Multigenome DNA sequence conservation identifies Hox cis-regulatory elements

To learn how well ungapped sequence comparisons of multiple species can predict cis-regulatory elements in Caenorhabditis elegans, we made such predictions across the large, complex ceh-13/lin-39 locus and tested them transgenically. We also examined how prediction quality varied with different genomes and parameters in our comparisons. Specifically, we sequenced ∼0.5% of the C. brenneri and C. sp. 3 PS1010 genomes, and compared five Caenorhabditis genomes (C. elegans, C. briggsae, C. brenneri, C. remanei, and C. sp. 3 PS1010) to find regulatory elements in 22.8 kb of noncoding sequence from the ceh-13/lin-39 Hox subcluster. We developed the MUSSA program to find ungapped DNA sequences with N-way transitive conservation, applied it to the ceh-13/lin-39 locus, and transgenically assayed 21 regions with both high and low degrees of conservation. This identified 10 functional regulatory elements whose activities matched known ceh-13/lin-39 expression, with 100% specificity and a 77% recovery rate. One element was so well conserved that a similar mouse Hox cluster sequence recapitulated the native nematode expression pattern when tested in worms. Our findings suggest that ungapped sequence comparisons can predict regulatory elements genome-wide

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain

Social complexity in bees is not sufficient to explain lack of reversions to solitary living over long time scales

BackgroundThe major lineages of eusocial insects, the ants, termites, stingless bees, honeybees and vespid wasps, all have ancient origins (> or = 65 mya) with no reversions to solitary behaviour. This has prompted the notion of a 'point of no return' whereby the evolutionary elaboration and integration of behavioural, genetic and morphological traits over a very long period of time leads to a situation where reversion to solitary living is no longer an evolutionary option.ResultsWe show that in another group of social insects, the allodapine bees, there was a single origin of sociality > 40 mya. We also provide data on the biology of a key allodapine species, Halterapis nigrinervis, showing that it is truly social. H. nigrinervis was thought to be the only allodapine that was not social, and our findings therefore indicate that there have been no losses of sociality among extant allodapine clades. Allodapine colony sizes rarely exceed 10 females per nest and all females in virtually all species are capable of nesting and reproducing independently, so these bees clearly do not fit the 'point of no return' concept.ConclusionWe argue that allodapine sociality has been maintained by ecological constraints and the benefits of alloparental care, as opposed to behavioural, genetic or morphological constraints to independent living. Allodapine brood are highly vulnerable to predation because they are progressively reared in an open nest (not in sealed brood cells), which provides potentially large benefits for alloparental care and incentives for reproductives to tolerate potential alloparents. We argue that similar vulnerabilities may also help explain the lack of reversions to solitary living in other taxa with ancient social origins.Luke B. Chenoweth, Simon M. Tierney, Jaclyn A. Smith, Steven J.B. Cooper and Michael P. Schwar

Pan-chromatic observations of the remarkable nova LMC 2012

We present the results of an intensive multiwavelength campaign on nova LMC 2012. This nova evolved very rapidly in all observed wavelengths. The time to fall two magnitudes in the V band was only 2 days. In X-rays the super soft phase began 13$\pm$5 days after discovery and ended around day 50 after discovery. During the super soft phase, the \Swift/XRT and \Chandra\ spectra were consistent with the underlying white dwarf being very hot, $\sim$ 1 MK, and luminous, $\sim$ 10$^{38}$ erg s$^{-1}$. The UV, optical, and near-IR photometry showed a periodic variation after the initial and rapid fading had ended. Timing analysis revealed a consistent 19.24$\pm$0.03 hr period in all UV, optical, and near-IR bands with amplitudes of $\sim$ 0.3 magnitudes which we associate with the orbital period of the central binary. No periods were detected in the corresponding X-ray data sets. A moderately high inclination system, $i$ = 60$\pm$10^{\arcdeg}, was inferred from the early optical emission lines. The {\it HST}/STIS UV spectra were highly unusual with only the \ion{N}{5} (1240\AA) line present and superposed on a blue continuum. The lack of emission lines and the observed UV and optical continua from four epochs can be fit with a low mass ejection event, $\sim$ 10$^{-6}$ M$_{\odot}$, from a hot and massive white dwarf near the Chandrasekhar limit. The white dwarf, in turn, significantly illuminated its subgiant companion which provided the bulk of the observed UV/optical continuum emission at the later dates. The inferred extreme white dwarf characteristics and low mass ejection event favor nova LMC 2012 being a recurrent nova of the U Sco subclass.Comment: 18 figures, 6 tables (one online only containing all the photometry

Increased lymphangiogenesis in joints of mice with inflammatory arthritis

Angiogenesis is involved in the pathogenesis of inflammatory arthritis, but little is known about the role of lymphangiogenesis in this setting. Here, we examined whether tumor necrosis factor (TNF) stimulates osteoclast precursors (OCPs) to produce the lymphatic growth factor, vascular endothelial growth factor-C (VEGF-C), and induce lymphangiogenesis. We used TNF-transgenic (Tg) mice and mice with serum-induced arthritis. OCPs were purified by fluorescence-activated cell sorting of CD11b+/Gr-1-/lo blood or bone marrow cells and subjected to microarray analysis or were generated from spleen or joint cells and treated with TNF. Expression of VEGFs was analyzed and examined by real-time reverse transcription-polymerase chain reaction and Western blotting. Immunostaining and magnetic resonance imaging were used to quantify lymphatic vessels and volumes of synovium and draining lymph nodes. TNF stimulated VEGF-C expression by OCPs and increased nuclear factor-kappa B (NF-κB) binding to an NF-κB sequence in the VEGF-C promoter. OCPs from joints of TNF-Tg mice express high levels of VEGF-C. Lymphatic vessel numbers and size were markedly increased in joint sections of TNF-Tg mice and mice with serum-induced arthritis. The severity of synovitis correlated with draining lymph node size. In summary, TNF induces OCPs to produce VEGF-C through NF-κB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis

Damping of Tensor Modes in Cosmology

An analytic formula is given for the traceless transverse part of the anisotropic stress tensor due to free streaming neutrinos, and used to derive an integro-differential equation for the propagation of cosmological gravitational waves. The solution shows that anisotropic stress reduces the squared amplitude by 35.6 % for wavelengths that enter the horizon during the radiation-dominated phase, independent of any cosmological parameters. This decreases the tensor temperature and polarization correlation functions for these wavelengths by the same amount. The effect is less for wavelengths that enter the horizon at later times. At the longest wavelengths the decrease in the tensor correlation functions due to neutrino free streaming ranges from 10.7% for $\Omega_Mh^2=0.1$ to 9.0% for $\Omega_Mh^2=0.15$. An Appendix gives a general proof that tensor as well as scalar modes satisfy a conservation law for perturbations outside the horizon, even when the anisotropic stress tensor is not negligible.Comment: 14 pages. The original version of this paper has been expanded to deal with perturbations of any wavelength. While for wavelengths short enough to enter the horizon during radiation dominance, temperature and polarization correlations are damped by 35.6%, at the longest wavelengths the damping is from 9.0% to 11%. An added Appendix gives a general proof that tensor as well as scalar modes satisfy a conservation law outside the horizon, even during neutrino decoupling. Some references are also adde

Psychoative herbs commercialized in streets of Diadema (SP, Brazil): risk in its consumption

O comércio popular de drogas vegetais sem a garantia da qualidade implica em risco sanitário. O presente estudo fez uma análise interdisciplinar da rede de comércio de drogas vegetais (DVs) com foco nas drogas vegetais psicoativas (DVPs), disponíveis no comércio popular da Cidade de Diadema, e os riscos associados ao seu consumo. Métodos da etnofarmacologia, tais como: entrevistas informais, semi-estruturadas e observação participante foram utilizados para a realização do trabalho de campo; durante o qual, selecionaram-se quatro comerciantes, a fim de registrar a obtenção, manipulação, acondicionamento e tipos de DVs comercializadas. Foram registradas 63 DVs que remetiam a atividade psicoativa (DVPs) e, categorizadas em estimulantes (67%), depressoras (27%), depressoras e estimulantes (1%) e finalmente algumas não puderam ser definidas (5%). Essas DVPs tiveram seus nomes populares, forma de preparo e uso, partes utilizadas, contraindicações e doses registradas. Dezoito das 63 DVPs foram selecionadas segundo critérios do estudo, e seus lotes foram adquiridos dos entrevistados, a fim de serem analisados pela microbiologia (61 lotes) e farmacognosia (somente 22 daqueles, referentes a apenas 8 DVPs). Os resultados obtidos por essas áreas, somados a consultas em literaturas científicas, acerca de descrições de reações adversas, serviram de subsídio para a análise final dessas DVPs no contexto da farmacovigilância. Observaram-se deficiências principalmente na manipulação e acondicionamento das DVs por parte dos comerciantes, favorecendo sua contaminação e degradação. Os resultados das análises microbiológicas detectaram que 16% das DVPs analisadas apresentaram populações de bactérias (aeróbias e enterobactérias) superiores a 105 UFC/g e 31%, populações de fungos (bolores e leveduras) superiores a 103 UFC/g e a presença de espécies microbianas indicadoras de risco em 17 DVPs, especificamente em 74% dos 61 lotes, além de fungos produtores de aflatoxinas B1 e/ou B2 em quatro deles. Os resultados da farmacognosia demonstraram que 73% dos lotes foram reprovados ao menos em um dos demais parâmetros analisados (presença de contaminantes, caracterização e perfil cromatográfico). Sendo que, 50% dos 22 lotes analisados não coincidem com as especificações da farmacopéia e 36% apresentaram contaminação por outros órgãos vegetais, superior ao permitido nas monografias e um lote apresentou contaminação por insetos. Todos os 22 lotes foram reprovados na avaliação do rótulo (nomenclatura e validade) e praticamente todas as embalagens foram consideradas inadequadas. Além dos dados obtidos nessas análises, descrições de contra-indicações, efeitos adversos e interações medicamentosas foram encontradas na literatura científica para as 3 DVPs que tiveram sua identidade confirmada pela farmacognosia (camomila, ginkgo biloba e guaraná). Os resultados obtidos nesse estudo possibilitam observar as prioridades de adequação sanitária do comércio popular de DVs, bem como, traçar um perfil da qualidade das DVPs comercializadas segundo os parâmetros analisados. Conclui-se que essas DVPs reúnem importantes fatores capazes de causar danos à saúde dos consumidores, especialmente para alguns grupos como gestantes e indivíduos imunossuprimidos.The popular trade of herbal drugs without quality assurance implies a health risk. This study was an interdisciplinary analysis of the herbal drugs (DVs) trade network with focus on psychoactive drug plant (DVPs) available on the Brazilian city of Diadema, and risks associated with its consumption. Methods of ethnopharmacology, such as informal interviews, semi-structured interviews and participant observation were used for the completion of the fieldwork, during which four tradesmen were selected to register the collection, handling, packaging and types of DVs marketed. We registered 63 DVs that referred to psychoactive activity (DVPs) and categorized as stimulants (67%), depressants (27%), depressants and stimulants (1%) and finally some could not be set (5%). These DVPs had their popular names, preparations and uses, used parts, contraindications, and doses recorded. Eighteen of the 63 DVPs were selected according to the study criteria, and their lots were purchased by the selected tradesmen to be examined by microbiology (61 lots) and Pharmacognosy (only 22 of those lots, related to only 8 DVPs). The results for these areas, together with query in the scientific literature concerning descriptions of adverse reactions, provided the grant for the final analysis of these DVPs in the context of pharmacovigilance. Deficiencies were observed mainly in the handling and packaging of DVs by the traders, favoring its contamination and degradation. The microbiological analysis found that 16% of DVPs analyzed showed populations of bacteria (aerobic and Enterobacteriaceae) exceeding 105 CFU/g and 31%, populations of fungi (molds and yeasts) exceeding 103 CFU/g and the presence of risk indicator microbial species in 17 DVPs, specifically in 74% of the 61 lots, in addition to aflatoxin B1 or B2 producing fungi in four of them. The results of pharmacognosy showed that 73% had failed at least one of the parameters (contaminants, characterization and chromatographic profile), 50% of the 22 lots analyzed did not match the specifications of the pharmacopoeia, 36% were contaminated by other plant organs than those permitted in the monographs and a lot contamination by insects was found. All 22 lots have been disapproved in the evaluation of the label (classification and validity) and virtually all packages were considered inadequate. In addition to data obtained from such analysis, descriptions of contraindications, adverse effects and drug interactions were found in the literature for 3 DVPs who had their identity confirmed by the Pharmacognosy (chamomile, ginkgo biloba and guarana). The results obtained here allow us to observe the priorities of sanitary adequacy of the DVs popular trade, as well as establishing a profile of quality of DVPs marketed according to the analyzed parameters. We conclude that these DVPs gather important factors that could cause damage to the consumers health, especially for some groups such as pregnant women and immunosuppressed individuals.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)TEDEBV UNIFESP: Teses e dissertaçõe

Hierarchies from Fluxes in String Compactifications

Warped compactifications with significant warping provide one of the few known mechanisms for naturally generating large hierarchies of physical scales. We demonstrate that this mechanism is realizable in string theory, and give examples involving orientifold compactifications of IIB string theory and F-theory compactifications on Calabi-Yau four-folds. In each case, the hierarchy of scales is fixed by a choice of RR and NS fluxes in the compact manifold. Our solutions involve compactifications of the Klebanov-Strassler gravity dual to a confining N=1 supersymmetric gauge theory,and the hierarchy reflects the small scale of chiral symmetry breaking in the dual gauge theory.Comment: 35 pages. v2: minor eqn. and reference change