Hypoxia. HIF-mediated articular chondrocyte function: prospects for cartilage repair

In a chronically hypoxic tissue such as cartilage, adaptations to hypoxia do not merely include cell survival responses, but also promotion of its specific function. This review will focus on describing such hypoxia-mediated chondrocyte function, in particular in the permanent articular cartilage. The molecular details of how chondrocytes sense and respond to hypoxia and how this promotes matrix synthesis have recently been examined, and specific manipulation of hypoxia-induced pathways is now considered to have potential therapeutic application to maintenance and repair of articular cartilage

Abdominal obesity‐related disturbance of insulin sensitivity is associated with cd8+ emra cells in the elderly

Aging and overweight increase the risk of developing type 2 diabetes mellitus. In this cross‐sectional study, we aimed to investigate the potential mediating role of T‐EMRA cells and inflammatory markers in the development of a decreased insulin sensitivity. A total of 134 healthy older volunteers were recruited (age 59.2 (SD 5.6) years). T cell subpopulations were analyzed by flow cytometry. Furthermore, body composition, HOMA‐IR, plasma tryptophan (Trp) metabolites, as well as cytokines and adipokines were determined. Using subgroup and covariance analyses, the influence of BMI on the parameters was evaluated. Moreover, correlation, multiple regression, and mediation analyses were performed. In the subgroup of participants with obesity, an increased proportion of CD8+EMRA cells and elevated concentrations of plasma kynurenine (KYN) were found compared to the lower‐weight subgroups. Linear regression analysis revealed that an elevated HOMA‐IR could be predicted by a higher proportion of CD8+EMRA cells and KYN levels. A mediation analysis showed a robust indirect effect of the Waist‐to‐hip ratio on HOMA‐IR mediated by CD8+EMRA cells. Thus, the deleterious effects of abdominal obesity on glucose metabolism might be mediated by CD8+EMRA cells in the elderly. Longitudinal studies should validate this assumption and analyze the suitability of CD8+EMRA cells as early predictors of incipient prediabetes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

The cytotoxicity and synergistic potential of aspirin and aspirin analogues towards oesophageal and colorectal cancer

Background: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC. Methods: The toxicity of aspirin and aspirin derivatives to OC and a colorectal cancer (CRC) cell line were investigated in the presence and absence of platins. Results: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 CRC cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line. Conclusion: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins

Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation

Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in Commd1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Self -mediated interactions among community forestry actors in Nepal: A political ecology of the UK's Livelihoods and Forestry Programme.

This dissertation uses a Political Ecology framework to examine bilateral aid in community forest management. Its findings develop Political Ecology as a theoretical framework by focusing on how organizational actors at multiple scales affect local relationships and events, and by incorporating insights from Actor-Network Theory to develop the concept of self-mediation. Self-mediation is the process of implicit compromise and unstated negotiation within an Actor-Network towards goal congruence. The livelihoods potential of community forestry is constrained by local power disparities, which are reinforced by the way community forestry is managed by Nepal's Department of Forests. Nepal forest policy and practice are in turn supported and reinforced by the assistance provided by bilateral donor projects. Thus, donor projects such as the United Kingdom's Livelihoods and Forestry Programme actually enable Nepal government forest policies and practices that implicitly maintain, or possibly even deepen, local power disparities. The Livelihoods and Forestry Programme sees itself as a change-agent working to improve rural livelihoods in Nepal. However, the program continues to provide financial and technical support to the forest bureaucracy even when the it makes restrictive policy and despite its implicit endorsement of local power disparities. This suggests that organizational actors are influenced and shaped by their institutional environment, the contours of which produce a certain momentum carried into interorganizational relationships and Actor-Networks. This momentum influences the trajectory of the Actor-Network, and thus constrains what each actor and the Actor-Network as a whole can and cannot do. The finding that bilateral aid reinforces existing social relations and simultaneously promotes and undermines improvements in sustainable livelihoods is not entirely new. However, the theoretical explanation that this paradox occurs through self-mediation is novel. Self-mediation can be characterized as the filtered flow of intention. Each actor within a network has its own set of goals or its own particular intention. In the process of developing a goal or an intention at the Actor-Network level, actor interactions effectively filter individual and collective intentions to eliminate what is not feasible at the Actor-Network level. Their impact is mediated by the actions and interactions of the community forestry Actor-Network itself.Ph.D.Biological SciencesForestrySocial SciencesSociologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124581/2/3150108.pd

A Conceptual Model for Anostracan Biogeography

The Anostraca are found globally in seasonally astatic basins, temporary pools and/or saline inland aquatic habitats. The primary question posed in this thesis is: why do anostracan taxa occur in some locations and not others? Of the more than 350 described species, greater than one third of anostracans are known to occur in only one location. Anostracan zoogeography research over large spatial scales has focused on climate and water quality data as the primary drivers of spatial distribution. Climate is difficult to quantify and water chemistry in astatic aquatic habitats is highly variable. Anostraca seem to defy any simple explanation of their zoogeography at any scale. In this thesis, the ideas that anostracan biogeography can be explained in terms of island biogeography and the Monopolisation Hypothesis are explored. Results from a series of research studies, undertaken in this thesis, directed to increasing our understanding of anostracan zoogeography highlight the following