GRB optical and IR rapid follow-up with the 2 m Liverpool Robotic Telescope

The Liverpool Telescope, owned and operated by Liverpool John Moores University and situated at Roque de los Muchachos, La Palma, is the first 2-m, fully instrumented robotic telescope. We plan to use the LT in conjunction with Gamma Ray Observatories (HETE-2, INTEGRAL, Swift) to study GRB physics. A special over-ride mode will enable observations commencing less than a minute after the GRB alert, including optical and near infrared imaging and spectroscopy. These observations, together with systematic monitoring of the burst through the afterglow, will help to unravel the nature of prompt optical flashes, short bursts, optically dark bursts, redshift distribution, GRB - supernova connection and other questions related to the GRB phenomenon. In particular, the combination of aperture, instrumentation and rapid automated response makes the Liverpool Telescope excellently suited to the investigation of optically dark bursts and currently optically unstudied short bursts

A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene

Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits

Copycat dynamics in leaderless animal group navigation

Background: Many animals are known to have improved navigational efficiency when moving together as a social group. One potential mechanism for social group navigation is known as the 'many wrongs principle', where information from many inaccurate compasses is pooled across the group. In order to understand how animal groups may use the many wrongs principle to navigate, it is important to consider how directional information is transferred and shared within the group. Methods: Here we use an individual-based model to explore the information-sharing and copying dynamics of a leaderless animal group navigating towards a target in a virtual environment. We assume that communication and information-sharing is indirect and arises through individuals partially copying the movement direction of their neighbours and weighting this information relative to their individual navigational knowledge. Results: We find that the best group navigation performance occurs when individuals directly copy the direction of movement of a subset of their neighbours while only giving a small (6%) weighting to their individual navigational knowledge. Surprisingly, such a strategy is shown to be highly efficient regardless of the level of individual navigational error. We find there is little relative improvement in navigational efficiency when individuals copy from more than 7 influential neighbours. Conclusions: Our findings suggest that we would expect navigating group-living animals to predominantly copy the movement of others rather than relying on their own navigational knowledge. We discuss our results in the context of individual and group navigation behaviour in animals

A mammalian functional-genetic approach to characterizing cancer therapeutics

Supplementary information is available online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/.Identifying mechanisms of drug action remains a fundamental impediment to the development and effective use of chemotherapeutics. Here we describe an RNA interference (RNAi)–based strategy to characterize small-molecule function in mammalian cells. By examining the response of cells expressing short hairpin RNAs (shRNAs) to a diverse selection of chemotherapeutics, we could generate a functional shRNA signature that was able to accurately group drugs into established biochemical modes of action. This, in turn, provided a diversely sampled reference set for high-resolution prediction of mechanisms of action for poorly characterized small molecules. We could further reduce the predictive shRNA target set to as few as eight genes and, by using a newly derived probability-based nearest-neighbors approach, could extend the predictive power of this shRNA set to characterize additional drug categories. Thus, a focused shRNA phenotypic signature can provide a highly sensitive and tractable approach for characterizing new anticancer drugs.National Institute of Mental Health (U.S.) (grant RO1 CA128803-03)American Association for Cancer ResearchMassachusetts Institute of Technology. Dept. of BiologyNational Cancer Institute (U.S.). Integrative Cancer Biology Program (grant 1-U54-CA112967

Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy

Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery; however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable selfassembled monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpGAuNPs were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor growth, and promoted survival in mice when compared to treatments with free CpG

Simultaneous Induction of Non-Canonical Autophagy and Apoptosis in Cancer Cells by ROS-Dependent ERK and JNK Activation

Background: Chemotherapy-induced reduction in tumor load is a function of apoptotic cell death, orchestrated by intracellular caspases. However, the effectiveness of these therapies is compromised by mutations affecting specific genes, controlling and/or regulating apoptotic signaling. Therefore, it is desirable to identify novel pathways of cell death, which could function in tandem with or in the absence of efficient apoptotic machinery. In this regard, recent evidence supports the existence of a novel cell death pathway termed autophagy, which is activated upon growth factor deprivation or exposure to genotoxic compounds. The functional relevance of this pathway in terms of its ability to serve as a stress response or a truly death effector mechanism is still in question; however, reports indicate that autophagy is a specialized form of cell death under certain conditions. Methodology/Principal Findings: We report here the simultaneous induction of non-canonical autophagy and apoptosis in human cancer cells upon exposure to a small molecule compound that triggers intracellular hydrogen peroxide (H2O2) production. Whereas, silencing of beclin1 neither inhibited the hallmarks of autophagy nor the induction of cell death, Atg 7 or Ulk1 knockdown significantly abrogated drug-induced H2O2-mediated autophagy. Furthermore, we provide evidence that activated extracellular regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) are upstream effectors controlling both autophagy and apoptosis in response to elevated intracellular H2O2. Interestingly, inhibition of JNK activity reversed the increase in Atg7 expression in this system, thus indicating that JNK may regulate autophagy by activating Atg7. Of note, the small molecule compound triggered autophagy and apoptosis in primary cells derived from patients with lymphoma, but not in non-transformed cells. Conclusions/Significance: Considering that loss of tumor suppressor beclin 1 is associated with neoplasia, the ability of this small molecule compound to engage both autophagic and apoptotic machineries via ROS production and subsequent activation of ERK and JNK could have potential translational implications.Singapore. Biomedical Research CouncilSingapore. Ministry of Educatio

From insect to man: Photorhabdus sheds light on the emergence of human pathogenicity

Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway

Structure-based programming of lymph-node targeting in molecular vaccines

In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes1, 2. Here we translate this ‘albumin hitchhiking’ approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Support (core) Grant P30-CA14051)National Cancer Institute (U.S.)National Institutes of Health (U.S.) (grant AI091693)National Institutes of Health (U.S.) (grant AI104715)National Institutes of Health (U.S.) (AI095109)United States. Dept. of Defense (contract W911NF-13-D-0001)United States. Dept. of Defense (contract W911NF-07-D-0004)Ragon Institute of MGH, MIT, and Harvar

The interaction of Wnt-11 and signalling cascades in prostate cancer

Prostate cancer (PCa) is the second most common cancer among the male population. Conventional therapies target androgen signalling, which drives tumour growth; however, they provide limited survival benefits for patients. It is essential, therefore, to develop a more specific biomarker than the current gold standard, PSA testing. The Wnt signalling pathway induces expression of target genes through cell surface receptors. A non-canonical member of this family, Wnt-11, is evolutionarily highly conserved and is normally expressed by various cells in the developing embryo, as well as in the heart, liver and skeletal muscle of adult humans. We comprehensively review several cell signalling pathways to explain how they interact with Wnt-11, demonstrating its use as a potential biomarker for PCa. Several studies have shown that the expression of Wnt-11 is associated with gastric, renal and colorectal adenocarcinomas and PCa. Moreover, Wnt-11 affects extracellular matrix composition and cytoskeletal rearrangement, and it is required for proliferation and/or survival during cell differentiation. It was found that PCa cell lines express high levels of Wnt-11, which allows differentiation of the epithelial prostate tumour cells to neuron-like (NE) cells. The NE cells produce additional factors that can cause regression after treatment. Accumulating evidence shows that Wnt-11 could be a potential biomarker in diagnosing PCa. Many studies have shown both non-canonical and canonical Wnts interact with several signalling cascades such as PKC, JNK, NF-κB, Rho, PKA and PI3K. In particular, evidence demonstrates Wnt-11 is involved in the progression of PCa, thus it could have the potential to become both a specific disease marker and an important therapeutic target

Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants: carrot study

<p>Abstract</p> <p>Background</p> <p>Prevention of serious infections in preterm infants is a challenge, since prematurity and low birth weight often requires many interventions and high utility of devices. Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system. In combination with delayed intestinal bacterial colonisation compared with term infants, this may increase the risk for serious infections. Acidic and neutral oligosaccharides play an important role in the development of the immune system, intestinal bacterial colonisation and functional integrity of the gut. This trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut.</p> <p>Methods/Design</p> <p>In a double-blind placebo controlled randomised trial, 120 preterm infants (gestational age <32 weeks and/or birth weight <1500 gram) are randomly allocated to receive enteral acidic and neutral oligosaccharides supplementation (20%/80%) or placebo supplementation (maltodextrin) between day 3 and 30 of life. Primary outcome is infectious morbidity (defined as the incidence of serious infections). The role of acidic and neutral oligosaccharides in modulation of the immune response is investigated by determining the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. The effect of enteral acidic and neutral oligosaccharides supplementation on postnatal adaptation of the gut is investigated by measuring feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora. Furthermore, short-term and long-term outcome are evaluated.</p> <p>Discussion</p> <p>Especially preterm infants, who are at increased risk for serious infections, may benefit from supplementation of prebiotics. Most studies with prebiotics only focus on the colonisation of the intestinal microflora. However, the pathways how prebiotics may influence the immune system are not yet fully understood. Studying the immune modulatory effects is complex because of the multicausal risk of infections in preterm infants. The combination of neutral oligosaccharides with acidic oligosaccharides may have an increased beneficial effect on the immune system. Increased insight in the effects of prebiotics on the developing immune system may help to decrease the (infectious) morbidity and mortality in preterm infants.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN16211826.</p