Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards

10.1186/2040-2392-5-7Molecular Autism51

Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ from the brain [1], [2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Aβ plaque pathology [3], [4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6]–[8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology

Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat

Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV-1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies

Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding

IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury.

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover, in vivo and in vitro data suggests astrocytes are a major source of IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury

Weak Glycolipid Binding of a Microdomain-Tracer Peptide Correlates with Aggregation and Slow Diffusion on Cell Membranes

10.1371/journal.pone.0051222PLoS ONE712

International Research Institute for Climate and Society

This report documents the process and results of the index insurance design effort leading to the index insurance contracts for Adi Ha in 2009. This report represents deliverables 1 and 2 in the terms of reference with Oxfam America, it outlines and compares analysis and design methodologies including the performance of rainfall simulators for index-based contract design. It also details contracts, methodologies, associated issues, and important lessons learned. A separate project report details the Experimental Games, deliverable 3 in the terms of reference. IRI has delivered contracts and methodology with a significant portion of the effort provided without cost to Oxfam America. This includes contributions from several external researchers who have contributed time at no cost. Substantial funders who have provided additional sponsorship include NOAA, NSF, (through its CRED DMUU center at Columbia), the Columbia Earth Institute postdoctoral program, the Columbia University Lamont postdoctoral program, and an Earth Institute CGSD seed grant. The insurance effort is one component of the Oxfam HARITA project, with the insurance designed to target key gaps left in the HARITA holistic climate risk management portfolio. Because this report focuses on the insurance contract design, it does not provide a comprehensive overview of the full climate risk management strategy, although it does refer to particular components in discussion of design issues. For a complete overview of the risk management and adaptation portfolio, the reader should refer to Oxfam HARITA project documentation. Many partners have participated substantially in the contract design effort. Major partners in this project include the Relief Society of Tigray (REST), Dedebit Credit and Savings Institution (DECSI), Nyala Insurance Company, the Ethiopian Productive Safety Net Program (PSNP), the Government of Ethiopian National Meteorological Agency (ENMA), Swiss Re, Mekele University, Oxfam Horn of Africa Regional Office, and Oxfam America (project coordinator). Any successes of this project depend strongly on the outstanding effort, skill, active engagement, and level of insights from the partners. Crop modeling parameters were obtained from LEAP and Mekele University. This project benefits strongly from groundwork and ongoing index insurance projects in Ethiopia and elsewhere by WFP and the World Bank CRMG

Heterologous Amyloid Seeding: Revisiting the Role of Acetylcholinesterase in Alzheimer's Disease

Neurodegenerative diseases associated with abnormal protein folding and ordered aggregation require an initial trigger which may be infectious, inherited, post-inflammatory or idiopathic. Proteolytic cleavage to generate vulnerable precursors, such as amyloid-β peptide (Aβ) production via β and γ secretases in Alzheimer's Disease (AD), is one such trigger, but the proteolytic removal of these fragments is also aetiologically important. The levels of Aβ in the central nervous system are regulated by several catabolic proteases, including insulysin (IDE) and neprilysin (NEP). The known association of human acetylcholinesterase (hAChE) with pathological aggregates in AD together with its ability to increase Aβ fibrilization prompted us to search for proteolytic triggers that could enhance this process. The hAChE C-terminal domain (T40, AChE575-614) is an exposed amphiphilic α-helix involved in enzyme oligomerisation, but it also contains a conformational switch region (CSR) with high propensity for conversion to non-native (hidden) β-strand, a property associated with amyloidogenicity. A synthetic peptide (AChE586-599) encompassing the CSR region shares homology with Aβ and forms β-sheet amyloid fibrils. We investigated the influence of IDE and NEP proteolysis on the formation and degradation of relevant hAChE β-sheet species. By combining reverse-phase HPLC and mass spectrometry, we established that the enzyme digestion profiles on T40 versus AChE586-599, or versus Aβ, differed. Moreover, IDE digestion of T40 triggered the conformational switch from α- to β-structures, resulting in surfactant CSR species that self-assembled into amyloid fibril precursors (oligomers). Crucially, these CSR species significantly increased Aβ fibril formation both by seeding the energetically unfavorable formation of amyloid nuclei and by enhancing the rate of amyloid elongation. Hence, these results may offer an explanation for observations that implicate hAChE in the extent of Aβ deposition in the brain. Furthermore, this process of heterologous amyloid seeding by a proteolytic fragment from another protein may represent a previously underestimated pathological trigger, implying that the abundance of the major amyloidogenic species (Aβ in AD, for example) may not be the only important factor in neurodegeneration

Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice

Race, Slavery, and the Expression of Sexual Violence in Louisa Picquet, The Octoroon

Historically, victims of sexual violence have rarely left written accounts of their abuse, so while sexual violence has long been associated with slavery in the United States, historians have few accounts from formerly enslaved people who experienced it first-hand. Through a close reading of the narrative of Louisa Picquet, a survivor of sexual violence in Georgia and Louisiana, this article reflects on the recovery of evidence of sexual violence under slavery through amanuensis-recorded testimony, the unintended evidence of survival within the violent archive of female slavery, and the expression of “race” as an authorial device through which to demonstrate the multigenerational nature of sexual victimhood