Effects of Early Life Stress on Anhedonia and Striatal Dopamine Concentration Depends on Variation in catechol-O-methyltransferase (COMT) Genotype

Depression is a serious, costly, and heterogeneous disorder for which no one genetic determinant has been identified. Research has shown that stress, and subsequent hypothalamic-pituitary-adrenal (HPA) axis dysregulation, is a significant predictor of depression, and one particular stressor that has been linked to vulnerability to depression and HPA axis dysregulation is early life trauma. Due to the heterogeneity and complexity of depression, it is likely that specific gene-environment interactions play a role in the development of depression. Interaction between catechol-O-methyltransferase (COMT) Val158Met variants with specific environmental factors can potentially increase vulnerability to depression. The present proposed experiment examines the interaction between COMT genotype and the effects of early life stress in a maternal separation paradigm on behavioral and neurological factors in a rodent model of depression. Outcome measures include anhedonia-like behavior, as indexed by performance on a sucrose consumption test, and striatal dopamine concentration, a neurological measure of depression. I hypothesize that across genotype, stress leads to decreased sucrose consumption and decreased striatal dopamine concentrations. However, the functional COMT Val158Met polymorphism will interact with stress such that these results are most pronounced among stressed Met/Met rats, as compared to Val/Met rats and Val/Val rats. These results may have implications for treatment of depression in COMT polymorphic individuals, who appear to be more sensitive to stress and more vulnerable to developing depression

Governing Through Accountability: Gender Equality and the United Nations

This article investigates the audit culture of UNIFEM, an international organization dedicated to bringing about global gender equality. UNIFEM's strategic plans, regional activities, and one fund-raising activity are analyzed to illustrate how pressures to "manage for results" combine with the UN's promotion of a transnational, modernist ethos to shape gender equity policy and, ultimately, what we know about women's lives. Résumé Cet article enquête la culture de vérification chez UNIFEM, un organisme dédié à amener l'égalité globale entre les sexes. Les plans stratégiques de l'UNIFEM, les activités régionales et une activité de levée de fonds sont analysées pour illustrer comment les pressions pour "gérer pour les résultats," combinées avec la promotion de l'ONU d'une philosophie transnationale,moderniste visée à l'établissement d'une politique pour l'équité entre les sexes, et ultimement, ce que nous connaissons sur les vies des femmes

PAK in Alzheimer disease, Huntington disease and X-linked mental retardation.

Developmental cognitive deficits including X-linked mental retardation (XLMR) can be caused by mutations in P21-activated kinase 3 (PAK3) that disrupt actin dynamics in dendritic spines. Neurodegenerative diseases such as Alzheimer disease (AD), where both PAK1 and PAK3 are dysregulated, may share final common pathways with XLMR. Independent of familial mutation, cognitive deficits emerging with aging, notably AD, begin after decades of normal function. This prolonged prodromal period involves the buildup of amyloid-β (Aβ) extracellular plaques and intraneuronal neurofibrillary tangles (NFT). Subsequently region dependent deficits in synapses, dendritic spines and cognition coincide with dysregulation in PAK1 and PAK. Specifically proximal to decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits. Downstream to PAK1, LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Aβ production. Aβ activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits. Reductions in PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity. Similarly other neurological disorders, including Huntington disease (HD) show dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms. Since PAK plays critical roles in learning and memory and is disrupted in many cognitive disorders, targeting PAK signaling in AD, HD and XLMR may be a novel common therapeutic target for AD, HD and XLMR

What was lost in translation in the DHA trial is whom you should intend to treat

The results of a randomized double-blind placebocontrolled trial with docosahexaenoic acid (DHA) supplementation in mild to moderate Alzheimer's disease (AD) published by Quinn and colleagues in JAMA argues against overall efficacy of DHA in slowing progression. However, certain caveats in the results caution against discarding DHA altogether, raising questions about oxidation, dosage, pharmacogenomics and stage of intervention

Cytoplasmic Injection of Zygotes to Genome Edit Naturally Occurring Sequence Variants Into Bovine Embryos

Genome editing provides opportunities to improve current cattle breeding strategies through targeted introduction of natural sequence variants, accelerating genetic gain. This can be achieved by harnessing homology-directed repair mechanisms following editor-induced cleavage of the genome in the presence of a repair template. Introducing the genome editors into zygotes and editing in embryos has the advantage of uncompromised development into live animals and alignment with contemporary embryo-based improvement practices. In our study, we investigated the potential to introduce sequence variants, known from the pre-melanosomal protein 17 (PMEL) and prolactin receptor (PRLR) genes, and produce non-mosaic, edited embryos, completely converted into the precision genotype. Injection of gRNA/Cas9 editors into bovine zygotes to introduce a 3 bp deletion variant into the PMEL gene produced up to 11% fully converted embryos. The conversion rate was increased to up to 48% with the use of TALEN but only when delivered by plasmid. Testing three gRNA/Cas9 editors in the context of several known PRLR sequence variants, different repair template designs and delivery as DNA, RNA or ribonucleoprotein achieved full conversion rates up to 8%. Furthermore, we developed a biopsy-based screening strategy for non-mosaic embryos which has the potential for exclusively producing non-mosaic animals with intended precision edits. Copyright © 2022 Wei, Brophy, Cole, Moormann, Boch and Laible

Lake-size dependency of wind shear and convection as controls on gas exchange

High-frequency physical observations from 40 temperate lakes were used to examine the relative contributions of wind shear (u*) and convection (w*) to turbulence in the surface mixed layer. Seasonal patterns of u* and w* were dissimilar; u* was often highest in the spring, while w * increased throughout the summer to a maximum in early fall. Convection was a larger mixed-layer turbulence source than wind shear (u */w*-1 for lakes* and w* differ in temporal pattern and magnitude across lakes, both convection and wind shear should be considered in future formulations of lake-air gas exchange, especially for small lakes. © 2012 by the American Geophysical Union.Jordan S. Read, David P. Hamilton, Ankur R. Desai, Kevin C. Rose, Sally MacIntyre, John D. Lenters, Robyn L. Smyth, Paul C. Hanson, Jonathan J. Cole, Peter A. Staehr, James A. Rusak, Donald C. Pierson, Justin D. Brookes, Alo Laas, and Chin H. W