Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis

OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92

Overconfidence is universal? Elicitation of genuine overconfidence (EGO) procedure reveals systematic differences across domain, task knowledge, and incentives in four populations

Overconfidence is sometimes assumed to be a human universal, but there remains a dearth of data systematically measuring overconfidence across populations and contexts. Moreover, cross-cultural experiments often fail to distinguish between placement and precision and worse still, often compare population-mean placement estimates rather than individual performance subtracted from placement. Here we introduce a procedure for concurrently capturing both placement and precision at an individual level based on individual performance: The Elicitation of Genuine Overconfidence (EGO) procedure. We conducted experiments using the EGO procedure, manipulating domain, task knowledge, and incentives across four populations—Japanese, Hong Kong Chinese, Euro Canadians, and East Asian Canadians. We find that previous measures of population-level overconfidence may have been misleading; rather than universal, overconfidence is highly context dependent. Our results reveal cross-cultural differences in sensitivity to incentives and differences in overconfidence strategies, with underconfidence, accuracy, and overconfidence. Comparing sexes, we find inconsistent results for overplacement, but that males are consistently more confident in their placement. These findings have implications for our understanding of the adaptive value of overconfidence and its role in explaining population-level and individual-level differences in economic and psychological behavior

Inclusion of additional studies yields different conclusions: Comment on Sedikides, Gaertner, & Vevea (2005), Journal of Personality and Social Psychology

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75100/1/j.1467-839X.2007.00211.x.pd

Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence

Background: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. Methods: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. Results: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. Conclusions: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation

Report on ICDP Deep Dust workshops: probing continental climate of the late Paleozoic icehouse–greenhouse transition and beyond

Chamberlin and Salisbury's assessment of the Permian a century ago captured the essence of the period: it is an interval of extremes yet one sufficiently recent to have affected a biosphere with near-modern complexity. The events of the Permian - the orogenic episodes, massive biospheric turnovers, both icehouse and greenhouse antitheses, and Mars-analog lithofacies - boggle the imagination and present us with great opportunities to explore Earth system behavior. The ICDP-funded workshops dubbed "Deep Dust," held in Oklahoma (USA) in March 2019 (67 participants from nine countries) and Paris (France) in January 2020 (33 participants from eight countries), focused on clarifying the scientific drivers and key sites for coring continuous sections of Permian continental (loess, lacustrine, and associated) strata that preserve high-resolution records. Combined, the two workshops hosted a total of 91 participants representing 14 countries, with broad expertise. Discussions at Deep Dust 1.0 (USA) focused on the primary research questions of paleoclimate, paleoenvironments, and paleoecology of icehouse collapse and the run-up to the Great Dying and both the modern and Permian deep microbial biosphere. Auxiliary science topics included tectonics, induced seismicity, geothermal energy, and planetary science. Deep Dust 1.0 also addressed site selection as well as scientific approaches, logistical challenges, and broader impacts and included a mid-workshop field trip to view the Permian of Oklahoma. Deep Dust 2.0 focused specifically on honing the European target. The Anadarko Basin (Oklahoma) and Paris Basin (France) represent the most promising initial targets to capture complete or near-complete stratigraphic coverage through continental successions that serve as reference points for western and eastern equatorial Pangaea. © 2020 Copernicus GmbH. All rights reserved

SWITCH 1/DYAD is a WINGS APART-LIKE antagonist that maintains sister chromatid cohesion in meiosis

During cell division, Soronin antagonises WAPL to prevent premature loss of sister chromatid cohesion. Here the authors show that, despite a lack of sequence similarity, the Arabidopsis SWI1 protein functions as a novel Soronin-like WAPL antagonist, suggesting convergent evolution with animals

EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment

<p>Abstract</p> <p>Purpose</p> <p>There are conflicting reports regarding the function of EFEMP1 in different cancer types. In this study, we sought to evaluate the role of EFEMP1 in malignant glioma biology.</p> <p>Experimental Design</p> <p>Real-time qRT-PCR was used to quantify <it>EFEMP1 </it>expression in 95 glioblastoma multiforme (GBM). Human high-grade glioma cell lines and primary cultures were engineered to express ectopic EFEMP1, a small hairpin RNA of EFEMP1, or treated with exogenous recombinant EFEMP1 protein. Following treatment, growth was assayed both <it>in vitro </it>and <it>in vivo </it>(subcutaneous (s.c.) and intracranial (i.c.) xenograft model systems).</p> <p>Results</p> <p>Cox regression revealed that EFEMP1 is a favorable prognostic marker for patients with GBM. Over-expression of EFEMP1 eliminated tumor development and suppressed angiogenesis, cell proliferation, and VEGFA expression, while the converse was true with knock-down of endogenous EFEMP1 expression. The EFEMP1 suppression of tumor onset time was nearly restored by ectopic VEGFA expression; however, overall tumor growth rate remained suppressed. This suggested that inhibition of angiogenesis was only partly responsible for EFEMP1's impact on glioma development. In glioma cells that were treated by exogenous EFEMP1 protein or over-expressed endogenous EFEMP1, the EGFR level was reduced and AKT signaling activity attenuated. Mixing of EFEMP1 protein with cells prior to s.c. and i.c. implantations or injection of the protein around the established s.c. xenografts, both significantly suppressed tumorigenicity.</p> <p>Conclusions</p> <p>Overall, our data reveals that EEFEMP1 suppresses glioma growth <it>in vivo</it>, both by modulating the tumor extracellular microenvironment and by altering critical intracellular oncogenic signaling pathways.</p

Menthol Cigarette Smoking and Obesity in Young Adult Daily Smokers in Hawaii

This study investigates 1) the relationship between menthol cigarette smoking and obesity and 2) the association of body mass index with the nicotine metabolite ratio among menthol and non-menthol daily smokers aged 18–35 (n = 175). A brief survey on smoking and measures of height and weight, carbon monoxide, and saliva samples were collected from participants from May to December 2013 in Honolulu, Hawaii. Multiple regression was used to estimate differences in body mass index among menthol and non-menthol smokers and the association of menthol smoking with obesity. We calculated the log of the nicotine metabolite ratio to examine differences in the nicotine metabolite ratio among normal, overweight, and obese smokers. Sixty-eight percent of smokers used menthol cigarettes. Results showed that 62% of normal, 54% of overweight, and 91% of obese smokers used menthol cigarettes (p = .000). The mean body mass index was significantly higher among menthol compared with non-menthol smokers (29.4 versus 24.5, p = .000). After controlling for gender, marital status, educational attainment, employment status, and race/ethnicity, menthol smokers were more than 3 times as likely as non-menthol smokers to be obese (p = .04). The nicotine metabolite ratio was significantly lower for overweight menthol smokers compared with non-menthol smokers (.16 versus .26, p = .02) in the unadjusted model, but was not significant after adjusting for the covariates. Consistent with prior studies, our data show that menthol smokers are more likely to be obese compared with non-menthol smokers. Future studies are needed to determine how flavored tobacco products influence obesity among smokers