.K. acknowledges support from an ERC Starting Grant (Grant Agreement No. 639889). We also thank the referee for their comments and suggestions which added clarity to this paper

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Sequence Skill Acquisition and Off-Line Learning in Normal Aging

It is well known that certain cognitive abilities decline with age. The ability to form certain new declarative memories, particularly memories for facts and events, has been widely shown to decline with advancing age. In contrast, the effects of aging on the ability to form new procedural memories such as skills are less well known, though it appears that older adults are able to acquire some new procedural skills over practice. The current study examines the effects of normal aging on procedural memory more closely by comparing the effects of aging on the encoding or acquisition stage of procedural learning versus its effects on the consolidation, or between-session stage of procedural learning. Twelve older and 14 young participants completed a sequence-learning task (the Serial Reaction Time Task) over a practice session and at a re-test session 24 hours later. Older participants actually demonstrated more sequence skill during acquisition than the young. However, older participants failed to show skill improvement at re-test as the young participants did. Age thus appears to have a differential effect upon procedural learning stages such that older adults' skill acquisition remains relatively intact, in some cases even superior, compared to that of young adults, while their skill consolidation may be poorer than that of young adults. Although the effect of normal aging on procedural consolidation remains unclear, aging may actually enhance skill acquisition on some procedural tasks

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

A Triple Protostar System Formed via Fragmentation of a Gravitationally Unstable Disk

Binary and multiple star systems are a frequent outcome of the star formation process, and as a result, almost half of all sun-like stars have at least one companion star. Theoretical studies indicate that there are two main pathways that can operate concurrently to form binary/multiple star systems: large scale fragmentation of turbulent gas cores and filaments or smaller scale fragmentation of a massive protostellar disk due to gravitational instability. Observational evidence for turbulent fragmentation on scales of $>$1000~AU has recently emerged. Previous evidence for disk fragmentation was limited to inferences based on the separations of more-evolved pre-main sequence and protostellar multiple systems. The triple protostar system L1448 IRS3B is an ideal candidate to search for evidence of disk fragmentation. L1448 IRS3B is in an early phase of the star formation process, likely less than 150,000 years in age, and all protostars in the system are separated by $<$200~AU. Here we report observations of dust and molecular gas emission that reveal a disk with spiral structure surrounding the three protostars. Two protostars near the center of the disk are separated by 61 AU, and a tertiary protostar is coincident with a spiral arm in the outer disk at a 183 AU separation. The inferred mass of the central pair of protostellar objects is $\sim$1 M$_{sun}$, while the disk surrounding the three protostars has a total mass of $\sim$0.30 M_{\sun}. The tertiary protostar itself has a minimum mass of $\sim$0.085 M$_{sun}$. We demonstrate that the disk around L1448 IRS3B appears susceptible to disk fragmentation at radii between 150~AU and 320~AU, overlapping with the location of the tertiary protostar. This is consistent with models for a protostellar disk that has recently undergone gravitational instability, spawning one or two companion stars.Comment: Published in Nature on Oct. 27th. 24 pages, 8 figure

Differences in the gas and dust distribution in the transitional disk of a sun-like young star, PDS 70

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe American Astronomical Society. All rights reserved. We present ALMA 0.87 mm continuum, HCO + J = 4-3 emission line, and CO J = 3-2 emission line data of the disk of material around the young, Sun-like star PDS 70. These data reveal the existence of a possible two-component transitional disk system with a radial dust gap of 0.″42 ±0.″05, an azimuthal gap in the HCO + J = 4-3 moment zero map, as well as two bridge-like features in the gas data. Interestingly these features in the gas disk have no analog in the dust disk making them of particular interest. We modeled the dust disk using the Monte Carlo radiative transfer code HOCHUNK3D using a two-disk component. We find that there is a radial gap that extends from 15 to 60 au in all grain sizes, which differs from previous work.This work is supported supported by the NASA XRP grants NNX17AF88G and NNX16AJ75G. MC thanks the support from the Centro de Astrofísica de Valparaíso. S.K. acknowledges support from an STFC Rutherford Fellowship (ST/J004030/1) and ERC Starting Grant (Grant Agreement No. 639889). This work is supported by the Astrobiology Center Program of National Institutes of Natural Sciences (NINS) (Grant Number: AB281013) and by MEXT KAKENHI No. 17K05399 (EA). Y.H. is currently supported by Jet Propulsion Laboratory, California Institute of Technology, under a contract from NASA. This paper makes use of the following ALMA data: ADS/JAO.ALMA#2015.1.00888.S. ALMA is a partnership of ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada), MOST and ASIAA (Taiwan), and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO, and NAOJ. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, In