LPAR2 Regulates LPA-Induced Osteoclast Sealing Zone Dynamics

Bone metastasis is an excruciating consequence of multiple primary cancers, and is commonly treated with bisphosphonate drugs. Osteoclasts, bone-resorbing cells vital to proper bone remodeling and fracture healing, are responsible for the formation of osteolytic bone tumors. Osteoclasts function through an actin-based structure called the actin sealing zone, or actin ring. Actin ring formation is required for proper bone resorption, and can be used to measure osteoclast function. The Lee lab is investigating the mechanisms of lysophosphatidic acid (LPA) treatment on osteoclasts. LPA is a lipid molecule found at elevated levels in the blood of cancer patients. In preliminary in vitro experiments, osteoclasts were directly treated with LPA. Cells were also exposed to LPA in the presence of a common bisphosphonate, Zometa, which is currently used to treat the osteoporosis commonly observed in cancer patients. In the absence of Zometa, LPA increases the actin ring circumference and the number of cellular nuclei. Zometa treatment decreases the actin ring perimeter and number of nuclei. Osteoclasts treated with Zometa and LPA simultaneously show an expanded actin ring and elevated number of nuclei, similar to the phenotype induced by exposure to LPA alone. Cells treated with Zometa after LPA exposure showed no observable response to the drug. LPA works through five known receptors, three of which are defined in osteoclasts. The LPA receptor (LPAR) 1/3 inhibitor Ki16425 did not suppress the actin ring increase by LPA. However, LPAR2 agonist FAP12 demonstrated effects identical to those observed in the presence of LPA on bone. Such data suggests that LPAR2 is responsible for the actin ring perimeter and nuclear quantity changes seen with LPA treatment. Small interfering RNAs (siRNAs) specific to LPAR2 were utilized to examine LPAR2 function. Knockdown of LPAR2 inhibited the actin ring expansion observed in cells with functional LPAR2. The results suggest that LPAR2 is a key element in LPA-induced actin sealing zone dynamics, and is consequently a new target for alternative drug therapies to treat LPA-induced bone metastasis.NIAMS RO1 AR051515 to BSLA five-year embargo was granted for this item

Deprescribing in Terminal Illness: The Role of the Hospice Nurse

Eliminating unnecessary, ineffective, or unsafe medications, also known as deprescribing, is important for the safety and wellbeing of patients who face terminal illness. Hospice nurses play a pivotal role in helping these patients navigate decisions about medicines as end of life approaches yet evidenced based guidelines and tools on how and when to do this are scarce. The purpose of this study was to gain insight on the attitudes and practices of hospice nurses at Hospice of Cincinnati (HOC) regarding medications and deprescribing and to disseminate evidenced based tools that they may incorporate into practice. The first part of the study consisted of an electronically administered survey to the home care and long-term care nurses working at HOC. Next, an educational session was held for the home care and long-term care nurses’ teams at HOC. The focus of the session was results of the survey as well as a proposed algorithm and communication techniques that the nurses may use to initiate therapeutic conversations about stopping certain medications. The proposed algorithm and scripts were tailored to the results of the survey and consistent with current literature. These tools have the potential to facilitate deprescribing earlier and with more ease, both of which serve to benefit the organization, the patient and families, as well as the nurses using them

Effects of oestrogenic chemicals on the liver

PhD ThesisOur environment and diet contains a variety of man-made endocrine disrupting chemicals which may pose a significant health threat for wildlife and humans. In particular, there is increasing concern regarding the adverse effects caused by xenoestrogens which are believed to trigger many endocrine-related diseases. Since high systemic levels of oestrogens are cholestatic, it was investigated whether xenoestrogens are able to cause adverse hepatic effects in vivo in mouse models and whether these effects are mediated by interaction with the murine oestrogen receptors (ERs). The food dye tartrazine has previously been shown to activate the human ERα and intraperitoneal injection caused cholestasis in mice. In this study, tartrazine failed to activate murine ERα and two murine ERβ variants in vitro suggesting that cholestasis occurred independent of the ERs. Data indicate, however, that tartrazine, its major metabolites and a contaminant inhibited murine dopamine sulfotransferase. Considering the role of sulfotransferases in bile acid secretion, these findings suggest that impairment of bile acid sulfation and subsequent secretion may be a key event in tartrazine-mediated cholestasis. Oral exposure to tartrazine caused inflammation in the liver and gastrointestinal tract in vivo in mice without evidence of cholestatic effects. Several soil extracts prepared from soil samples collected from around an urban landfill site activated human and murine ERα and two murine ERβ variants in vitro. Pooled oestrogenic soil extracts had mild cholestatic effects in a mouse model. Given the cholestatic features of the liver disease primary biliary cholangitis (PBC), which is linked to exposure to xenobiotics associated with a toxic environment and proximities to waste sites, environmental xenoestrogens could be a component of a xenobiotic insult that triggers PBC. These findings indicate that if significant exposure to environmental xenoestrogens occurs, they can have adverse hepatic effects and may be part of a trigger process in cholestatic liver diseases

Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1

Microcephalin‐1 (MCPH1) exists as 2 isoforms that regulate cyclin‐dependent kinase‐1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin‐dependent kinase‐1–dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase‐promoting complex/cyclosome–CDH1 E3 ligase complex. Anaphase‐promoting complex/cyclosome–CDH1 target proteins generally have D‐Box or KEN‐Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D‐Box dependent, whereas the short isoform was KEN‐Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.—Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1. FASEB J. 33, 2796–2808 (2019). www.fasebj.or

Plant community structure determines primary productivity in shallow, eutrophic lakes

Regime shifts are commonly associated with the loss of submerged macrophytes in shallow lakes; yet, the effects of this on whole-lake primary productivity remain poorly understood. This study compares the annual gross primary production (GPP) of two shallow, eutrophic lakes with different plant community structures but similar nutrient concentrations. Daily GPP rates were substantially higher in the lake containing submerged macrophytes (586 ± 23 g C m−2 year−1) than in the lake featuring only phytoplankton and periphyton (408 ± 23 g C m−2 year−1; P \u3c 0.0001). Comparing lake-centre diel oxygen curves to compartmental estimates of GPP confirmed that single-site oxygen curves may provide unreliable estimates of whole-lake GPP. The discrepancy between approaches was greatest in the macrophyte-dominated lake during the summer, with a high proportion of GPP occurring in the littoral zone. Our empirical results were used to construct a simple conceptual model relating GPP to nutrient availability for these alternative ecological regimes. This model predicted that lakes featuring submerged macrophytes may commonly support higher rates of GPP than phytoplankton-dominated lakes, but only within a moderate range of nutrient availability (total phosphorus ranging from 30 to 100 μg L−1) and with mean lake depths shallower than 3 or 4 m. We conclude that shallow lakes with a submerged macrophyte–epiphyton complex may frequently support a higher annual primary production than comparable lakes that contain only phytoplankton and periphyton. We thus suggest that a regime shift involving the loss of submerged macrophytes may decrease the primary productivity of many lakes, with potential consequences for the entire food webs of these ecosystems

Beton in de Belgische architectuur, 3: van Foncolin tot CBR

Geprefabriceerd beton is het meest toegepaste bouwsysteem in de hedendaagse utiliteitsbouw. Vaak wordt ook de gevel in het systeem ingepast. In België spreekt men dan van architectonisch beton. In deze derde bijdrage in de serie over beton in de Belgische architectuur passeren enkele mijlpalen de revue