Microarray analysis of human hepatic aging

Two sets of liver tissue samples of human subjects were investigated by gene expression microarray analysis. One set had normal and disease samples with their telomere lengths; the other set consisted of groups of normal young and old donors, mostly post mortem. The goal was to identify genes related to aging and inflammation and to investigate the hypothesis that telomere length is a biomarker for these processes.The first set of ten surgical liver biopsies were run on the single channel microarray, Codelink Human Bioarray. Because of the liver diseases in the subjects (3 with Hepatitis C, 3 with Primary Sclerosing Cholangitis, 1 with a liver cyst, and 3 controls), the standard preliminary procedure of simple variance filtering was deemed insufficient. Instead, the samples were adjusted for disease using Analysis of Covariance, to identify genes of potential interest. This was conducted in three pairs based on age, telomere length and disease, because of the small sample size. With this procedure, about 1,600 genes had an alpha significance of less than five percent (14.7% total for all comparisons). Hierarchical clustering of these genes grouped the Hepatitis C patients and the young patients, as a partial validation of this model.The second dataset was obtained from the Gene Expression Omnibus (GEO), GSE9588. The samples were run on the Rosetta/Merck Human 44k 1.1 dual channel microarray platform, against a control of 191 pooled human liver samples. The original study analyzed the surgical and post mortem liver samples with respect to disease and single nucleotide polymorphisms. Sixty-seven samples were selected from this dataset, ages 20-29 or ages 70-81. Their telomere lengths are unknown. Simple variance filtering resulted in 1,965 differentially expressed genes.To reduce false positives further, various microarray techniques were employed, including hierarchical clustering, principal component analysis, k-means clustering and Pavlitis Template Modeling. The last technique matches expression to the relative telomere length or age. Resulting genes were then run through the gene ontology programs DAVID and PANTHER, which find gene networks.Networks that were differentially up regulated based on age include ubiquitin, a protein intracellular ransport marker often linked to protein targeted for degradation, as well as cytochrome p450 (CYP), a mono-oxygenase in the endoplasmic reticulum of hepatocytes involved in the breakdown of steroids, fatty acids and xenobiotics. The cytochrome p450 network was up regulated in the older group, but not in elderly who also had steatosis (fatty liver) or who had drug liver risk from the use of a medication. Networks down regulated or mixed based on age included the broad categories of "receptors" and "immunity and defense." IL8, which is involved in inflammation, was one of these hits. Networks that were down regulated with shorter telomere length included genes related to chromatin restructuring and transcription regulation, including the selective down regulation of several Histone H4 isoforms.Hypotheses generated from this study include the identification of six poorly characterized receptors which may be involved in liver regeneration. Additionally, there may be a mechanistic problem between CYP transcription and activated protein, because of the high CYP mRNA levels seen here in elderly, compared to the unchanged or decreased protein levels found in other studies. Additionally, elderly with steatosis or drug liver risk may have a higher hepatocyte turn over and higher Hepatocyte Growth Factor (HGF) expression, since HGF suppresses CYP.M.S., Biomedical Science -- Drexel University, 200

Floor determination in the operation of a lift by a mobile guide robot

Robotic assistants operating in multi-floor buildings are required to use lifts to transition between floors. To reduce the need for environments to be tailored to suit robots, and to make robot assistants more applicable, it is desirable that they should make use of existing navigational cues and interfaces designed for human users. In this paper, we examine the scenario whereby a guide robot uses a lift to transition between floors in a building. We describe an experiment into combining multiple data sources, available to a typical robot with simple sensors, to determine which floor of the building it is on. We show the robustness of this approach to realistic scenarios in a busy working environment

Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype

Histopathology, clinical chemistry, hematology and gene expression data were collected from the rat liver and blood after treatment with eight known hepatotoxins

Quantifiable Biomarkers of Normal Aging in the Japanese Medaka Fish (Oryzias latipes)

BACKGROUND: Small laboratory fish share many anatomical and histological characteristics with other vertebrates, yet can be maintained in large numbers at low cost for lifetime studies. Here we characterize biomarkers associated with normal aging in the Japanese medaka (Oryzias latipes), a species that has been widely used in toxicology studies and has potential utility as a model organism for experimental aging research. PRINCIPAL FINDINGS: The median lifespan of medaka was approximately 22 months under laboratory conditions. We performed quantitative histological analysis of tissues from age-grouped individuals representing young adults (6 months old), mature adults (16 months old), and adults that had survived beyond the median lifespan (24 months). Livers of 24-month old individuals showed extensive morphologic changes, including spongiosis hepatis, steatosis, ballooning degeneration, inflammation, and nuclear pyknosis. There were also phagolysosomes, vacuoles, and residual bodies in parenchymal cells and congestion of sinusoidal vessels. Livers of aged individuals were characterized by increases in lipofuscin deposits and in the number of TUNEL-positive apoptotic cells. Some of these degenerative characteristics were seen, to a lesser extent, in the livers of 16-month old individuals, but not in 6-month old individuals. The basal layer of the dermis showed an age-dependent decline in the number of dividing cells and an increase in senescence-associated β-galactosidase. The hearts of aged individuals were characterized by fibrosis and lipofuscin deposition. There was also a loss of pigmented cells from the retinal epithelium. By contrast, age-associated changes were not apparent in skeletal muscle, the ocular lens, or the brain. SIGNIFICANCE: The results provide a set of markers that can be used to trace the process of normal tissue aging in medaka and to evaluate the effect of environmental stressors

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Micron-scale laser-wire scanner for the KEK Accelerator Test Facility extraction line

A laser-wire transverse electron beam size measurement system has been constructed and operated at the Accelerator Test Facility (ATF) extraction line at KEK. The construction of the system is described in detail along with the environment of the ATF related to the laser wire. A special set of electron beam optics was developed to generate an approximately 1 mu m vertical focus at the laser-wire location. The results of our operation at the ATF extraction line are presented, where a minimum rms electron beam size of 4: 8 +/- 0: 3 mu m was measured, and smaller electron beam sizes can be measured by developing the method further. The beam size at the laser-wire location was changed using quadrupoles and the resulting electron beam size measured, and vertical emittance extracted

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Celiac plexus neurolysis for abdominal cancers: going beyond pancreatic cancer pain

Introduction:. Celiac plexus neurolysis (CPN) has been verified for mitigating pancreatic cancer pain. However, information regarding CPN's use beyond this remains limited. Objectives:. Identify which cancers benefit from CPN, which symptoms improve, and when symptoms improve. Methods:. Retrospective analysis was conducted on 173 patients who received CPN for pain caused by various malignancies. Mean symptom changes on the MD Anderson Symptom Inventory (MDASI) from baseline to 2 weeks, 1 month, and 2 months after CPN were analyzed overall and then by cancer type: pancreatic (all stages and stages III–IV), hepatobiliary, and nonpancreatic, nonhepatobiliary gastrointestinal (NPNH-gastrointestinal). Results:. Eighty-two pancreatic, 43 NPNH-gastrointestinal, 14 hepatobiliary, and 34 patients with other cancers met inclusion criteria. Statistically significant changes included decrease in the pain score at 1 month by 1.01 points for all cancers, 1.65 points for all pancreatic cancers, and 1.88 points for late-stage pancreatic cancers. At 2 months, pain decreased by 1.50 points for all cancers, 1.68 points for all pancreatic cancers, 2.37 points for late-stage pancreatic cancers, and 1.50 points in NPNH-gastrointestinal cancers. At 2 months, quality of life improved by 1.07 points for all cancers and 1.53 points for all pancreatic cancers. Sleep improved at 2 months for all cancers by 0.73 points and 1.60 points in late-stage pancreatic cancers. At 2 months, pancreatic cancer patients improved in general activity by 0.93 points, walking by 1.00 points, and working by 1.12 points. Conclusion:. Celiac plexus neurolysis can decrease cancer symptom burden beyond pain including quality of life and sleep for pancreatic and nonpancreatic cancers, as well as general activity for pancreatic cancers