Physiological levels of estradiol limit murine osteoarthritis progression

Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17β-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms

Pulsed administration for physiological estrogen replacement in mice

Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid. </p

Evidence of phonon-assisted tunnelling in electrical conduction through DNA molecules

We propose a phonon-assisted tunnelling model for explanation of conductivity dependence on temperature and temperature-dependent I-V characteristics in deoxyribonucleic acid (DNA) molecules. The capability of this model for explanation of conductivity peculiarities in DNA is illustrated by comparison of the temperature dependent I-V data extracted from some articles with tunnelling rate dependences on temperature and field strength computed according to the phonon-assisted tunnelling theory. PACS Codes: 87.15.-v, 71.38.-k, 73.40.GkComment: 6 pages, 3 figure

Influence of environmental parameters on movements and habitat utilization of humpback whales (Megaptera novaeangliae) in the Madagascar breeding ground

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Royal Society Open Science 3 (2016): 160616, doi:10.1098/rsos.160616.Assessing the movement patterns and key habitat features of breeding humpback whales is a prerequisite for the conservation management of this philopatric species. To investigate the interactions between humpback whale movements and environmental conditions off Madagascar, we deployed 25 satellite tags in the northeast and southwest coast of Madagascar. For each recorded position, we collated estimates of environmental variables and computed two behavioural metrics: behavioural state of ‘transiting’ (consistent/directional) versus ‘localized’ (variable/non-directional), and active swimming speed (i.e. speed relative to the current). On coastal habitats (i.e. bathymetry < 200 m and in adjacent areas), females showed localized behaviour in deep waters (191 ± 20 m) and at large distances (14 ± 0.6 km) from shore, suggesting that their breeding habitat extends beyond the shallowest waters available close to the coastline. Males' active swimming speed decreased in shallow waters, but environmental parameters did not influence their likelihood to exhibit localized movements, which was probably dominated by social factors instead. In oceanic habitats, both males and females showed localized behaviours in shallow waters and favoured high chlorophyll-a concentrations. Active swimming speed accounts for a large proportion of observed movement speed; however, breeding humpback whales probably exploit prevailing ocean currents to maximize displacement. This study provides evidence that coastal areas, generally subject to strong human pressure, remain the core habitat of humpback whales off Madagascar. Our results expand the knowledge of humpback whale habitat use in oceanic habitat and response to variability of environmental factors such as oceanic current and chlorophyll level.Funding was provided by Total Foundation to NeuroPSI, and by individuals and foundations to the WCS Ocean Giants Program

Lexical selection in action: Evidence from spontaneous punning

Analysis of a corpus of spontaneously produced Japanese puns from a single speaker over a two-year period provides a view of how a punster selects a source word for a pun and transforms it into another word for humorous effect. The pun-making process is driven by a principle of similarity: the source word should as far as possible be preserved (in terms of segmental sequence) in the pun. This renders homophones (English example: band–banned) the pun type of choice, with part–whole relationships of embedding (cap–capture), and mutations of the source word (peas–bees) rather less favored. Similarity also governs mutations in that single-phoneme substitutions outnumber larger changes, and in phoneme substitutions, subphonemic features tend to be preserved. The process of spontaneous punning thus applies, on line, the same similarity criteria as govern explicit similarity judgments and offline decisions about pun success (e.g., for inclusion in published collections). Finally, the process of spoken-word recognition is word-play-friendly in that it involves multiple word-form activation and competition, which, coupled with known techniques in use in difficult listening conditions, enables listeners to generate most pun types as offshoots of normal listening procedures

Reduced Bone Mass and Muscle Strength in Male 5α-Reductase Type 1 Inactivated Mice

Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1−/− mice. Four-month-old male Srd5a1−/− mice had reduced trabecular bone mineral density (−36%, p<0.05) and cortical bone mineral content (−15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1−/− mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1−/− mice. Male Srd5a1−/− mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1−/− mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1−/− mice, is an indirect effect mediated by elevated circulating androgen levels

Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2

Estrogen receptor‐α (ERα) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERα domains for the osteogenic response to mechanical loading, gene‐targeted mouse models with (1) a complete ERα inactivation (ERα−/−), (2) specific inactivation of activation function 1 (AF‐1) in ERα (ERαAF‐10), or (3) specific inactivation of ERαAF‐2 (ERαAF‐20) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERα−/− mice displayed a severely reduced osteogenic response to loading with changes in cortical area (−78% ± 15%, p < 0.01) and periosteal BFR (−81% ± 9%, p < 0.01) being significantly lower than in wild‐type (WT) mice. ERαAF‐10 mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area −40% ± 11%, p < 0.05 and periosteal BFR −41% ± 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERαAF‐20 mice. Mechanical loading of transgenic estrogen response element (ERE)‐luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE‐mediated pathways. In conclusion, ERα is required for the osteogenic response to mechanical loading in a ligand‐independent manner involving AF‐1 but not AF‐2

A multi-region assessment of population rates of cardiac catheterization and yield of high-risk coronary artery disease

<p>Abstract</p> <p>Background</p> <p>There is variation in cardiac catheterization utilization across jurisdictions. Previous work from Alberta, Canada, showed no evidence of a plateau in the yield of high-risk disease at cardiac catheterization rates as high as 600 per 100,000 population suggesting that the optimal rate is higher. This work aims 1) To determine if a previously demonstrated linear relationship between the yield of high-risk coronary disease and cardiac catheterization rates persists with contemporary data and 2) to explore whether the linear relationship exists in other jurisdictions.</p> <p>Methods</p> <p>Detailed clinical information on all patients undergoing cardiac catheterization in 3 Canadian provinces was available through the Alberta Provincial Project for Outcomes Assessment in Coronary Heart (APPROACH) disease and partner initiatives in British Columbia and Nova Scotia. Population rates of catheterization and high-risk coronary disease detection for each health region in these three provinces, and age-adjusted rates produced using direct standardization. A mixed effects regression analysis was performed to assess the relationship between catheterization rate and high-risk coronary disease detection.</p> <p>Results</p> <p>In the contemporary Alberta data, we found a linear relationship between the population catheterization rate and the high-risk yield. Although the yield was slightly less in time period 2 (2002-2006) than in time period 1(1995-2001), there was no statistical evidence of a plateau. The linear relationship between catheterization rate and high-risk yield was similarly demonstrated in British Columbia and Nova Scotia and appears to extend, without a plateau in yield, to rates over 800 procedures per 100,000 population.</p> <p>Conclusions</p> <p>Our study demonstrates a consistent finding, over time and across jurisdictions, of linearly increasing detection of high-risk CAD as population rates of cardiac catheterization increase. This internationally-relevant finding can inform country-level planning of invasive cardiac care services.</p

The role of activation functions 1 and 2 of estrogen receptor-α for the effects of estradiol and selective estrogen receptor modulators in male mice

Estradiol (E2) is important for male skeletal health and the effect of E2 is mediated via estrogen receptor (ER)-α. This was demonstrated by the findings that men with an inactivating mutation in aromatase or a non-functional ERα had osteopenia and continued longitudinal growth after sexual maturation. The aim of the present study was to evaluate the role of different domains of ERα for the effects of E2 and SERMs on bone mass in males. Three mouse models lacking either ERαAF-1 (ERαAF-1(0)), ERαAF-2 (ERαAF-2(0)) or the total ERα (ERα(−/−)) were orchidectomized (orx) and treated with E2 or placebo. E2 treatment increased the trabecular and cortical bone mass and bone strength, while it reduced the thymus weight and bone marrow cellularity in orx wild type (WT) mice. These parameters did not respond to E2 treatment in orx ERα(−/−) or ERαAF-2(0) mice. However, the effects of E2 in orx ERαAF-1(0) mice were tissue-dependent, with a clear response in cortical bone parameters and bone marrow cellularity, but no response in trabecular bone. To determine the role of ERαAF-1 for the effects of SERMs, we treated orx WT and ERαAF-1(0) mice with Raloxifene (Ral), Lasofoxifene (Las), Bazedoxifene (Bza) or vehicle. These SERMs increased total body areal bone mineral density (BMD) and trabecular volumetric BMD to a similar extent in orx WT mice. Furthermore, only Las increased cortical thickness significantly and only Bza increased bone strength significantly. However, all SERMs showed a tendency towards increased cortical bone parameters. Importantly, all SERM-effects were absent in the orx ERαAF-1(0) mice. In conclusion, ERαAF-2 is required for the estrogenic effects on all evaluated parameters, while the role of ERαAF-1 is tissue specific. All evaluated effects of Ral, Las and Bza are dependent on a functional ERαAF-1. Our findings might contribute to the development of bone specific SERMs in males

Does Diving Limit Brain Size in Cetaceans?

We test the longstanding hypothesis, known as the dive constraint hypothesis, that the oxygenation demands of diving pose a constraint on aquatic mammal brain size.Using a sample of 23 cetacean species we examine the relationship among six different measures of relative brain size, body size, and maximum diving duration. Unlike previous tests we include body size as a covariate and perform independent contrast analyses to control for phylogeny. We show that diving does not limit brain size in cetaceans and therefore provide no support for the dive constraint hypothesis. Instead, body size is the main predictor of maximum diving duration in cetaceans. Furthermore, our findings show that it is important to conduct robust tests of evolutionary hypotheses by employing a variety of measures of the dependent variable, in this case, relative brain size