A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

The effect of polymer/plasticiser ratio in film forming solutions on the properties of chitosan films

In this work physical-chemical properties of chitosan/ glycerol film forming solutions (FFS) and the resulting films were analysed. Solutions were prepared using different concentrations of plasticising agent (glycerol) and chitosan. Films were produced by solvent casting and equilibrated in a controlled atmosphere. FFS water activity and rheological behaviour were determined. Films water content, solubility, water vapour and oxygen permeabilities, thickness, and mechanical and thermal properties were determined. Fourier transform infrared (FTIR) spectroscopy was also used to study the chitosan/glycerol interactions. Results demonstrate that FFS chitosan concentration influenced solutions consistency coefficient and this was related with differences in films water retention and structure. Plasticiser addition led to an increase in films moisture content, solubility and water vapour permeability, water affinity and structural changes. Films thermo-mechanical properties are significantly affected by both chitosan and glycerol addition. FTIR experiments confirm these results. This work highlights the importance of glycerol and water plasticisation in films properties.This work was supported by National Funds from FCT - Fundacao para a Ciencia e a Tecnologia, through project PEst-OE/EQB/LA0016/2011.Authors Joana F. Fundo, Andrea C. Galvis-Sanchez and Mafalda A. C. Quintas acknowledge FCT for research grants SFRH/ BD / 62176 / 2009, SFRH/BPD/37890/2007 and SFRH / BPD / 41715 / 2007, respectively

Results of urinary bacterial cultures and antibiotic susceptibility testing of dogs and cats in the UK.

OBJECTIVES: Bacterial urinary tract infections are a common diagnosis in small animal practice and antibiotics are often administered empirically. The aim of this study was to investigate the aetiology and antibiotic resistance of uropathogens in dogs and cats in the UK. MATERIALS AND METHODS: Retrospective study of uroculture and antibiotic susceptibility testing results (n=808) by disk diffusion processed at a veterinary pathology laboratory between 2011 and 2012. RESULTS: Significant bacteriuria was detected in 18.4% of samples from dogs and 10.0% from cats, most of which (>90%) yielded a single organism. Escherichia coli was the most prevalent bacterial species (54.7% and 55.6% of feline and canine isolates, respectively) followed by Proteus mirabilis in dog samples (22.7%) and Enterococcus spp. in cat samples (23.2%). Approximately a third of E. coli isolates were resistant to ampicillin but resistance was much lower among Enterococcus spp. and P. mirabilis. Resistance to amoxicillin-clavulanic acid also seemed to be emerging, particularly in E. coli (almost 20% resistant). In contrast, resistance to trimethoprim-sulfamethoxazole for uropathogens remained <13% except for P. mirabilis (19.4%). Overall, fluoroquinolones showed the best in vitro activity (resistance mostly below 10% for enrofloxacin and marbofloxacin). CLINICAL SIGNIFICANCE: Our results provide evidence of the emergence of resistance to antibiotics commonly used to treat bacterial urinary tract infections. Continued monitoring of the patterns of antibiotic resistance in uropathogens is needed to assess the adequacy of recommendations on the empiric therapy of these infections

Quality of life and eating disorders: a systematic review

This article provides a systematic review of articles on quality of life (QoL) among individuals with eating disorders. A literature search was conducted using six databases. Manual searches were also performed in two specialized journals, covering the period from January 1975 to June 2008. The search strategies identified a total of 29,537 articles. Forty-one studies met the inclusion criteria, and 36 were analyzed in the present review. Patients with eating disorders showed reduced QoL as compared to normal controls and individuals with other psychiatric disorders. The mental health component of QoL showed greater impairment than the physical component. Patients with binge eating disorders showed reduced physical and psychological QoL. We identified few studies on QoL in bulimia nervosa-only patients. QoL assessment of anorexia nervosa patients showed a modest impact on the physical domain. However, this finding should be interpreted with caution, since it may be due to an artifact in the disorder's psychopathology rather than better health status per se.O objetivo foi fazer uma revisão sistemática dos estudos que avaliam qualidade de vida em pessoas com transtornos alimentares. Foram realizadas buscas bibliográficas em seis bases de dados e buscas manuais em duas revistas, abrangendo o período de janeiro de 1975 até junho de 2008. As estratégias de busca forneceram um total de 29.537 referências. Quarenta e um estudos preencheram os critérios de inclusão desta revisão e 36 foram analisados no presente trabalho. De modo geral, os estudos revelam prejuízos na qualidade de vida de pacientes com transtornos alimentares quando comparados a grupos normais ou outras patologias psiquiátricas. O aspecto mental da qualidade de vida mostra-se mais prejudicado. A avaliação da qualidade de vida em sujeitos com transtorno da compulsão alimentar periódica revela prejuízos nos aspectos físico e mental da qualidade de vida. Há pouca evidência e discussão para indivíduos com bulimia nervosa isoladamente. Em sujeitos com anorexia nervosa, a avaliação requer cautela, já que o aparente menor impacto físico pode ser reflexo da psicopatologia específica deste transtorno e não do funcionamento saudável.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUNIFESP, EPMSciEL

Comparative 3D analyses and palaeoecology of giant early amphibians (Temnospondyli: Stereospondyli)

Macroevolutionary, palaeoecological and biomechanical analyses in deep time offer the possibility to decipher the structural constraints, ecomorphological patterns and evolutionary history of extinct groups. Here, 3D comparative biomechanical analyses of the extinct giant early amphibian group of stereospondyls together with living lissamphibians and crocodiles, shows that: i) stereospondyls had peculiar palaeoecological niches with proper bites and stress patterns very different than those of giant salamanders and crocodiles; ii) their extinction may be correlated with the appearance of neosuchians, which display morphofunctional innovations. Stereospondyls weathered the end-Permian mass extinction, re-radiated, acquired gigantic sizes and dominated (semi) aquatic ecosystems during the Triassic. Because these ecosystems are today occupied by crocodilians, and stereospondyls are extinct amphibians, their palaeobiology is a matter of an intensive debate: stereospondyls were a priori compared with putative living analogous such as giant salamanders and/or crocodilians and our new results try to close this debate.Peer ReviewedPostprint (published version

Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.Howard Hughes Medical InstituteRikagaku Kenkyūjo (Japan

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]