A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Psychometric properties of a generic, patient-centred palliative care outcome measure of symptom burden for people with progressive long term neurological conditions

Background There is no standard palliative care outcome measure for people with progressive long term neurological conditions (LTNC). This study aims to determine the psychometric properties of a new 8-item palliative care outcome scale of symptom burden (IPOS Neuro-S8) in this population. Data and Methods Data were merged from a Phase II palliative care intervention study in multiple sclerosis (MS) and a longitudinal observational study in idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). The IPOS Neuro-S8 was assessed for its data quality, score distribution, ceiling and floor effects, reliability, factor structure, convergent and discriminant validity, concurrent validity with generic (Palliative care Outcome Scale) and condition specific measures (Multiple Sclerosis Impact Scale; Non-motor Symptoms Questionnaire; Parkinson's Disease Questionnaire), responsiveness and minimally clinically important difference. Results Of the 134 participants, MS patients had a mean Extended Disability Status Scale score 7.8 (SD = 1.0), patients with an IPD, MSA or PSP were in Hoehn & Yahr stage 3±5. The IPOS Neuro-S8 had high data quality (2% missing), mean score 8 (SD = 5; range 0±32), no ceiling effects, borderline floor effects, good internal consistency (Cronbach's α = 0.7) and moderate test-retest reliability (intraclass coefficient = 0.6). The results supported a moderately correlated two-factor structure (Pearson's r = 0.5). It was moderately correlated with generic and condition specific measures (Pearson's r: 0.5±0.6). There was some evidence for discriminant validity in IPD, MSA and PSP (p = 0.020), and for good responsiveness and longitudinal construct validity. Conclusions IPOS Neuro-S8 shows acceptable to promising psychometric properties in common forms of progressive LTNCs. Future work needs to confirm these findings with larger samples and its usefulness in wider disease groups

Oil and Gas Projects in the Western Amazon: Threats to Wilderness, Biodiversity, and Indigenous Peoples

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The western Amazon is the most biologically rich part of the Amazon basin and is home to a great diversity of indigenous ethnic groups, including some of the world’s last uncontacted peoples living in voluntary isolation. Unlike the eastern Brazilian Amazon, it is still a largely intact ecosystem. Underlying this landscape are large reserves of oil and gas, many yet untapped. The growing global demand is leading to unprecedented exploration and development in the region. Without improved policies, the increasing scope and magnitude of planned extraction means that environmental and social impacts are likely to intensify. We review the most pressing oil- and gas-related conservation policy issues confronting the region. These include the need for regional Strategic Environmental Impact Assessments and the adoption of roadless extraction techniques. We also consider the conflicts where the blocks overlap indigenous peoples’ territories

Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease

Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers

ABC Transporter Pdr10 Regulates the Membrane Microenvironment of Pdr12 in Saccharomyces cerevisiae

The eukaryotic plasma membrane exhibits both asymmetric distribution of lipids between the inner and the outer leaflet and lateral segregation of membrane components within the plane of the bilayer. In budding yeast (Saccharomyces cerevisiae), maintenance of leaflet asymmetry requires P-type ATPases, which are proposed to act as inward-directed lipid translocases (Dnf1, Dnf2, and the associated protein Lem3), and ATP-binding cassette (ABC) transporters, which are proposed to act as outward-directed lipid translocases (Pdr5 and Yor1). The S. cerevisiae genome encodes two other Pdr5-related ABC transporters: Pdr10 (67% identity) and Pdr15 (75% identity). We report the first analysis of Pdr10 localization and function. A Pdr10-GFP chimera was located in discrete puncta in the plasma membrane and was found in the detergent-resistant membrane fraction. Compared to control cells, a pdr10∆ mutant was resistant to sorbate but hypersensitive to the chitin-binding agent Calcofluor White. Calcofluor sensitivity was attributable to a partial defect in endocytosis of the chitin synthase Chs3, while sorbate resistance was attributable to accumulation of a higher than normal level of the sorbate exporter Pdr12. Epistasis analysis indicated that Pdr10 function requires Pdr5, Pdr12, Lem3, and mature sphingolipids. Strikingly, Pdr12 was shifted to the detergent-resistant membrane fraction in pdr10∆ cells. Pdr10 therefore acts as a negative regulator for incorporation of Pdr12 into detergent-resistant membranes, a novel role for members of the ABC transporter superfamily

Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?

The sequestration of Plasmodium falciparum–infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration

A Synthesis of Tagging Studies Examining the Behaviour and Survival of Anadromous Salmonids in Marine Environments

This paper synthesizes tagging studies to highlight the current state of knowledge concerning the behaviour and survival of anadromous salmonids in the marine environment. Scientific literature was reviewed to quantify the number and type of studies that have investigated behaviour and survival of anadromous forms of Pacific salmon (Oncorhynchus spp.), Atlantic salmon (Salmo salar), brown trout (Salmo trutta), steelhead (Oncorhynchus mykiss), and cutthroat trout (Oncorhynchus clarkii). We examined three categories of tags including electronic (e.g. acoustic, radio, archival), passive (e.g. external marks, Carlin, coded wire, passive integrated transponder [PIT]), and biological (e.g. otolith, genetic, scale, parasites). Based on 207 papers, survival rates and behaviour in marine environments were found to be extremely variable spatially and temporally, with some of the most influential factors being temperature, population, physiological state, and fish size. Salmonids at all life stages were consistently found to swim at an average speed of approximately one body length per second, which likely corresponds with the speed at which transport costs are minimal. We found that there is relatively little research conducted on open-ocean migrating salmonids, and some species (e.g. masu [O. masou] and amago [O. rhodurus]) are underrepresented in the literature. The most common forms of tagging used across life stages were various forms of external tags, coded wire tags, and acoustic tags, however, the majority of studies did not measure tagging/handling effects on the fish, tag loss/failure, or tag detection probabilities when estimating survival. Through the interdisciplinary application of existing and novel technologies, future research examining the behaviour and survival of anadromous salmonids could incorporate important drivers such as oceanography, tagging/handling effects, predation, and physiology

On the mating system of the cooperatively breeding saddle-backed tamarin ( Saguinus fuscicollis )

This paper reports on 5 years of observatiors of individually marked saddle-backed tamarins ( Saguinus fuscicollis , Callitrichidae). Although callitrichids have long been presumed to have a monogamous social system, this study shows that the breeding structure of saddle-back tamarin groups is highly variable. Groups most commonly include two or more adult males and a single reproductive female, but occasionally contain only a single pair of adults, or less often, two reproductively active females and one or more males. Data on group compositions, group formations, intergroup movements and copulations show that the social and mating systems of this species are more flexible than those of any other non-human primate yet studied. Infants (usually twins) were cared for by all group members. There were two classes of helpers: young, nonreproductive individuals who helped to care for full or half siblings, and cooperatively polyandrous males who cared for infants whom they may have fathered. The observations suggest that non-reproductive helpers may benefit from their helping behavior through a combination of inclusive fitness gains, reciprocal altruism, and the value of gaining experience at parental care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46874/1/265_2004_Article_BF00295541.pd