Diet-induced obesity leads to behavioral indicators of pain preceding structural joint damage in wild-type mice

Introduction: Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Despite the clinical association, no studies have directly assessed whether diet-induced obesity accelerates IVD degeneration, back pain, or investigated the biological mediators underlying this association. In this study, we examine the effects of chronic consumption of a high-fat or high-fat/high-sugar (western) diet on the IVD, knee joint, and pain-associated outcomes. Methods: Male C57BL/6N mice were randomized into one of three diet groups (chow control; high-fat; high-fat, high-sugar western diet) at 10 weeks of age and remained on the diet for 12, 24, or 40 weeks. At endpoint, animals were assessed for behavioral indicators of pain, joint tissues were collected for histological and molecular analysis, serum was collected to assess for markers of systemic inflammation, and IBA-1, GFAP, and CGRP were measured in spinal cords by immunohistochemistry. Results: Animals fed obesogenic (high-fat or western) diets showed behavioral indicators of pain beginning at 12 weeks and persisting up to 40 weeks of diet consumption. Histological indicators of moderate joint degeneration were detected in the IVD and knee following 40 weeks on the experimental diets. Mice fed the obesogenic diets showed synovitis, increased intradiscal expression of inflammatory cytokines and circulating levels of MCP-1 compared to control. Linear regression modeling demonstrated that age and diet were both significant predictors of most pain-related behavioral outcomes, but not histopathological joint degeneration. Synovitis was associated with alterations in spontaneous activity. Conclusion: Diet-induced obesity accelerates IVD degeneration and knee OA in mice; however, pain-related behaviors precede and are independent of histopathological structural damage. These findings contribute to understanding the source of obesity-related back pain and the contribution of structural IVD degeneration

Use of high-plex data reveals novel insights into the tumour microenvironment of clear cell renal cell carcinoma

This work was supported by Medical Research Scotland (MRS), NHS Lothian, NanoStringTechnologies, and the Industrial Centre for AI Research in Digital Diagnostics (iCAIRD) which is funded by Innovate UK on behalf of UK Research and Innovation (UKRI) [project number: 104690].Although Immune Checkpoint Inhibitors (ICIs) have significantly improved the oncological outcomes, about one third of patients affected by Clear Cell Renal Cell Carcinoma (ccRCC) still experience recurrence. Current prognostic algorithms like the Leibovich Score (LS) rely on morphological features manually assessed by pathologists, and are therefore subject to bias. Moreover, these tools do not consider the heterogeneous molecular milieu present in the Tumour Microenvironment (TME), which may have prognostic value. We systematically developed a semi-automated method to investigate 62 markers and their combinations in 150 primary ccRCCs using multiplex Immunofluorescence (mIF), NanoString GeoMx® Digital Spatial Profiling (DSP) and Artificial Intelligence (AI)-assisted image analysis in order to find novel prognostic signatures and investigate their spatial relationship. We found that coexpression of Cancer Stem Cell (CSC) and Epithelial-to-Mesenchymal Transition (EMT) markers such as OCT4 and ZEB1 are indicative of poor outcome. OCT4 and the immune markers CD8, CD34 and CD163 significantly stratified patients at intermediate LS. Furthermore, augmenting the LS with OCT4 and CD34 improved patient stratification by outcome. Our results support the hypothesis that combining molecular markers has prognostic value and can be integrated with morphological features to improve risk stratification and personalised therapy. To conclude, GeoMx® DSP and AI image analysis are complementary tools providing high multiplexing capability required to investigate the TME of ccRCC, while reducing observer bias.Publisher PDFPeer reviewe

Bactericidal activities and post-antibiotic effects of ofloxacin and ceftriaxone against drug-resistant Salmonella enterica serovar Typhi.

BACKGROUND: The clinical response to ceftriaxone in patients with typhoid fever is significantly slower than with ofloxacin, despite infection with Salmonella enterica serovar Typhi (S. Typhi) isolates with similar susceptibilities (MIC 0.03-0.12 mg/L). The response to ofloxacin is slower if the isolate has intermediate susceptibility (MIC 0.25-1.0 mg/L). OBJECTIVES: To determine the bactericidal activity and post-antibiotic effect (PAE) of ceftriaxone and ofloxacin against S. Typhi. METHODS: The mean time to reach a 99.9% reduction in log10 count (bactericidal activity) and PAE of ceftriaxone and ofloxacin were determined for 18 clinical isolates of S. Typhi in time-kill experiments (MIC range for ofloxacin 0.06-1.0 mg/L and for ceftriaxone 0.03-0.12 mg/L). RESULTS: The mean (SD) bactericidal activity of ofloxacin was 33.1 (15.2) min and 384.4 (60) min for ceftriaxone. After a 30 min exposure to ofloxacin, the mean (SD) duration of PAE was 154.7 (52.6) min. There was no detectable PAE after 1 h of exposure to ceftriaxone. For ofloxacin, bactericidal activity and PAE did not significantly differ between isolates with full or intermediate susceptibility provided ofloxacin concentrations were maintained at 4×MIC. CONCLUSIONS: Infections with S. Typhi with intermediate ofloxacin susceptibility may respond to doses that maintain ofloxacin concentrations at 4×MIC at the site of infection. The slow bactericidal activity of ceftriaxone and absent PAE may explain the slow clinical response in typhoid

Icebergs in the North Atlantic: Modelling circulation changes and glacio-marine deposition

In order to investigate meltwater events in the North Atlantic, a simple iceberg generation, drift, and melting routine was implemented in a high-resolution OGCM. Starting from the modelled last glacial state, every 25th day cylindrical model icebergs 300 meters high were released at 32 specific points along the coasts. Icebergs launched at the Barents Shelf margin spread a light meltwater lid over the Norwegian and Greenland Seas, shutting down the deep convection and the anti-clockwise circulation in this area. Due to the constraining ocean circulation, the icebergs produce a tongue of relatively cold and fresh water extending eastward from Hudson Strait that must develop at this location, regardless of iceberg origin. From the total amount of freshwater inferred by the icebergs, the thickness of the deposited IRD could be calculated in dependance of iceberg sediment concentration. In this way, typical extent and thickness of Heinrich layers could be reproduced, running the model for 250 years of steady state with constant iceberg meltwater inflow

Ghosts of Yellowstone: Multi-Decadal Histories of Wildlife Populations Captured by Bones on a Modern Landscape

Natural accumulations of skeletal material (death assemblages) have the potential to provide historical data on species diversity and population structure for regions lacking decades of wildlife monitoring, thereby contributing valuable baseline data for conservation and management strategies. Previous studies of the ecological and temporal resolutions of death assemblages from terrestrial large-mammal communities, however, have largely focused on broad patterns of community composition in tropical settings. Here, I expand the environmental sampling of large-mammal death assemblages into a temperate biome and explore more demanding assessments of ecological fidelity by testing their capacity to record past population fluctuations of individual species in the well-studied ungulate community of Yellowstone National Park (Yellowstone). Despite dramatic ecological changes following the 1988 wildfires and 1995 wolf re-introduction, the Yellowstone death assemblage is highly faithful to the living community in species richness and community structure. These results agree with studies of tropical death assemblages and establish the broad capability of vertebrate remains to provide high-quality ecological data from disparate ecosystems and biomes. Importantly, the Yellowstone death assemblage also correctly identifies species that changed significantly in abundance over the last 20 to ∼80 years and the directions of those shifts (including local invasions and extinctions). The relative frequency of fresh versus weathered bones for individual species is also consistent with documented trends in living population sizes. Radiocarbon dating verifies the historical source of bones from Equus caballus (horse): a functionally extinct species. Bone surveys are a broadly valuable tool for obtaining population trends and baseline shifts over decadal-to-centennial timescales

Next-to-eikonal corrections to soft gluon radiation: a diagrammatic approach

We consider the problem of soft gluon resummation for gauge theory amplitudes and cross sections, at next-to-eikonal order, using a Feynman diagram approach. At the amplitude level, we prove exponentiation for the set of factorizable contributions, and construct effective Feynman rules which can be used to compute next-to-eikonal emissions directly in the logarithm of the amplitude, finding agreement with earlier results obtained using path-integral methods. For cross sections, we also consider sub-eikonal corrections to the phase space for multiple soft-gluon emissions, which contribute to next-to-eikonal logarithms. To clarify the discussion, we examine a class of log(1 - x) terms in the Drell-Yan cross-section up to two loops. Our results are the first steps towards a systematic generalization of threshold resummations to next-to-leading power in the threshold expansion.Comment: 66 pages, 19 figure

Storytelling as 'unorthodox' agency:negotiating the 2012 family immigration rules (United Kingdom)

This article attends to the lived experience of binational families subject to the 2012 family immigration rules (FIR). It seeks to enrich the pre-existing discussions of family migration within the European Union (EU) and the United Kingdom, focusing on the ‘micro-political’ experiences of those whose lives have been adversely affected by their introduction. It draws on the life writings of binational families, suggesting that a micro-political focus reveals an ongoing neuropolitical experience that traditional accounts of moral agency are ill-equipped to negotiate. The article suggests an unorthodox interpretation of agency premised on storytelling, while probing the tensions that emerge when this lived experience is framed in such a manner. It concludes by positing a series of questions relating to the value of a neuropolitical labelling of the subject and suggests a need to further engage with traumatic interpretations of harm at the intersection of citizenship rights and mobility rights

Application of compression test in analysis of mechanical and color changes in grapefruit juice powder as related to glass transition and water activity

Physicochemical and structural properties of grapefruit juice powder were studied as affected by water activity. Powdered juice was obtained by freeze-drying and equilibrated at different water vapor pressure atmospheres in order to give samples with water activity in the range of 0-084 The mechanical properties of the powder were measured by confined compression tests and the compressed samples, which presented uniform surface and thickness, were subjected to color analysis The maximum force attained during the compression tests and the color coordinates could be quantified with good reproducibility. The results were related to water activity and to glass transition temperature The occurrence of mechanical changes in the powder was shown to precede significant color changes with increasing water activity. Considering the susceptibility to stickiness, the stability limit was observed at T-T(g) approximate to 2 degrees C, with a high degree of mechanical changes being detected at T-Tg 16 degrees C, whereas for significant color changes this critical temperature difference was around 32 degrees CAuthors thank the Ministerio de Educacion y Ciencia and the Fondo Europeo de Desarrollo Regional (FEDER) for the financial support throughout the projects AGL2002-01793 and AGL 200505994. Vania R. N. Tells acknowledges the support of the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) as an external grant (Proc. BEX 4452/06-2).Telis, VRN.; Martínez Navarrete, N. (2010). Application of compression test in analysis of mechanical and color changes in grapefruit juice powder as related to glass transition and water activity. Food Science and Technology. 43(5):744-751. https://doi.org/10.1016/j.lwt.2009.12.007S74475143

DESIGNING PORT INFRASTRUCTURE FOR SEA LEVEL CHANGE: A SURVEY OF U.S. ENGINEERS

Seaports are particularly vulnerable to the impacts of climate change due to their coastal location. With the potential threat of up to 2.5m in sea level rise by 2100, resilient port infrastructure is vital for the continued operation of ports. There are strong economic and social incentives for seaports to provide long-term resilience against climate conditions. For example, service disruptions can cost billions of dollars and impact the livelihoods of those who depend on the port. Engineers play a pivotal role in improving the resilience of ports, as they are responsible for designing port infrastructure that will be adequately prepared for future sea level change (SLC). However, incorporating SLC is a challenging task due to the uncertainty of SLC projections, the long service lives of port infrastructure, and the differing guidelines and recommendations for managing SLC. Through an online survey of 85 U.S. port and marine infrastructure engineers, this research explores the engineering community’s attitude and approach to planning for SLC for large-scale maritime infrastructure projects. Survey findings highlight the extent that projects incorporate SLC, the wide range of factors that drive the inclusion of SLC, and the numerous barriers that prevent engineers from incorporating SLC into design. This research emphasizes that traditional engineering practices may no longer be appropriate for dealing with climate change design variables and their associated uncertainties. Furthermore, results call for collaboration among engineers, port authorities, and policy makers to develop design standards and practical design methods for designing resilient port infrastructure

Perception and beliefs about mental illness among adults in Karfi village, northern Nigeria

BACKGROUND: This study was designed to examine the knowledge, attitude and beliefs about causes, manifestations and treatment of mental illness among adults in a rural community in northern Nigeria. METHODS: A cross sectional study design was used. A pre-tested, semi-structured questionnaire was administered to 250 adults residing in Karfi village, northern Nigeria. RESULTS: The most common symptoms proffered by respondents as manifestations of mental illness included aggression/destructiveness (22.0%), loquaciousness (21.2%), eccentric behavior (16.1%) and wandering (13.3%). Drug misuse including alcohol, cannabis, and other street drugs was identified in 34.3% of the responses as a major cause of mental illness, followed by divine wrath/ God's will (19%), and magic/spirit possession (18.0%). About 46% of respondents preferred orthodox medical care for the mentally sick while 34% were more inclined to spiritual healing. Almost half of the respondents harbored negative feelings towards the mentally ill. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects (OR = 7.6, 95% confidence interval = 3.8–15.1). CONCLUSIONS: Our study demonstrates the need for community educational programs in Nigeria aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons