Nonenzymatic Glycosylafion of Bovine Retinal Microvessel Basement Membranes In Vitro Kinetic Analysis and Inhibition by Aspirin

Incubation of intact bovine retinal microvessels or isolated retinal microvessel basement membranes (RVBM) with radioactive D-glucose or L-glucose, followed by basement membrane collagenous protein purification, resulted in the isolation of nonenzymatically glycosylated RVBM collagens. Type IV collagen was identified in the RVBM by selective salt fractionation, SDS-polyacrylamide gel electrophoresis, amino acid analysis, and immunoprecipitation with specific antibody. Kinetic analysis of the condensation of glucose with RVBM was carried out by labeling retinal microvessel basement membranes with D-[2- C|-glucose. The rate constant for aldimine product formation, k,, was 1.95 ± 0.24 (SD) X 10~4 mM" 1 h~', and the rate constant for the reversed reaction, k_ l9 was 5.9 ± 1.0 X 10~2 h" 1 . Based on a rate constant for the Amadori rearrangement, k 2 , of 8.8 ± 1.0 X 10~3 h" 1 , which was the rate-determining step, the half life of this reaction was 80 ± 9 h. These data may be useful in estimating the glycosylation of retinal microvessel basement membranes in vivo. The nonenzymatic glycosylation of retinal microvessel basement membrane proteins was progressively inhibited by increasing concentrations (0.1 to 2.0 mM) of aspirin. Invest Ophthalmol Vis Sci 25: [884][885][886][887][888][889][890][891] 1 One way hyperglycemia, per se, may play a role in the primary pathology of diabetic retinopathy is by altering the structure and function of retinal microvessel basement membrane proteins through increased nonenzymatic glycosylation. D-glucose, an aldehyde, undergoes a condensation reaction with the amino groups of proteins with the formation of an aldimine or Schiff-base linkage that subsequently may undergo an Amadori rearrangement to form a more stable condensation product. High levels of ambient glucose hav

Long-term patient-reported outcome measures after injury: National trauma research action plan (NTRAP) scoping review protocol

Background: A significant proportion of patients who survive traumatic injury continue to suffer impaired functional status and increased mortality long after discharge. However, despite the need to improve long-term outcomes, trauma registries in the USA do not collect data on outcomes or care processes after discharge. One of the main barriers is the lack of consensus regarding the optimal outcome metrics.Objectives: To describe the methodology of a scoping review evaluating current evidence on the available measures for tracking functional and patient-reported outcomes after injury. The aim of the review was to identify and summarize measures that are being used to track long-term functional recovery and patient-reported outcomes among adults after injury.Methods: A systematic search of PubMed and Embase will be performed using the search terms for the population (adult trauma patients), type of outcomes (long-term physical, mental, cognitive, and quality of life), and measures available to track them. Studies identified will be reviewed and assessed for relevance by at least two reviewers. Data will be extracted and summarized using descriptive statistics and a narrative synthesis of the results. This protocol is being reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines.Dissemination: This scoping review will provide information regarding the currently available metrics for tracking functional and patient-reported outcomes after injury. The review will be presented to a multi-disciplinary stakeholder group that will evaluate these outcome metrics using an online Delphi approach to achieve consensus as part of the development of the National Trauma Research Action Plan (NTRAP). The results of this review will be presented at relevant national surgical conferences and published in peer-reviewed scientific journals

Crossing the Phantom Divide Line in a DGP-Inspired F(R,ϕ)F(R,\phi)-Gravity

We study possible crossing of the phantom divide line in a DGP-inspired $F(R,\phi)$ braneworld scenario where scalar field and curvature quintessence are treated in a unified framework. With some specific form of $F(R,\phi)$ and by adopting a suitable ansatz, we show that there are appropriate regions of the parameters space which account for late-time acceleration and admit crossing of the phantom divide line.Comment: 23 Pages, 10 figs, Submitted to JCA

Hybrid Simulation Theory for Continuous Beams

Hybrid simulation is an experimental technique involving the integration of a physical system and a computational system with the use of actuators and sensors. This method has a long history in the experimental community and has been used for nearly 40 years. However, there is a distinct lack of theoretical research on the performance of this method. Hybrid simulation experiments are performed with the implicit assumption of an accurate result as long as sensor and actuator errors are minimized. However, no theoretical results confirm this intuition nor is it understood how minimal the error should be and what the essential controlling factors are. To address this deficit in knowledge, this study considers the problem as one of tracking the trajectory of a dynamical system in a suitably defined configuration space. To make progress, the study strictly considers a theoretical hybrid system. This allows for precise definitions of errors during hybrid simulation. As a model system, the study looks at an elastic beam as well as a viscoelastic beam. In both cases, systems with a continuous distribution of mass are considered as occur in real physical systems. Errors in the system are then tracked during harmonic excitation using space-time L2-norms defined over the system's configuration space. A parametric study is then presented of how magnitude and phase errors in the control system relate to the performance of hybrid simulation. It is seen that there are sharp sensitivities to control system errors. Further, the existence of unacceptably high errors whenever the excitations exceed the system's fundamental frequency is shown to be present in hybrid simulation

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

A Seismic Performance Classification Framework to Provide Increased Seismic Resilience

Several performance measures are being used in modern seismic engineering applications, suggesting that seismic performance could be classified a number of ways. This paper reviews a range of performance measures currently being adopted and then proposes a new seismic performance classification framework based on expected annual losses (EAL). The motivation for an EAL-based performance framework stems from the observation that, in addition to limiting lives lost during earthquakes, changes are needed to improve the resilience of our societies, and it is proposed that increased resilience in developed countries could be achieved by limiting monetary losses. In order to set suitable preliminary values of EAL for performance classification, values of EAL reported in the literature are reviewed. Uncertainties in current EAL estimates are discussed and then an EAL-based seismic performance classification framework is proposed. The proposal is made that the EAL should be computed on a storey-by-storey basis in recognition that EAL for different storeys of a building could vary significantly and also recognizing that a single building may have multiple owners

Environmental immune disruptors, inflammation and cancer risk

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E₂ , nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://carcin.oxfordjournals.org/. The publisher and the author(s) have made this article open access

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p