Conditional Deletion of Sost in MSC‐derived lineages Identifies Specific Cell Type Contributions to Bone Mass and B Cell Development

Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost knockout mice (Sost‐/‐) causes high bone mass (HBM) similar to Sclerosteosis patients. Sost‐/‐ mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to aged matched controls, and it has been postulated that the main source of skeletal Sclerostin is the osteocyte. To understand the cell‐type specific contributions to the HBM phenotype described in Sost‐/‐ mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss‐of‐function (SostiCOIN/iCOIN) mice with specific deletions in (1) the limb mesenchyme (Prx1‐Cre; targets osteoprogenitors and their progeny); (2) mid‐stage osteoblasts and their progenitors (Col1‐Cre); (3) mature osteocytes (Dmp1‐Cre) and (4) hypertrophic chondrocytes and their progenitors (ColX‐Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1‐Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B cell defect described in the global knockout. Despite wildtype expression of Sost in the axial skeleton of Prx1‐Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the Sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1‐osteoprogenitor derived lineages contribute significant amounts of Sclerostin protein to the paracrine pool of Sost, in bone

Evaluation of the Hare-PSCAN in a Non-Clinical Population

Using 100 university undergraduates as participants, this study examined the structural reliability and construct validity of Hare and Hervé\u27s P-SCAN (Hare & Hervé, 1999) a 90-item measure that purports to serve as an “… early warning system” or “rough screening device” (p. 1) for identifying individuals with substantial psychopathic features. Internal consistency indices (e.g. Cronbach\u27s α, mean inter-item correlations) for the three P-SCAN subscales (Interpersonal, Affective, Lifestyle) suggested excellent reliability. Statistically significant, though modest correlations (range 0.21–0.33) were obtained in 5 of 6 comparisons with the self-report Primary psychopathy and Secondary psychopathy scales developed by Levenson, Kiehl, and Fitzpatrick (1995) for use with non-institutional populations. Evidence for the external validity of the P-SCAN was obtained via significant positive correlations (range 0.22–0.24) with participants\u27 scores on a self-report measure of antisocial activity. Limitations of this study and interpretations of P-SCAN as a measure of psychopathic features are discussed

Comparison of restricted maximum likelihood and method ℜ for estimating heritability and predicting breeding value under selection

Method ℜ and Restricted Maximum Likelihood (REML) were compared for estimating heritability (h2) and subsequent prediction of breeding values (a) with data subject to selection. A single-trait animal model was used to generate the data and to predict breeding values. The data originated from 10 sires and 100 dams and simulation progressed for 10 overlapping generations. In simulating the data, genetic evaluation used the underlying parameter values and sires and dams were chosen by truncation selection for greatest predicted breeding values. Four alternative pedigree structures were evaluated: complete pedigree information, 50% of phenotypes with sire identities missing, 50% of phenotypes with dam identities missing, and 50% of phenotypes with sire and dams identities missing. Under selection and with complete pedigree data, Method ℜ was a slightly less consistent estimator of h2 than REML. Estimates of h2 by both methods were biased downward when there was selection and loss of pedigree information and were unbiased when no selection was practiced. The empirical mean square error (EMSE) of Method ℜ was several times larger than the EMSE of REML. In a subsequent analysis, different combinations of generations selected and generations sampled were simulated in an effort to disentangle the effects of both factors on Method ℜ estimates of h2. It was observed that Method ℜ overestimated h2 when both the sampling that is intrinsic in the method and the selection occurred in generations 6 to 10. In a final experiment, BLUP(α) were predicted with h2 estimated by either Method ℜ or REML. Subsequently, five more generations of selection were practiced, and the mean square error of prediction (MSEP) of BLUP(α) was calculated with estimated h2 by either method, or the true value of the parameter. The MSEP of empirical BLUP(α) using Method ℜ was greater than the MSEP of empirical BLUP(α) using REML. The latter statistic was closer to prediction error variance of BLUP(α) than the MSEP of empirical BLUP(α) using Method ℜ, indicating that empirical BLUP(α) calculated using REML produced accurate predictions of breeding values under selection. In conclusion, the variability of h2 estimates calculated with Method ℜ was greater than the variability of h2 estimates calculated with REML, with or without selection. Also, the MSEP of EBLUP(α) calculated using estimates of h2 by Method ℜ was larger than MSEP of EBLUP(α) calculated with REML estimates of h2.Fil: Cantet, Rodolfo Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; ArgentinaFil: Birchmeier, Ana Nélida. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; ArgentinaFil: Santos Cristal, M. G.. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; ArgentinaFil: Schindler de Avila, V. E.. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; Argentin

Effects of pregabalin on neurobehavior in an adult male rat model of PTSD.

Posttraumatic stress disorder (PTSD) can be a very debilitating condition. Effective approaches to prevent and treat PTSD are important areas of basic science research. Pregabalin (PGB), a gabapentinoid derivative of γ-aminobutyric acid, possesses the potential to positively affect neurobehavioral changes associated with PTSD. Using a rodent model of PTSD, the aims of this study were to determine the effects of PGB as a possible prevention for the development of PTSD-like symptoms and its use as a possible treatment. A prospective, experimental, between groups design was used in conjunction with a three-day restraint/shock PTSD stress model. Sixty rats were randomly assigned between two groups, non-stressed and stressed (PTSD). Each of the main two groups was then randomly assigned into six experimental groups: control vehicle, control PGB, control naïve, PTSD vehicle, PTSD Pre-PGB (prophylactic), PTSD Post-PGB (non-prophylactic). The neurobehavioral components of PTSD were evaluated using the elevated plus maze (EPM), Morris water maze (MWM), and forced swim test (FST). Pregabalin administered 24 hours before the initial PTSD event or for 10 days following the last PTSD stress event did not statistically improve mean open arm exploration on the EPM, spatial memory, and learning in the MWM or behavioral despair measured by the FST (p > 0.05)