A cellular and regulatory map of the GABAergic nervous system of C. elegans

Neurotransmitter maps are important complements to anatomical maps and represent an invaluable resource to understand nervous system function and development. We report here a comprehensive map of neurons in the C. elegans nervous system that contain the neurotransmitter GABA, revealing twice as many GABA-positive neuron classes as previously reported. We define previously unknown glia-like cells that take up GABA, as well as 'GABA uptake neurons' which do not synthesize GABA but take it up from the extracellular environment, and we map the expression of previously uncharacterized ionotropic GABA receptors. We use the map of GABA-positive neurons for a comprehensive analysis of transcriptional regulators that define the GABA phenotype. We synthesize our findings of specification of GABAergic neurons with previous reports on the specification of glutamatergic and cholinergic neurons into a nervous system-wide regulatory map which defines neurotransmitter specification mechanisms for more than half of all neuron classes in C. elegans

Molecular Imaging of Pulmonary Tuberculosis in an Ex-Vivo Mouse Model Using Spectral Photon-Counting Computed Tomography and Micro-CT

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm(3) and 2.83 mm(3), respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Induction of adipocyte differentiation by polybrominated diphenyl ethers (PBDEs) in 3T3-L1 cells.

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants that were extensively used in commercial products. PBDEs are ubiquitous environmental contaminants that are both lipophilic and bioaccumulative. Effects of PBDEs on adipogenesis were studied in the 3T3-L1 preadipocyte cell model in the presence and absence of a known adipogenic agent, dexamethasone (DEX). A PBDE mixture designed to mimic body burden of North Americans was tested, in addition to the technical mixture DE-71 and the individual congener BDE-47. The mixture, DE-71, and BDE-47 all induced adipocyte differentiation as assessed by markers for terminal differentiation [fatty acid binding protein 4 (aP2) and perilipin] and lipid accumulation. Characterization of the differentiation process in response to PBDEs indicated that adipogenesis induced by a minimally effective dose of DEX was enhanced by these PBDEs. Moreover, C/EBPα, PPARγ, and LXRα were induced late in the differentiation process. Taken together, these data indicate that adipocyte differentiation is induced by PBDEs; they act in the absence of glucocorticoid and enhance glucocorticoid-mediated adipogenesis

mRNA Expression of PPARγ, C/EBPα, and LXRα during differentiation following treatment with 250 nM DEX, 25.5

<p> μ<b>M PBDE, 12</b> μ<b>M DE-71, or 12</b> μ<b>M BDE-47 in relative units.</b> For <i>PPARγ</i> RNA expression during days 1, 2, 4, the number of experimental repeats is 4 for all treatment groups. For days 5, 6, 8, the number of experimental repeats is 5 for all treatment groups. For <i>C/EBPα</i> and LXRα RNA expression during days 1, 2, 4, the number of experimental repeats is 3 for all treatment groups. For days 5, 6, 8, the number of experimental repeats is 5 for all treatment groups. * statistical difference between control and DEX at the given time point, p<0.05; ^a statistical difference between control and PBDE, p<0.05; ^b statistical difference between control and BDE-47, p<0.05. Data is expressed as mean ± SEM.</p

RT-PCR for terminal differentiation markers expressed in relative units following treatment with 250 nM DEX, 25.5

<p> μ<b>M PBDE mixture, 12</b> μ<b>M DE-71, or 12</b> μ<b>M BDE-47.</b> With regards to aP2 RNA expression levels, for days 1, 2, 4, the number of experimental replicates is 4 for all groups except 250 nM DEX (n = 3). For days 5, 6, 8, the number of experimental replicates is 5 for all treatment groups. With regards to perilipin RNA expression levels, for days 1, 2, 4, the number of experimental replicates is 3 for all treatment groups. For days 5, 6, 8, the number of experimental replicates is 5 for all treatment groups. * indicates a significant difference between control and DEX within the given time point (p<0.05). ^a indicates a significant difference between control and PBDE (p<0.05). ^b indicates a significant difference between control and BDE-47 (p<0.05). ^c indicates a significant difference between control and DE-71 (p<0.05). Data is expressed as mean ± SEM.</p

Exposure protocols for PBDEs.

<p>A) Differentiation protocol for PBDEs. B) Protocol for co-treatment with glucocorticoids (5 nM DEX).</p

Nile red staining of lipids.

<p>A) DMSO. B) 250 nM DEX. C) 3.2 μM PBDE mixture. D) 25.5 μM PBDE mixture. E) 3 μM DE-71. F) 12 μM DE-71. G) 1.5 μM BDE-47. H) 12 μM BDE-47. I) Percentage of adipocytes present following differentiation.</p