The presence of ascorbate induces expression of brain derived neurotrophic factor in SH-SY5Y neuroblastoma cells after peroxide insult, which is associated with increased survival

Oxidative stress and free radical production have been implicated in Alzheimer's disease, where low levels of the antioxidant vitamin C (ascorbate) have been shown to be associated with the disease. In this study, neuroblastoma SH-SY5Y cells were treated with hydrogen peroxide in the presence of ascorbate in order to elucidate the me0chanism(s) of protection against oxidative stress afforded by ascorbate. Protein oxidation, glutathione levels, cell viability and the effects on the proteome and its oxidized counterpart were monitored. SH-SY5Y cells treated with ascorbate prior to co-incubation with peroxide showed increased viability in comparison to cells treated with peroxide alone. This dual treatment also caused an increase in protein carbonyl content and a decrease in glutathione levels within the cells. Proteins, extracted from SH-SY5Y cells that were treated with either ascorbate or peroxide alone or with ascorbate prior to peroxide, were separated by two-dimensional gel electrophoresis and analyzed for oxidation. Co-incubation for 24 hours decreased the number of oxidised proteins (e.g. acyl CoA oxidase 3) and induced brain derived neurotrophic factor (BDNF) expression. Enhanced expression of BDNF may contribute to the protective effects of ascorbate against oxidative stress in neuronal cells

Contrasting Demographic History and Phylogeographic Patterns in Two Indo-Pacific Gastropods

Marine species with ranges that span the Indo-Australian Archipelago (IAA) exhibit a range of phylogeographic patterns, most of which are interpreted in the context of vicariance between Indian and Pacific Ocean populations during Pliocene and Pleistocene low sea level stands. However, patterns often vary among ecologically similar taxa, sometimes even within genera. This study compares phylogeographic patterns in two species of highly dispersive Neritid gastropod, Nerita albicilla and Nerita plicata, with nearly sympatric ranges that span the Indo-Pacific. Mitochondrial COI sequences from \u3e 1000 individuals from 97 sites reveal similar phylogenies in both species (two divergent clades differing by 3.2% and 2.3%, for N. albicilla and N. plicata respectively). However, despite ecological similarity and congeneric status, the two species exhibit phylogeographic discordance, with N. albicilla maintaining reciprocal monophyly of Indian and Pacific Ocean populations, while N. plicata is panmictic between oceans, but displays a genetic cline in the Central Pacific. Although this difference might be explained by qualitatively different demographic histories, parameter estimates from three coalescent models indicate that both species have high levels of gene flow between demes (2Ne m \u3e 75), and share a common history of population expansion that is likely associated with cyclical flooding of continental shelves and island lagoons following low sea level stands. Results indicate that ecologically similar co-distributed species may respond very differently to shared environmental processes, suggesting that relatively minor differences in traits such as pelagic larval duration or microhabitat association may profoundly impact phylogeographic structure

Long-Term Low-Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning: A Project FRONTIER Study

Exposure to elements in groundwater (toxic or beneficial) is commonplace yet, outside of lead and mercury, little research has examined the impact of many commonly occurring environmental exposures on mental abilities during the aging process. Inorganic arsenic is a known neurotoxin that has both neurodevelopmental and neurocognitive consequences. The aim of this study was to examine the potential association between current and long-term arsenic exposure and detailed neuropsychological functioning in a sample of rural-dwelling adults and elders. Data were analyzed from 434 participants (133 men and 301 women) of Project FRONTIER, a community-based participatory research study of the epidemiology of health issues of rural-dwelling adults and elders. The results of the study showed that GIS-based groundwater arsenic exposure (current and long-term) was significantly related to poorer scores in language, visuospatial skills, and executive functioning. Additionally, long-term low-level exposure to arsenic was significantly correlated to poorer scores in global cognition, processing speed and immediate memory. The finding of a correlation between arsenic and the domains of executive functioning and memory is of critical importance as these are cognitive domains that reflect the earliest manifestations of Alzheimer’s disease. Additional work is warranted given the population health implications associated with long-term low-level arsenic exposure

Identification of Multiple Subsets of Ventral Interneurons and Differential Distribution along the Rostrocaudal Axis of the Developing Spinal Cord

The spinal cord contains neuronal circuits termed Central Pattern Generators (CPGs) that coordinate rhythmic motor activities. CPG circuits consist of motor neurons and multiple interneuron cell types, many of which are derived from four distinct cardinal classes of ventral interneurons, called V0, V1, V2 and V3. While significant progress has been made on elucidating the molecular and genetic mechanisms that control ventral interneuron differentiation, little is known about their distribution along the antero-posterior axis of the spinal cord and their diversification. Here, we report that V0, V1 and V2 interneurons exhibit distinct organizational patterns at brachial, thoracic and lumbar levels of the developing spinal cord. In addition, we demonstrate that each cardinal class of ventral interneurons can be subdivided into several subsets according to the combinatorial expression of different sets of transcription factors, and that these subsets are differentially distributed along the rostrocaudal axis of the spinal cord. This comprehensive molecular profiling of ventral interneurons provides an important resource for investigating neuronal diversification in the developing spinal cord and for understanding the contribution of specific interneuron subsets on CPG circuits and motor control

Connecting communities to health research: Development of the Project CONNECT minority research registry

Prevention and treatment standards are based on evidence obtained in behavioral and clinical research. However, racial and ethnic minorities remain relatively absent from the science that develops these standards. While investigators have successfully recruited participants for individual studies using tailored recruitment methods, these strategies require considerable time and resources. Research registries, typically developed around a disease or condition, serve as a promising model for a targeted recruitment method to increase minority participation in health research. This study assessed the tailored recruitment methods used to populate a health research registry targeting African-American community members

Advances in microfluidic in vitro systems for neurological disease modeling

Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure‐prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro‐engineer cell‐scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to “Organ‐on‐chip” models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and “Organ‐on‐chip” systems have enabled new understanding of metabolic coupling and blood–brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro‐pathophysiological systems, moving from “Organ‐on‐chip” to “Disease‐on‐chip.” This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases

MANUSCRIPT IN PRESS: DEMENTIA & GERIATRIC COGNITIVE DISORDERS: Molecular Neuropsychology: Creation of Test-Specific Blood Biomarker Algorithms

Prior work on the link between blood-based biomarkers and cognitive status has largely been based on dichotomous classifications rather than detailed neuropsychological functioning. The current project was designed to create serum-based biomarker algorithms that predict neuropsychological test performance

Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

Background: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN1261900107913

Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes

BACKGROUND: Obesity and type 2 diabetes (T2DM) are associated with increased circulating free fatty acids and triacylglycerols. However, very little is known about specific molecular lipid species associated with these diseases. In order to gain further insight into this, we performed plasma lipidomic analysis in a rodent model of obesity and insulin resistance as well as in lean, obese and obese individuals with T2DM. METHODOLOGY/PRINCIPAL FINDINGS: Lipidomic analysis using liquid chromatography coupled to mass spectrometry revealed marked changes in the plasma of 12 week high fat fed mice. Although a number of triacylglycerol and diacylglycerol species were elevated along with of a number of sphingolipids, a particularly interesting finding was the high fat diet (HFD)-induced reduction in lysophosphatidylcholine (LPC) levels. As liver, skeletal muscle and adipose tissue play an important role in metabolism, we next determined whether the HFD altered LPCs in these tissues. In contrast to our findings in plasma, only very modest changes in tissue LPCs were noted. To determine when the change in plasma LPCs occurred in response to the HFD, mice were studied after 1, 3 and 6 weeks of HFD. The HFD caused rapid alterations in plasma LPCs with most changes occurring within the first week. Consistent with our rodent model, data from our small human cohort showed a reduction in a number of LPC species in obese and obese individuals with T2DM. Interestingly, no differences were found between the obese otherwise healthy individuals and the obese T2DM patients. CONCLUSION: Irrespective of species, our lipidomic profiling revealed a generalized decrease in circulating LPC species in states of obesity. Moreover, our data indicate that diet and adiposity, rather than insulin resistance or diabetes per se, play an important role in altering the plasma LPC profile

ENCODE whole-genome data in the UCSC genome browser (2011 update)

The ENCODE project is an international consortium with a goal of cataloguing all the functional elements in the human genome. The ENCODE Data Coordination Center (DCC) at the University of California, Santa Cruz serves as the central repository for ENCODE data. In this role, the DCC offers a collection of high-throughput, genome-wide data generated with technologies such as ChIP-Seq, RNA-Seq, DNA digestion and others. This data helps illuminate transcription factor-binding sites, histone marks, chromatin accessibility, DNA methylation, RNA expression, RNA binding and other cell-state indicators. It includes sequences with quality scores, alignments, signals calculated from the alignments, and in most cases, element or peak calls calculated from the signal data. Each data set is available for visualization and download via the UCSC Genome Browser (http://genome.ucsc.edu/). ENCODE data can also be retrieved using a metadata system that captures the experimental parameters of each assay. The ENCODE web portal at UCSC (http://encodeproject.org/) provides information about the ENCODE data and links for access