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Alzheimer's disease (AD) is responsible for 60%–80% of identified cases of dementia. While the generation and accumulation of amyloid precursor protein (APP) fragments is accepted as a key step in AD pathogenesis, the precise role of these fragments remains poorly understood. To overcome this deficit, we induced the expression of the soluble C-terminal fragment of APP (C99), the rate-limiting peptide for the generation of amyloid fragments, in yeast that contain thermosensitive mutations in genes encoding proteasome subunits. Our previous work with this system demonstrated that these proteasome-deficient yeast cells, expressing C99 when proteasome activity was blunted, generated amyloid fragments similar to those observed in AD patients. We now report the phenotypic repercussions of inducing C99 expression in proteasome-deficient cells. We show increased levels of protein aggregates, cellular stress and chaperone expression, electron-dense accumulations in the nuclear envelope/ER, abnormal DNA condensation, and an induction of apoptosis. Taken together, these findings suggest that the generation of C99 and its associated fragments in yeast cells with compromised proteasomal activity results in phenotypes that may be relevant to the neuropathological processes observed in AD patients. These data also suggest that this yeast model should be useful for testing therapeutics that target AD-associated amyloid, since it allows for the assessment of the reversal of the perturbed cellular physiology observed when degradation pathways are dysfunctional.

Bolivia tiene un gran potencial para mitigar el cambio climático a través de la reducción de la deforestación. Mientras que las posibles complicaciones han sido intensamente debatidas, se ha realizado poco análisis cuantitativo al respecto. Introducimos el modelo OSIRIS-Bolivia, con el fin de crear una base cuantitativa para la toma de decisiones. OSIRIS-Bolivia es una herramienta en Excel capaz de analizar los efectos de los incentivos REDD en Bolivia. Esta herramienta está basada en un modelo econométrico-espacial de la deforestación en el periodo 2001-2005, y usa información sobre cobertura forestal, tasas de deforestación, condiciones geograficas, y causantes de la deforestación, así como los costos de oportunidad agrícolas, para más de 120.000 píxeles en todo el país. Se trata de un modelo de equilibrio parcial, en el sentido que toma en cuenta el hecho de que reducciones en la deforestación en un lugar causarán una reducción en la oferta de productos agrícolas, lo que a su vez hará subir los precios agrícolas y aumentará la presión para deforestar en otro lugar (fugas de carbono). El modelo nos puede ayudar a resolver preguntas como: ¿donde es más probable que funcione REDD?, ¿cuanto dinero necesitamos para reducir la deforestación en cierto porcentaje?, ¿cuales son los potenciales problemas de REDD?

This research and evaluation report undertaken by Dr Liz Curran of the Australian National University (pro bono) looks at research over the two years of the life of a family violence project (with base line data collected in a First Phase Report in November 217) examining a Secondary Consultation (SC) service integrated with Training and Outreach program as well as capacity for strategic advocacy. The Consumer Action Law Centre project (with part funding from the Victorian Department of Justice & Regulation) aims to overcome barriers for people experiencing family violence identified in previous studies. The research findings (detailed in this report) are that legal assistance services, such as this one of the Consumer Action Law Centre, working with trusted community professionals (to whom people experiencing family violence are likely to turn) if done in a holistic, integrated and seamless, respectful way can enable credit & debt legal issues to be addressed in a timely, creative and effective way. It does this by breaking down barriers that exist to those needing legal help. The report provides some universal insights into the plight and impacts of family violence and ways for effective service delivery without ignoring the challenges for both individuals and a variety of services in providing critical support for victim/survivors of family violence and their family.

Rebuilding of infarcted myocardium by mesenchymal stem cells (MSCs) has not been successful because of poor cell survival due in part to insufficient blood supply after myocardial infarction (MI). We hypothesize that targeted delivery of vascular endothelial growth factor (VEGF) to MI can help regenerate vasculature in support of MSC therapy in a rat model of MI. VEGF-encapsulated immunoliposomes targeting overexpressed P-selectin in MI tissue were infused by tail vein immediately after MI. One week later, MSCs were injected intramyocardially. The cardiac function loss was moderated slightly by targeted delivery of VEGF or MSC treatment. Targeted VEGF+MSC combination treatment showed highest attenuation in cardiac function loss. The combination treatment also increased blood vessel density (80%) and decreased collagen content in post-MI tissue (33%). Engraftment of MSCs in the combination treatment group was significantly increased and the engrafted cells contributed to the restoration of blood vessels. From the Clinical Editor VEGF immunoliposomes targeting myocardial infarction tissue resulted in significantly higher attenuation of cardiac function loss when used in combination with mesenchymal stem cells. MSCs were previously found to have poor ability to restore cardiac tissue, likely as a result of poor blood supply in the affected areas. This new method counterbalances that weakness by the known effects of VEGF, as demonstrated in a rat model.

GM2 gangliosidoses, including Tay–Sachs disease and Sandhoff disease, are lysosomal storage disorders caused by deficiencies in β-N-acetylhexosaminidase (Hex). Patients are afflicted primarily with progressive central nervous system (CNS) dysfunction. Studies in mice, cats, and sheep have indicated safety and widespread distribution of Hex in the CNS after intracranial vector infusion of AAVrh8 vectors encoding species-specific Hex α- or β-subunits at a 1:1 ratio. Here, a safety study was conducted in cynomolgus macaques (cm), modeling previous animal studies, with bilateral infusion in the thalamus as well as in left lateral ventricle of AAVrh8 vectors encoding cm Hex α- and β-subunits. Three doses (3.2 × 1012 vg [n = 3]; 3.2 × 1011 vg [n = 2]; or 1.1 × 1011 vg [n = 2]) were tested, with controls infused with vehicle (n = 1) or transgene empty AAVrh8 vector at the highest dose (n = 2). Most monkeys receiving AAVrh8-cmHexα/β developed dyskinesias, ataxia, and loss of dexterity, with higher dose animals eventually becoming apathetic. Time to onset of symptoms was dose dependent, with the highest-dose cohort producing symptoms within a month of infusion. One monkey in the lowest-dose cohort was behaviorally asymptomatic but had magnetic resonance imaging abnormalities in the thalami. Histopathology was similar in all monkeys injected with AAVrh8-cmHexα/β, showing severe white and gray matter necrosis along the injection track, reactive vasculature, and the presence of neurons with granular eosinophilic material. Lesions were minimal to absent in both control cohorts. Despite cellular loss, a dramatic increase in Hex activity was measured in the thalamus, and none of the animals presented with antibody titers against Hex. The high overexpression of Hex protein is likely to blame for this negative outcome, and this study demonstrates the variations in safety profiles of AAVrh8-Hexα/β intracranial injection among different species, despite encoding for self-proteins.

Background Simian immunodeficiency virus (SIV) infection and persistent CD8+ lymphocyte depletion rapidly leads to encephalitis and neuronal injury. The objective of this study is to confirm that CD8-depletion alone does not affect brain pathology in the absence of SIV infection.

Proton magnetic resonance spectroscopy has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate and N-Acetylaspartate/creatine are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed, proton magnetic resonance spectroscopy revealed a decrease in N-Acetylaspartate, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

This article introduces a pilot clinic that has been designed and implemented at Portsmouth Law School in partnership with the School of Health Sciences. The benefits and challenges of interdisciplinary team working identified in the health science and legal education literature will be discussed. It looks at the rationale for this innovative development and speculates on the potential for a new professional curriculum that may emerge.The philosophy driving this pilot clinic is to contribute to breaking down silo thinking in professional students and build trust in the health and legal systems. This initiative will expose health professional and law students to holistic and therapeutic approaches to problem solving, teaching teamwork, collaboration and to breaking down the negative stereotypes of lawyers.The proposed pilot clinic at the University of Portsmouth will provide new opportunities for students studying law and adult nursing to explore how interdisciplinary practice might build bonds of trust between professionals. It will also enable those involved to see potential networks, signposts and links, in order to improve client outcomes.This new development, taking lessons from educational practice in health sciences, provides professional and teaching staff operating the clinic to build a new collaborative and dynamic joint curriculum. This new form of clinic, it is argued, provides an alternative to traditional perceptions of clinical teaching across multidisciplinary paradigms.

This report was commisioned by Bendigo Community Health Service and Loddon Campapse Community Legal Centre

This report documents the reasons for health justice partnerships, the literature, the methodology, the field research which used a participatory action research approach with a continuous learning and development framework. This Draft Working Paper sets out the summary of qualitative and quantitative data, the findings, conclusions lessons and recommendation emerging from this longitudinal study on the Bendigo Health Justice Partnership, in advance of the Full Final Research and Evaluation Report which will be released in 2017.ARC Justice (specifically one of its programs, the Loddon Campaspe Community Legal Centre (LCCLC)) and the Bendigo Community Health Service formed a partnership in 2013 to commence a Health Justice Partnership (HJP) in January 2014 to better reach those clients experiencing disadvantage.ANU (through the author Dr Liz Curran) was commissioned to conduct empirical research and an evaluation of the pilot project's impact on the social determinants of health, its outcomes and the effectiveness of Health Justice Partnerships in reaching clients who would otherwise not gain legal help with a range of problems capable of a legal solution.This Draft Working Paper is released, in advance of the Full Final Report, so that agencies, researchers and funders and policy makers developing or working in Health Justice Partnerships or multi-disciplinary practices can benefit and be informed by the research and evaluation given the wide range of issues emerging from the research canvasses while the Full Final Report is finalised.The Full Final Research & Evaluation Report will be released in 2017 but, in the interim, people using SSRN can utilise the research for their work. This responds to the numerous requests to share the research at the earliest opportunity so as to inform service delivery and funding applications which may occur before the release of the Final Report.

In spite of the growing linguistic diversity in U.S. classrooms, many teachers are not being adequately prepared to work with English language learners (ELLs). One area of particular concern for teachers is how to manage today's linguistically diverse classrooms. This article suggests ways educators can reflect on English language learners' needs and consider the implications for classroom management. The author focuses on the need to (a) understand the perspective of ELLs and the natural responses to being immersed in a second language, (b) use pedagogical strategies that aid in second language acquisition, and (c) create a classroom climate that affirms linguistic diversity.

Research has shown that ~ 25% - 30% breast cancers overexpress Her-2/neu receptor. The major problem in the management of Her-2/neu overexpressed breast cancer is its multi-drug resistantce (MDR). P-glycoprotein (P-gp) mediated MDR has been recognized as one of the major mechanisms in drug resistance in breast cancer. Therefore, developing a breast cancer cell line with both Her-2/neu and MDR positive becomes necessary. Dual positive breast cancer cell line was developed by transfection of the multidrug resistance gene (MDR1 gene) to human breast carcinoma cell line BT-474 (Her-2/neu +), followed by selection on clochicine. The presence of membrane protein Her-2 and P-gp were tested by immunohistochemical methods. The multidrug resistance was tested by the treatment efficacy of doxorubicin. The overexpression of p-glycoprotein in multidrug resistant cells and the presence of membrane protein Her-2 were confirmed by immunocytochemistry staining as well as Western Blot. Fluorescence imaging study showed tha...

The stem cell therapy to treat myocardial infarction (MI) has shown disappointed results largely due to the poor survival of transplanted stem cells in the MI region. We propose a combination therapy by targeted delivery of a proangiogenic compound, vascular endothelial growth factor (VEGF), to MI region to improve the micro-environment, which may enhance the survival of transplanted stem cells, and further improve the cardiac function. In this study, P-selectin conjugated immunoliposomes containing VEGF were given to the MI rats through tail vein injection immediately after surgery. Mesenchymal stem cells (MSCs) were transplanted to the MI region one week later. Left ventricular percent fractional shortening were measured 1 week and 4 weeks post MI using echocardiography. Results indicate that MI rats with no treatment lost 8% contractility (∼40% of its heart function) from 1 week to 4 weeks post-MI. Either targeted VEGF or MSCs treatment alone can slow down the loss by half to 4%. The combination of targeted VEGF and MSCs treatment further decreased the contractility loss to 0.7%. In conclusion, the combination treatment of targeted VEGF and MSCs results in a larger recovery in cardiac function compared to either targeted VEGF or stem cell treatment alone.

Bolivia has significant potential to abate climate change by reducing deforestation. This opportunity presents economic and environmental tradeoffs. While these tradeoffs have been hotly debated, they have as yet been the subject of little quantitative analysis. We introduce the OSIRIS-Bolivia model to provide a quantitative basis for decision-making. OSIRIS-Bolivia is an Excel-based tool for analyzing the potential effects of incentive payments to reduce emissions from deforestation (REDD) in Bolivia. It is based on a spatial econometric model of deforestation in Bolivia during the period 2001-2005, and uses information on forest cover, deforestation rates, geographical conditions, and drivers of deforestation, including agricultural opportunity costs, for more than 120,000 pixels covering the whole country. OSIRIS-Bolivia is based on a partial equilibrium model in which reductions in deforestation in one region reduce the supply of agricultural products to the domestic market, which in turn causes an increase in the price of agricultural products, making conversion of land to agriculture more attractive and thus stimulating an increase in deforestation in other regions (leakage). The model can help answer questions such as: Where in Bolivia are carbon incentive payments most likely to result in reduced deforestation? Who are most likely to benefit from REDD? How much money will it take to reduce deforestation by a given amount? To what extent might transaction costs or preferences for agricultural income undermine the goals of the REDD program?

This Report details research undertaken by Dr Liz Curran on behalf of Legal Aid ACT. The research looked at Legal Aid ACT and the quality of its legal services to clients.The study, after it was commissioned, ended up coinciding with indications by the Commonwealth Attorney General’s Office that it is to review and measure the outcomes of legal assistance services under a recent National Partnership Agreement (NPA) between the Commonwealth, State and Territory Governments. The research for this report anticipates this review by trying to provide a definition and approach to the measurement of ‘successful outcomes’ in a legal aid services context, as referred to in the NPA. Service delivery and humanitarian agencies world-wide are increasingly being asked to report and measure results-based outcomes. Although there has been surprisingly little outcome measurement undertaken internationally or domestically, there is some literature detailing how it might be done. The literature overwhelmingly concludes that results-based outcomes are difficult and challenging areas to measure. Therefore, while the main purpose of this project is to measure and enhance the quality of legal aid services delivered by Legal Aid ACT, this Report has wider importance and broader implications for other agencies. Legal Aid ACT has demonstrated foresight in commissioning this research early, somewhat in anticipation of the need to define outcomes for legal aid services.It is hoped that this Report will both assist Legal Aid ACT and inform public debate, helping shape realistic accountabilities, policy development and – most importantly – good and effective service delivery on behalf legal aid service sector clients and the wider community.

There is a critical need for animal models to study aspects type 2 diabetes mellitus pathogenesis and prevention. While the rhesus macaque is such an established model, the common marmoset has added benefits including reduced zoonotic risks, shorter life span, and a predisposition to birth twins demonstrating chimerism. The marmoset as a model organism for the study of metabolic syndrome has not been fully evaluated. Marmosets fed high-fat or glucose-enriched diets were followed longitudinally to observe effects on morphometric and metabolic measures. Effects on pancreatic histomorphometry and vascular pathology were examined terminally. The glucose–enriched diet group developed an obese phenotype and a prolonged hyperglycemic state evidenced by a rapid and persistent increase in mean glycosylated hemoglobin (HgbA1c) observed as early as week 16. In contrast, marmosets fed a high-fat diet did not maintain an obese phenotype and demonstrated a delayed increase in HgbA1c that did not reach statistical significance until week 40. Consumption of either diet resulted in profound pancreatic islet hyperplasia suggesting a compensation for increased insulin requirements. Although the high fat diet group developed atherosclerosis of increased severity, the presence of lesions correlated with glucose intolerance only in the glucose-enriched diet group. The altered timing of glucose dysregulation, differential contribution to obesity, and variation in vascular pathology suggests mechanisms of effect specific to dietary nutrient content. Feeding nutritionally modified diets to common marmosets recapitulates aspects of metabolic disease and represents a model that may prove instrumental to elucidating the contribution of nutrient excess to disease development.

Proton magnetic resonance spectroscopy has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate and N-Acetylaspartate/creatine are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed, proton magnetic resonance spectroscopy revealed a decrease in N-Acetylaspartate, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia.

The GM2 gangliosidoses are lysosomal storage disorders that encompass both Tay-Sachs and Sandhoff diseases. These diseases are associated with deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). These deficiencies result in accumulation of GM2 ganglioside (GM2) in the central nervous system leading to neuronal dysfunction and death. HexA is a heterodimer composed of α and β subunits encoded by HEXA and HEXB genes respectively. Gene therapy approaches using direct injection of AAV vectors into the brain of both small and large disease models (mice, cats, and sheep) have all been successful in treating CNS pathology as well as extending lifespan. These studies utilized two AAVrh8 vectors encoding species-specific alpha and beta subunits of HexA under a CBA promoter with a WPRE (CBA-HexA-WPRE). However, when preclinical safety studies were performed in cynomolgus macaques (cm) using the same strategy, severe neurotoxicity was observed for doses 0.1-3.2E12 vg, which are comparable to those tested in other species on a vg/kg brain weight basis. We hypothesized that the cause of unexpected toxicity was due to high expression of HexA. In order to reduce expression of HexA while maintaining our AAV dose (1.78E12-5.34E13 vg/kg brain weight), we generated a series of new vectors with different combinations of promoters and expression elements with a gradient of HexA expression levels. We tested 7 designs of AAVrh8 vectors encoding cm HexA subunits in athymic nude mice (3.3 E13 vg/kg brain weight). In mice injected with the original vector, AAVrh8-CBA-cmHexA-WPRE, we observed increased levels of reactive astrocytes (GFAP) and activated microglia (Iba1) at the injection site. We used this as a screen to test the other vectors for lower gliosis while expressing HexA activity above normal. Three vector designs emerged and were tested in cynomolgus macaques (n=2, 90 days) infused bilaterally into the thalamus and cerebral lateral ventricle at the intermediate dose (5.34 E12 vg/kg brain weight) as in the first study. The behavior of all monkeys remained normal throughout the study. An abnormal T2 weighted MRI signal was documented at day 90 post-injection in one injection site in a monkey in the cohort with the highest HexA activity (up to 88 fold over normal). This signal was absent in day 30 and 60 brain MRI. Neurohistopathological examination revealed considerable neurodegeneration at this site. The other two cohorts had minimal to no neurotoxicity associated with increased HexA expression (up to 9 fold). Two new AAV vectors have been identified for safe overexpression of HexA in the primate brain.

Diagnosis: Rat bite fever (RBF) due to Streptobacillus moniliformis. A Gram stain showed highly pleomorphic, gram-negative rods that were identified as S. moniliformis (figure l).The patient was given a regimen of penicillin (2 million U every 4 h intravenously). RBF has been associated with serious sequelae, such as endocarditis, hepatitis, meningitis, and nephritis. The patient did not meet Duke's criteria for diagnosis of endocarditis [1]. A transthoracic echocardiogram did not show vegetations. There was no evidence of involvement of other organs. Subsequent blood cultures showed no growth. The patient was treated with 7 days of intravenous penicillin, followed by 7 days of oral penicillin. She remained afebrile, no new skin eruptions appeared, and all residual lesions desquamated and healed. She did not return for her scheduled follow-up appointment. In a telephone interview that was conducted a week after she finished her course of penicillin, she stated that she had mild arthralgias but otherwise felt well, with no new skin eruptions. Six months after the initial presentation, the cryoglobulinemia had resolved, the antinuclear antibody titer had decreased to 1:40, and the patient remained symptom free. More than 2 million animal bites are reported each year in the United States, of which 1b% are attributable to rats [2]. t e ited States, of ic ~-1 are attributable to rats [2]. Although RBF is considered to be a rare illness, it is likely that it is underdiagnosed. S. moniliformis is found in the nasopharynx of most rats and is excreted in their urine. Nasopharyngeal carriage rates in healthy laboratory rats range from 10% to 100%; rates among wild rats have been estimated at 50%-100% [2]. The organism is usually transmitted by a bite or scratch from an infected animal, but it may also be acquired by simply handling the animal or from exposure to rat urine when handling cage materials [2]. On further questioning, the patient mentioned that she regularly cleaned the cages of all of her animals. She also informed us that she let her pet rats lick her teeth! RBF is characterized by the acute onset of shaking chills, fever, vomiting, and severe myalgias. After a few days, a maculopapular skin eruption appears, followed by arthralgias in up to 50% of cases. The eruption is usually seen on the extensor surface of the extremities and frequently involves the palms and soles. It can also be petechial, purpuric, or pustular and lasts for -3 weeks. Approximately 20% of the rashes undergo desquamation [3]. Usually the illness is self-limited. However, in a small number of untreated cases, serious sequelae, such as meningitis, endocarditis, hepatitis, nephritis, and brain or joint abscess may develop, with a mortality rate of 13% [4], increasing to 53% in cases with cardiac involvement [5]. Nineteen cases of S. moniliformis endocarditis have been reported; these cases occurred predominantly in patients with previously damaged heart valves [5, 6]. However, RBF is not a reportable disease, and the actual incidence of endocarditis associated with RBF is not known.

Background Marmosets are playing an increasingly large and important role in biomedical research. They share genetic, anatomical, and physiological similarities with humans and other primate model species, but their smaller sizes, reproductive efficiency, and amenability to genetic manipulation offer an added practicality. While their unique biology can be exploited to provide insights into disease and function, it is also important that researchers are aware of the differences that exist between marmosets and other species. The New World monkey family Callitrichidae, containing both marmoset and tamarin species, typically produces dizygotic twins that show chimerism in the blood and other cells from the hematopoietic lineage. Recently, a study extended these findings to identify chimerism in many tissues, including somatic tissues from other lineages and germ cells. This has raised the intriguing possibility that chimerism may play an increasingly pervasive role in marmoset biology, ranging from natural behavioral implications to increased variability and complexity in biomedical studies. Results Using a quantitative PCR based methodology, Y-chromosomes can be reliably detected in the females with male fraternal twins allowing for a relative quantification of chimerism levels between individuals and tissues. With this approach in common marmosets (Callithrix jacchus) and cotton-top tamarins (Saguinus oedipus), chimerism was detected across a broad array of tissues. Chimerism levels were significantly higher in tissues primarily derived from the hematopoietic lineage, while they were lower, though still detectable, in tissues with other origins. Interestingly, animals with a characteristic marmoset wasting disease show higher levels of chimerism in those tissues affected. Fibroblast cell lines from chimeric individuals, however, are not found to be chimeric themselves. Conclusion Taken together, the levels of chimerism in tissues of different origins coupled with other lines of evidence suggest that indeed only hematopoietic cell lineages are chimeric in callitrichids. The chimerism detected in other tissues is likely the result of blood or lymphocytic infiltration. Using molecular methods to detect chimerism in a tissue sample seems to have allowed a substantial increase in the ability to detect these minor cell populations.