Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep

Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesised to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep, with higher numbers of tyrosine hydroxylase (TH)‐immunoreactive (‐ir) cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30–90 or 60–90 resulted in increased numbers of VTA TH‐ir cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T‐treated ewes, which was primarily accounted for by greater numbers of TH‐ir cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T‐treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels within dopamine cells. Sex differences were also noted in numbers of TH‐ir cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH‐ir cells in the substantia nigra, suggesting that this sex difference is organised independently of prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T.We report a sex difference in ventral tegmental area (VTA) dopamine cells in the adult sheep with higher numbers of tyrosine hydroxylase (TH)‐immunoreactive cells in males than females. Moreover, prenatal exposure to excess T during gestational days 30–90 or 60–90 caused increased numbers of VTA TH‐immunoreactive cells in adult ewes compared to control females. Sex differences were also demonstrated in the substantia nigra, but prenatal T had no effect on TH in this area. Results indicate that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels in the VTA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111123/1/ejn12871.pd

Chitosan microparticles gel for In vitro 3D culture of human chondrocytes

[EN] Chondrocytes are frequently cultured embedded in gels that provide them with a three-dimensional environment. Nevertheless cells in these constructs cannot remodel their neighbourhood when producing their own extracellular matrix. In this work we explore 3D environments that the cells can easily remodel. For this, human mature chondrocytes were cultured in the three-dimensional environment created by chitosan microparticles whose diameter is in the order of magnitude of the cell size. Chondrocytes and microparticles suspensions were mixed and the agglomerates were cultured in static tubes in chondrogenic medium. The poor adhesion between cells and chitosan surface maintained the mobility of the ensemble. In these conditions chondrocytes are viable during the 28 days of culture. The cells produce glycosaminoglycans, S100 and collagen type II up to 14 days of culture although production of type I collagen is also noticeable.J.L. Gomez Ribelles acknowledges the support of the Spanish Ministerio de Ciencia e Innovacion through MAT2010-21611-C03-00 project (including the FEDER financial support). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. N Garcia-Giralt acknowledges the support by grants from the Generalitat de Catalunya (DIUE 2009 SGR 818, 2009 SGR 971) and the Red Tematica de Investigacion Cooperativa en Envejecimiento y Fragilidad (RETICEF) and FEDER funds. Grand MAT2007-66759-C03-02 of Plan Nacional del MINISTERIO DE EDUCACION Y CIENCIA are also acknowledged.Garcia-Giralt, N.; García Cruz, DM.; Nogues, X.; Escobar Ivirico, JL.; Gómez Ribelles, JL. (2013). Chitosan microparticles gel for In vitro 3D culture of human chondrocytes. RSC Advances. 3(18):6362-6368. doi:10.1039/c3ra23173aS6362636831

The contribution of caregiver psychosocial factors to distress associated with behavioural and psychological symptoms in dementia

Copyright © 2016 John Wiley & Sons, Ltd. Objective: The objective of the study is to examine caregiver factors as predictors of BPSD-related distress and their potential mechanisms. Method: Informal caregivers of people with dementia (n = 157) recruited from 28 community mental health teams in six NHS Trusts across England completed questionnaires regarding psychosocial factors (relationship quality, competence, guilt, health-related quality of life in the caregiver and person with dementia, reactivity to behavioural and psychological symptoms in dementia [BPSD] and burden) and frequency of BPSD. Analyses of BPSD-related distress include hierarchical multiple regression, mediation, moderation and path analysis. Results: Caregiver psychosocial factors explained 56% of the variance in BPSD-related distress. After controlling for these factors, frequency of BPSD was not a significant predictor of BPSD-related distress. Caregiver reactivity to BPSD, burden, competence and relationship quality directly influenced BPSD-related distress. Guilt influenced distress indirectly via competence, burden and reactivity to BPSD. The final model accounted for 41% of the variance in BPSD-related distress and achieved a good fit to the data (χ 2 = 23.920, df = 19, p = 0.199). Conclusions: Caregiver psychosocial factors including sense of competence, guilt, burden and reactivity to BPSD contribute to BPSD-related distress. Tailored interventions for managing behaviour problems in family settings could focus on these factors associated with BPSD-related distress to minimise distress in families. Copyright © 2016 John Wiley & Sons, Ltd

The Charge Form Factor of the Neutron at Low Momentum Transfer from the 2H⃗(e⃗,e′n)p^{2}\vec{\rm H}(\vec{\rm e},{\rm e}'{\rm n}){\rm p} Reaction

We report new measurements of the neutron charge form factor at low momentum transfer using quasielastic electrodisintegration of the deuteron. Longitudinally polarized electrons at an energy of 850 MeV were scattered from an isotopically pure, highly polarized deuterium gas target. The scattered electrons and coincident neutrons were measured by the Bates Large Acceptance Spectrometer Toroid (BLAST) detector. The neutron form factor ratio $G^{n}_{E}/G^{n}_{M}$ was extracted from the beam-target vector asymmetry $A_{ed}^{V}$ at four-momentum transfers $Q^{2}=0.14$, 0.20, 0.29 and 0.42 (GeV/c)$^{2}$.Comment: 5 pages, 3 figures, submitted to Phys. Rev. Let

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

Cyclophilins (Cyps) are a major family of drug targets that are challenging to prosecute with small molecules because the shallow nature and high degree of conservation of the active site across human isoforms offers limited opportunities for potent and selective inhibition. Herein a computational approach based on molecular dynamics simulations and free energy calculations was combined with biophysical assays and X-ray crystallography to explore a flip in the binding mode of a reported urea-based Cyp inhibitor. This approach enabled access to a distal pocket that is poorly conserved among key Cyp isoforms, and led to the discovery of a new family of sub-micromolar cell-active inhibitors that offer unprecedented opportunities for the development of next-generation drug therapies based on Cyp inhibition. The computational approach is applicable to a broad range of organic functional groups and could prove widely enabling in molecular design

Cell-based Approaches to Joint Surface Repair : A Research Perspective

The authors are grateful for support to their research from Arthritis Research UK (grants 19271, 19429, 19667, 20050). None of the authors received any funding related to the writing of this manuscript, and the funding bodies did not play any role in the writing of the manuscript or decision to submit the manuscript for publication.Peer reviewedPublisher PD