Weak pairwise correlations imply strongly correlated network states in a neural population

Biological networks have so many possible states that exhaustive sampling is impossible. Successful analysis thus depends on simplifying hypotheses, but experiments on many systems hint that complicated, higher order interactions among large groups of elements play an important role. In the vertebrate retina, we show that weak correlations between pairs of neurons coexist with strongly collective behavior in the responses of ten or more neurons. Surprisingly, we find that this collective behavior is described quantitatively by models that capture the observed pairwise correlations but assume no higher order interactions. These maximum entropy models are equivalent to Ising models, and predict that larger networks are completely dominated by correlation effects. This suggests that the neural code has associative or error-correcting properties, and we provide preliminary evidence for such behavior. As a first test for the generality of these ideas, we show that similar results are obtained from networks of cultured cortical neurons.Comment: Full account of work presented at the conference on Computational and Systems Neuroscience (COSYNE), 17-20 March 2005, in Salt Lake City, Utah (http://cosyne.org

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats

<p>Abstract</p> <p>Background</p> <p>Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages.</p> <p>Methods</p> <p><it>In utero </it>exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR.</p> <p>Results</p> <p>Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism.</p> <p>Conclusions</p> <p>Our data suggest that <it>in utero </it>exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.</p

Parma consensus statement on metabolic disruptors

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome

Human T cell recognition of the blood stage antigen Plasmodium hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) in acute malaria

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium </it>purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against <it>Plasmodium yoelii </it>pRBC challenge in a T cell-dependent manner and has, therefore, been proposed as a novel vaccine candidate. It is not known whether natural exposure to <it>Plasmodium falciparum </it>stimulates HGXPRT T cell reactivity in humans.</p> <p>Methods</p> <p>PBMC and plasma collected from malaria-exposed Indonesians during infection and 7–28 days after anti-malarial therapy, were assessed for HGXPRT recognition using CFSE proliferation, IFNγ ELISPOT assay and ELISA.</p> <p>Results</p> <p>HGXPRT-specific T cell proliferation was found in 44% of patients during acute infection; in 80% of responders both CD4⁺and CD8⁺T cell subsets proliferated. Antigen-specific T cell proliferation was largely lost within 28 days of parasite clearance. HGXPRT-specific IFN-γ production was more frequent 28 days after treatment than during acute infection. HGXPRT-specific plasma IgG was undetectable even in individuals exposed to malaria for at least two years.</p> <p>Conclusion</p> <p>The prevalence of acute proliferative and convalescent IFNγ responses to HGXPRT demonstrates cellular immunogenicity in humans. Further studies to determine minimal HGXPRT epitopes, the specificity of responses for Plasmodia and associations with protection are required. Frequent and robust T cell proliferation, high sequence conservation among <it>Plasmodium </it>species and absent IgG responses distinguish HGXPRT from other malaria antigens.</p

Fusion of the Mycobacterium tuberculosis Antigen 85A to an Oligomerization Domain Enhances Its Immunogenicity in Both Mice and Non-Human Primates

To prevent important infectious diseases such as tuberculosis, malaria and HIV, vaccines inducing greater T cell responses are required. In this study, we investigated whether fusion of the M. tuberculosis antigen 85A to recently described adjuvant IMX313, a hybrid avian C4bp oligomerization domain, could increase T cell responses in pre-clinical vaccine model species. In mice, the fused antigen 85A showed consistent increases in CD4+ and CD8+ T cell responses after DNA and MVA vaccination. In rhesus macaques, higher IFN-γ responses were observed in animals vaccinated with MVA-Ag85A IMX313 after both primary and secondary immunizations. In both animal models, fusion to IMX313 induced a quantitative enhancement in the response without altering its quality: multifunctional cytokines were uniformly increased and differentiation into effector and memory T cell subsets was augmented rather than skewed. An extensive in vivo characterization suggests that IMX313 improves the initiation of immune responses as an increase in antigen 85A specific cells was observed as early as day 3 after vaccination. This report demonstrates that antigen multimerization using IMX313 is a simple and effective cross-species method to improve vaccine immunogenicity with potentially broad applicability

In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.São Paulo Research Foundation grants: (2011/24038-1 [MRDL], 2009/08559-1 [HBdS], CAPES/IGC 04/ 2012 [MRDL, CET])

Endocrine disruptors and obesity

The purpose of this review is to summarise current evidence that some environmental chemicals may be able to interfere in endocrine regulation of energy metabolism and adipose tissue structure. Recent findings demonstrate that such endocrine disrupting chemicals, termed “obesogens”, can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period. In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer

Anti-cancer drug validation: the contribution of tissue engineered models

Abstract Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current Bstate of art^ on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their studyThis article is a result of the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This article was also supported by the EU Framework Programme for Research and Innovation HORIZON 2020 (H2020) under grant agreement n° 668983 — FoReCaST. FCT distinction attributed to Joaquim M. Oliveira (IF/00423/2012) and Vitor M. Correlo (IF/01214/2014) under the Investigator FCT program is also greatly acknowledged.info:eu-repo/semantics/publishedVersio