An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Dietary calcium and zinc deficiency risks are decreasing but remain prevalent

Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 ± 211 and 16 ± 3 mg capita−1 d−1 (±SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

How to identify essential genes from molecular networks?

<p>Abstract</p> <p>Background</p> <p>The prediction of essential genes from molecular networks is a way to test the understanding of essentiality in the context of what is known about the network. However, the current knowledge on molecular network structures is incomplete yet, and consequently the strategies aimed to predict essential genes are prone to uncertain predictions. We propose that simultaneously evaluating different network structures and different algorithms representing gene essentiality (centrality measures) may identify essential genes in networks in a reliable fashion.</p> <p>Results</p> <p>By simultaneously analyzing 16 different centrality measures on 18 different reconstructed metabolic networks for <it>Saccharomyces cerevisiae</it>, we show that no single centrality measure identifies essential genes from these networks in a statistically significant way; however, the combination of at least 2 centrality measures achieves a reliable prediction of most but not all of the essential genes. No improvement is achieved in the prediction of essential genes when 3 or 4 centrality measures were combined.</p> <p>Conclusion</p> <p>The method reported here describes a reliable procedure to predict essential genes from molecular networks. Our results show that essential genes may be predicted only by combining centrality measures, revealing the complex nature of the function of essential genes.</p

Short-Term Synaptic Plasticity in the Dentate Gyrus of Monkeys

The hippocampus plays an important role in learning and memory. Synaptic plasticity in the hippocampus, short-term and long-term, is postulated to be a neural substrate of memory trace. Paired-pulse stimulation is a standard technique for evaluating a form of short-term synaptic plasticity in rodents. However, evidence is lacking for paired-pulse responses in the primate hippocampus. In the present study, we recorded paired-pulse responses in the dentate gyrus of monkeys while stimulating to the medial part of the perforant path at several inter-pulse intervals (IPIs) using low and high stimulus intensities. When the stimulus intensity was low, the first pulse produced early strong depression (at IPIs of 10–30 ms) and late slight depression (at IPIs of 100–1000 ms) of field excitatory postsynaptic potentials (fEPSPs) generated by the second pulse, interposing no depression IPIs (50–70 ms). When the stimulus intensity was high, fEPSPs generated by the second pulse were depressed by the first pulse at all IPIs except for the longest one (2000 ms). Population spikes (PSs) generated by the second pulse were completely blocked or strongly depressed at shorter IPIs (10–100 or 200 ms, respectively), while no depression or slight facilitation occurred at longer IPIs (500–2000 ms). Administration of diazepam slightly increased fEPSPs, while it decreased PSs produced by the first pulse. It also enhanced the facilitation of PSs produced by the second stimulation at longer IPIs. The present results, in comparison with previous studies using rodents, indicate that paired-pulse responses of fEPSPs in the monkey are basically similar to those of rodents, although paired-pulse responses of PSs in the monkey are more delayed than those in rodents and have a different sensitivity to diazepam

The Behavioural Response of Australian Fur Seals to Motor Boat Noise

Australian fur seals breed on thirteen islands located in the Bass Strait, Australia. Land access to these islands is restricted, minimising human presence but boat access is still permissible with limitations on approach distances. Thirty-two controlled noise exposure experiments were conducted on breeding Australian fur seals to determine their behavioural response to controlled in-air motor boat noise on Kanowna Island (39°10′S, 146°18′E). Our results show there were significant differences in the seals' behaviour at low (64–70 dB) versus high (75–85 dB) sound levels, with seals orientating themselves towards or physically moving away from the louder boat noise at three different sound levels. Furthermore, seals responded more aggressively with one another and were more alert when they heard louder boat noise. Australian fur seals demonstrated plasticity in their vocal responses to boat noise with calls being significantly different between the various sound intensities and barks tending to get faster as the boat noise got louder. These results suggest that Australian fur seals on Kanowna Island show behavioural disturbance to high level boat noise. Consequently, it is recommended that an appropriate level of received boat sound emissions at breeding fur seal colonies be below 74 dB and that these findings be taken into account when evaluating appropriate approach distances and speed limits for boats

An evaluation of the structural validity of the Shoulder Pain and Disability Index (SPADI) using the Rasch model

Purpose: The Shoulder Pain and Disability Index (SPADI) has been extensively evaluated for its psychometric properties using classic test theory (CTT). The purpose of this study was to evaluate its structural validity using Rasch model analysis. Methods: Responses to the SPADI from 1030 patients referred for physiotherapy with shoulder pain and enrolled in a prospective cohort study were available for Rasch model analysis. Overall fit, individual person and item fit, response format, dependence, unidimensionality, targeting, reliability and differential item functioning (DIF) were examined. Results: The SPADI pain subscale initially demonstrated a misfit due to DIF by age and gender. After iterative analysis it showed good fit to the Rasch model with acceptable targeting and unidimensionality (overall fit (chi-square statistic 57.2, p=0.1); mean item fit residual 0.19 (1.5) and mean person fit residual 0.44 (1.1); person separation index (PSI) of 0.83). The disability subscale however shows significant misfit due to uniform DIF even after iterative analyses were used to explore different solutions to the sources of misfit (overall fit (chi-square statistic 57.2, p=0.1); mean item fit residual -0.54 (1.26) and mean person fit residual -0.38 (1.0); PSI 0.84). Conclusions: Rasch Model analysis of the SPADI has identified some strengths and limitations not previously observed using CTT methods. The SPADI should be treated as two separate subscales. The SPADI is a widely used outcome measure in clinical practice and research, however the scores derived from it must be interpreted with caution. The pain subscale fits the Rasch model expectations well. The disability subscale does not fit the Rasch model and its current format does not meet the criteria for true interval-level measurement required for use as a primary endpoint in clinical trials. Clinicians should therefore exercise caution when interpreting score changes on the disability subscale and attempt to compare their scores to age and sex stratified data

Randomized Controlled Trials of HIV/AIDS Prevention and Treatment in Africa: Results from the Cochrane HIV/AIDS Specialized Register

INTRODUCTION: To effectively address HIV/AIDS in Africa, evidence on preventing new infections and providing effective treatment is needed. Ideally, decisions on which interventions are effective should be based on evidence from randomized controlled trials (RCTs). Our previous research described African RCTs of HIV/AIDS reported between 1987 and 2003. This study updates that analysis with RCTs published between 2004 and 2008. OBJECTIVES: To describe RCTs of HIV/AIDS conducted in Africa and reported between 2004 and 2008. METHODS: We searched the Cochrane HIV/AIDS Specialized Register in September 2009. Two researchers independently evaluated studies for inclusion and extracted data using standardized forms. Details included location of trials, interventions, methodological quality, location of principal investigators and funders. RESULTS: Our search identified 834 RCTs, with 68 conducted in Africa. Forty-three assessed prevention-interventions and 25 treatment-interventions. Fifteen of the 43 prevention RCTs focused on preventing mother-to-child HIV transmission. Thirteen of the 25 treatment trials focused on opportunistic infections. Trials were conducted in 16 countries with most in South Africa (20), Zambia (12) and Zimbabwe (9). The median sample size was 628 (range 33-9645). Methods used for the generation of the allocation sequence and allocation concealment were adequate in 38 and 32 trials, respectively, and 58 reports included a CONSORT recommended flow diagram. Twenty-nine principal investigators resided in the United States of America (USA) and 18 were from African countries. Trials were co-funded by different agencies with most of the funding obtained from USA governmental and non-governmental agencies. Nineteen pharmaceutical companies provided partial funding to 15 RCTs and African agencies co-funded 17 RCTs. Ethical approval was reported in 65 trials and informed consent in 61 trials. CONCLUSION: Prevention trials dominate the trial landscape in Africa. Of note, few principal investigators and funders are from Africa. These findings mirror our previous work and continue to indicate a need for strengthening trial research capacity in Africa

First Human Model of In Vitro Candida albicans Persistence within Granuloma for the Reliable Study of Host-Fungi Interactions

BACKGROUND: The balance between human innate immune system and Candida albicans virulence signaling mechanisms ultimately dictates the outcome of fungal invasiveness and its pathology. To better understand the pathophysiology and to identify fungal virulence-associated factors in the context of persistence in humans, complex models are indispensable. Although fungal virulence factors have been extensively studied in vitro and in vivo using different immune cell subsets and cell lines, it is unclear how C. albicans survives inside complex tissue granulomas. METHODOLOGY/PRINCIPAL FINDING: We developed an original model of in vitro human granuloma, reproducing the natural granulomatous response to C. albicans. Persistent granulomas were obtained when the ratio of phagocytes to fungi was high. This in vitro fungal granuloma mimics natural granulomas, with infected macrophages surrounded by helper and cytotoxic T lymphocytes. A small proportion of granulomas exhibited C. albicans hyphae. Histological and time-lapse analysis showed that C. albicans blastoconidia were located within the granulomas before hyphae formation. Using staining techniques, fungal load calculations, as well as confocal and scanning electron microscopy, we describe the kinetics of fungal granuloma formation. We provide the first direct evidence that C. albicans are not eliminated by immunocompetent cells inside in vitro human granulomas. In fact, after an initial candicidal period, the remaining yeast proliferate and persist under very complex immune responses. CONCLUSIONS/SIGNIFICANCE: Using an original in vitro model of human fungal granuloma, we herein present the evidence that C. albicans persist and grow into immunocompetent granulomatous structures. These results will guide us towards a better understanding of fungal invasiveness and, henceforth, will also help in the development of better strategies for its control in human physiological conditions