bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception
Authors: Weikum Whitney M. , Oberlander Tim F. , Hensch Takao K. , Werker Janet F.
Published: October 2012

Language acquisition reflects a complex interplay between biology and early experience. Psychotropic medication exposure has been shown to alter neural plasticity and shift sensitive periods in perceptual development. Notably, serotonin reuptake inhibitors (SRIs) are antidepressant agents increasingly prescribed to manage antenatal mood disorders, and depressed maternal mood per se during pregnancy impacts infant behavior, also raising concerns about long-term consequences following such developmental exposure. We studied whether infants’ language development is altered by prenatal exposure to SRIs and whether such effects differ from exposure to maternal mood disturbances. Infants from non–SRI-treated mothers with little or no depression (control), depressed but non–SRI-treated (depressed-only), and depressed and treated with an SRI (SRI-exposed) were studied at 36 wk gestation (while still in utero) on a consonant and vowel discrimination task and at 6 and 10 mo of age on a nonnative speech and visual language discrimination task. Whereas the control infants responded as expected (success at 6 mo and failure at 10 mo) the SRI-exposed infants failed to discriminate the language differences at either age and the depressed-only infants succeeded at 10 mo instead of 6 mo. Fetuses at 36 wk gestation in the control condition performed as expected, with a response on vowel but not consonant discrimination, whereas the SRI-exposed fetuses showed accelerated perceptual development by discriminating both vowels and consonants. Thus, prenatal depressed maternal mood and SRI exposure were found to shift developmental milestones bidirectionally on infant speech perception tasks.
Early environments and the ecology of inflammation
Authors: McDade Thomas W.
Published: October 2012

Recent research has implicated inflammatory processes in the pathophysiology of a wide range of chronic degenerative diseases, although inflammation has long been recognized as a critical line of defense against infectious disease. However, current scientific understandings of the links between chronic low-grade inflammation and diseases of aging are based primarily on research in high-income nations with low levels of infectious disease and high levels of overweight/obesity. From a comparative and historical point of view, this epidemiological situation is relatively unique, and it may not capture the full range of ecological variation necessary to understand the processes that shape the development of inflammatory phenotypes. The human immune system is characterized by substantial developmental plasticity, and a comparative, developmental, ecological framework is proposed to cast light on the complex associations among early environments, regulation of inflammation, and disease. Recent studies in the Philippines and lowland Ecuador reveal low levels of chronic inflammation, despite higher burdens of infectious disease, and point to nutritional and microbial exposures in infancy as important determinants of inflammation in adulthood. By shaping the regulation of inflammation, early environments moderate responses to inflammatory stimuli later in life, with implications for the association between inflammation and chronic diseases. Attention to the eco-logics of inflammation may point to promising directions for future research, enriching our understanding of this important physiological system and informing approaches to the prevention and treatment of disease.
Early childhood poverty, immune-mediated disease processes, and adult productivity
Authors: Ziol-Guest Kathleen M. , Duncan Greg J. , Kalil Ariel , Boyce W. Thomas
Published: October 2012

This study seeks to understand whether poverty very early in life is associated with early-onset adult conditions related to immune-mediated chronic diseases. It also tests the role that these immune-mediated chronic diseases may play in accounting for the associations between early poverty and adult productivity. Data (
n
= 1,070) come from the US Panel Study of Income Dynamics and include economic conditions in utero and throughout childhood and adolescence coupled with adult (age 30–41 y) self-reports of health and economic productivity. Results show that low income, particularly in very early childhood (between the prenatal and second year of life), is associated with increases in early-adult hypertension, arthritis, and limitations on activities of daily living. Moreover, these relationships and particularly arthritis partially account for the associations between early childhood poverty and adult productivity as measured by adult work hours and earnings. The results suggest that the associations between early childhood poverty and these adult disease states may be immune-mediated.
Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat
Authors: Bagot Rosemary C. , Zhang Tie-Yuan , Wen Xianglan , Nguyen Thi Thu Thao , Nguyen Huy-Binh , Diorio Josie , Wong Tak Pan , Meaney Michael J.
Published: October 2012

Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the
Grm1
gene in the rat as a function of maternal care.
Grm1
encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.e., high-LG mothers) that was associated with a decrease in the methylation of
Grm1
. ChIP assays showed increased levels of histone 3 lysine 9 acetylation and histone 3 lysine 4 trimethylation of
Grm1
in hippocampus from the adult offspring of high-LG compared with low-LG mothers. These histone posttranslational modifications were highly correlated, and both associate inversely with DNA methylation and positively with transcription. Studies of mGluR1 function showed increased hippocampal mGluR1-induced long-term depression in the adult offspring of high-LG compared with low-LG mothers, as well as increased paired-pulse depression (PPD). PPD is an inhibitory feedback mechanism that prevents excessive glutamate release during high-frequency stimulation. The maternal effects on both long-term depression and PPD were eliminated by treatment with an mGluR1-selective antagonist. These findings suggest that variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes implicated in glutamatergic synaptic signaling.
Phylogenomics and a posteriori data partitioning resolve the Cretaceous angiosperm radiation Malpighiales
Authors: Xi Zhenxiang , Ruhfel Brad R. , Schaefer Hanno , Amorim André M. , Sugumaran M. , Wurdack Kenneth J. , Endress Peter K. , Matthews Merran L. , Stevens Peter F. , Mathews Sarah , Davis Charles C.
Published: October 2012

The angiosperm order Malpighiales includes ∼16,000 species and constitutes up to 40% of the understory tree diversity in tropical rain forests. Despite remarkable progress in angiosperm systematics during the last 20 y, relationships within Malpighiales remain poorly resolved, possibly owing to its rapid rise during the mid-Cretaceous. Using phylogenomic approaches, including analyses of 82 plastid genes from 58 species, we identified 12 additional clades in Malpighiales and substantially increased resolution along the backbone. This greatly improved phylogeny revealed a dynamic history of shifts in net diversification rates across Malpighiales, with bursts of diversification noted in the Barbados cherries (Malpighiaceae), cocas (Erythroxylaceae), and passion flowers (Passifloraceae). We found that commonly used a priori approaches for partitioning concatenated data in maximum likelihood analyses, by gene or by codon position, performed poorly relative to the use of partitions identified a posteriori using a Bayesian mixture model. We also found better branch support in trees inferred from a taxon-rich, data-sparse matrix, which deeply sampled only the phylogenetically critical placeholders, than in trees inferred from a taxon-sparse matrix with little missing data. Although this matrix has more missing data, our a posteriori partitioning strategy reduced the possibility of producing multiple distinct but equally optimal topologies and increased phylogenetic decisiveness, compared with the strategy of partitioning by gene. These approaches are likely to help improve phylogenetic resolution in other poorly resolved major clades of angiosperms and to be more broadly useful in studies across the Tree of Life.
A composite bacteriophage alters colonization by an intestinal commensal bacterium
Authors: Duerkop Breck A. , Clements Charmaine V. , Rollins Darcy , Rodrigues Jorge L. M. , Hooper Lora V.
Published: October 2012

The mammalian intestine is home to a dense community of bacteria and its associated bacteriophage (phage). Virtually nothing is known about how phages impact the establishment and maintenance of resident bacterial communities in the intestine. Here, we examine the phages harbored by
Enterococcus faecalis
, a commensal of the human intestine. We show that
E. faecalis
strain V583 produces a composite phage (ϕV1/7) derived from two distinct chromosomally encoded prophage elements. One prophage, prophage 1 (ϕV1), encodes the structural genes necessary for phage particle production. Another prophage, prophage 7 (ϕV7), is required for phage infection of susceptible host bacteria. Production of ϕV1/7 is controlled, in part, by nutrient availability, because ϕV1/7 particle numbers are elevated by free amino acids in culture and during growth in the mouse intestine. ϕV1/7 confers an advantage to
E. faecalis
V583 during competition with other
E. faecalis
strains in vitro and in vivo. Thus, we propose that
E. faecalis
V583 uses phage particles to establish and maintain dominance of its intestinal niche in the presence of closely related competing strains. Our findings indicate that bacteriophages can impact the dynamics of bacterial colonization in the mammalian intestinal ecosystem.
ESCRT-III binding protein MITD1 is involved in cytokinesis and has an unanticipated PLD fold that binds membranes
Authors: Hadders Michael A. , Agromayor Monica , Obita Takayuki , Perisic Olga , Caballe Anna , Kloc Magdalena , Lamers Meindert H. , Williams Roger L. , Martin-Serrano Juan
Published: October 2012

The endosomal sorting complexes required for transport (ESCRT) proteins have a critical function in abscission, the final separation of the daughter cells during cytokinesis. Here, we describe the structure and function of a previously uncharacterized ESCRT-III interacting protein, MIT-domain containing protein 1 (MITD1). Crystal structures of MITD1 reveal a dimer, with a microtubule-interacting and trafficking (MIT) domain at the N terminus and a unique, unanticipated phospholipase D-like (PLD) domain at the C terminus that binds membranes. We show that the MIT domain binds to a subset of ESCRT-III subunits and that this interaction mediates MITD1 recruitment to the midbody during cytokinesis. Depletion of MITD1 causes a distinct cytokinetic phenotype consistent with destabilization of the midbody and abscission failure. These results suggest a model whereby MITD1 coordinates the activity of ESCRT-III during abscission with earlier events in the final stages of cell division.
Calcium-dependent regulation of cyclic photosynthetic electron transfer by a CAS, ANR1, and PGRL1 complex
Authors: Terashima Mia , Petroutsos Dimitris , Hüdig Meike , Tolstygina Irina , Trompelt Kerstin , Gäbelein Philipp , Fufezan Christian , Kudla Jörg , Weinl Stefan , Finazzi Giovanni , Hippler Michael
Published: October 2012

Cyclic photosynthetic electron flow (CEF) is crucial to photosynthesis because it participates in the control of chloroplast energy and redox metabolism, and it is particularly induced under adverse environmental conditions. Here we report that down-regulation of the chloroplast localized Ca
2+
sensor (CAS) protein by an RNAi approach in
Chlamydomonas reinhardtii
results in strong inhibition of CEF under anoxia. Importantly, this inhibition is rescued by an increase in the extracellular Ca
2+
concentration, inferring that CEF is Ca
2+
-dependent. Furthermore, we identified a protein, anaerobic response 1 (ANR1), that is also required for effective acclimation to anaerobiosis. Depletion of ANR1 by artificial microRNA expression mimics the CAS-depletion phenotype, and under anaerobic conditions the two proteins coexist within a large active photosystem I-cytochrome
b

6

/f
complex. Moreover, we provide evidence that CAS and ANR1 interact with each other as well as with PGR5-Like 1 (PGRL1) in vivo. Overall our data establish a Ca
2+
-dependent regulation of CEF via the combined function of ANR1, CAS, and PGRL1, associated with each other in a multiprotein complex.
Adjuvant solution for pandemic influenza vaccine production
Authors: Clegg Christopher H. , Roque Richard , Van Hoeven Neal , Perrone Lucy , Baldwin Susan L. , Rininger Joseph A. , Bowen Richard A. , Reed Steven G.
Published: October 2012

Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.
Pole-to-pole biogeography of surface and deep marine bacterial communities
Authors: Ghiglione Jean-François , Galand Pierre E. , Pommier Thomas , Pedrós-Alió Carlos , Maas Elizabeth W. , Bakker Kevin , Bertilson Stefan , Kirchman David L. , Lovejoy Connie , Yager Patricia L. , Murray Alison E.
Published: October 2012

The Antarctic and Arctic regions offer a unique opportunity to test factors shaping biogeography of marine microbial communities because these regions are geographically far apart, yet share similar selection pressures. Here, we report a comprehensive comparison of bacterioplankton diversity between polar oceans, using standardized methods for pyrosequencing the V6 region of the small subunit ribosomal (SSU) rRNA gene. Bacterial communities from lower latitude oceans were included, providing a global perspective. A clear difference between Southern and Arctic Ocean surface communities was evident, with 78% of operational taxonomic units (OTUs) unique to the Southern Ocean and 70% unique to the Arctic Ocean. Although polar ocean bacterial communities were more similar to each other than to lower latitude pelagic communities, analyses of depths, seasons, and coastal vs. open waters, the Southern and Arctic Ocean bacterioplankton communities consistently clustered separately from each other. Coastal surface Southern and Arctic Ocean communities were more dissimilar from their respective open ocean communities. In contrast, deep ocean communities differed less between poles and lower latitude deep waters and displayed different diversity patterns compared with the surface. In addition, estimated diversity (Chao1) for surface and deep communities did not correlate significantly with latitude or temperature. Our results suggest differences in environmental conditions at the poles and different selection mechanisms controlling surface and deep ocean community structure and diversity. Surface bacterioplankton may be subjected to more short-term, variable conditions, whereas deep communities appear to be structured by longer water-mass residence time and connectivity through ocean circulation.
Climate negotiations under scientific uncertainty
Authors: Barrett Scott , Dannenberg Astrid
Published: October 2012

How does uncertainty about “dangerous” climate change affect the prospects for international cooperation? Climate negotiations usually are depicted as a prisoners’ dilemma game; collectively, countries are better off reducing their emissions, but self-interest impels them to keep on emitting. We provide experimental evidence, grounded in an analytical framework, showing that the fear of crossing a dangerous threshold can turn climate negotiations into a coordination game, making collective action to avoid a dangerous threshold virtually assured. These results are robust to uncertainty about the impact of crossing a threshold, but uncertainty about the location of the threshold turns the game back into a prisoners’ dilemma, causing cooperation to collapse. Our research explains the paradox of why countries would agree to a collective goal, aimed at reducing the risk of catastrophe, but act as if they were blind to this risk.
Area–heterogeneity tradeoff and the diversity of ecological communities
Authors: Allouche Omri , Kalyuzhny Michael , Moreno-Rueda Gregorio , Pizarro Manuel , Kadmon Ronen
Published: October 2012

For more than 50 y ecologists have believed that spatial heterogeneity in habitat conditions promotes species richness by increasing opportunities for niche partitioning. However, a recent stochastic model combining the main elements of niche theory and island biogeography theory suggests that environmental heterogeneity has a general unimodal rather than a positive effect on species richness. This result was explained by an inherent tradeoff between environmental heterogeneity and the amount of suitable area available for individual species: for a given area, as heterogeneity increases, the amount of effective area available for individual species decreases, thereby reducing population sizes and increasing the likelihood of stochastic extinctions. Here we provide a comprehensive evaluation of this hypothesis. First we analyze an extensive database of breeding bird distribution in Catalonia and show that patterns of species richness, species abundance, and extinction rates are consistent with the predictions of the area–heterogeneity tradeoff and its proposed mechanisms. We then perform a metaanalysis of heterogeneity–diversity relationships in 54 published datasets and show that empirical data better fit the unimodal pattern predicted by the area–heterogeneity tradeoff than the positive pattern predicted by classic niche theory. Simulations in which species may have variable niche widths along a continuous environmental gradient are consistent with all empirical findings. The area–heterogeneity tradeoff brings a unique perspective to current theories of species diversity and has important implications for biodiversity conservation.
How social and genetic factors predict friendship networks
Authors: Boardman Jason D. , Domingue Benjamin W. , Fletcher Jason M.
Published: October 2012

Recent research suggests that the genotype of one individual in a friendship pair is predictive of the genotype of his/her friend. These results provide tentative support for the genetic homophily perspective, which has important implications for social and genetic epidemiology because it substantiates a particular form of gene–environment correlation. This process may also have important implications for social scientists who study the social factors related to health and health-related behaviors. We extend this work by considering the ways in which school context shapes genetically similar friendships. Using the network, school, and genetic information from the National Longitudinal Study of Adolescent Health, we show that genetic homophily for the TaqI A polymorphism within the
DRD2
gene is stronger in schools with greater levels of inequality. Our results suggest that individuals with similar genotypes may not actively select into friendships; rather, they may be placed into these contexts by institutional mechanisms outside of their control. Our work highlights the fundamental role played by broad social structures in the extent to which genetic factors explain complex behaviors, such as friendships.
De novo prediction of protein folding pathways and structure using the principle of sequential stabilization
Authors: Adhikari Aashish N. , Freed Karl F. , Sosnick Tobin R.
Published: October 2012

Motivated by the relationship between the folding mechanism and the native structure, we develop a unified approach for predicting folding pathways and tertiary structure using only the primary sequence as input. Simulations begin from a realistic unfolded state devoid of secondary structure and use a chain representation lacking explicit side chains, rendering the simulations many orders of magnitude faster than molecular dynamics simulations. The multiple round nature of the algorithm mimics the authentic folding process and tests the effectiveness of sequential stabilization (SS) as a search strategy wherein 2° structural elements add onto existing structures in a process of progressive learning and stabilization of structure found in prior rounds of folding. Because no a priori knowledge is used, we can identify kinetically significant non-native interactions and intermediates, sometimes generated by only two mutations, while the evolution of contact matrices is often consistent with experiments. Moreover, structure prediction improves substantially by incorporating information from prior rounds. The success of our simple, homology-free approach affirms the validity of our description of the primary determinants of folding pathways and structure, and the effectiveness of SS as a search strategy.
Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system
Authors: Kirkby Nicholas S. , Lundberg Martina H. , Harrington Louise S. , Leadbeater Philip D. M. , Milne Ginger L. , Potter Claire M. F. , Al-Yamani Malak , Adeyemi Oladipupo , Warner Timothy D. , Mitchell Jane A.
Published: October 2012

Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors
Authors: Oakley Robert H. , Revollo Javier , Cidlowski John A.
Published: October 2012

G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin–dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1–dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.
Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases
Authors: Hall John C. , Casciola-Rosen Livia , Berger Alan E. , Kapsogeorgou Efstathia K. , Cheadle Chris , Tzioufas Athanasios G. , Baer Alan N. , Rosen Antony
Published: October 2012

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ–induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.
Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21
Authors: Roy Anindita , Cowan Gillian , Mead Adam J. , Filippi Sarah , Bohn Georg , Chaidos Aristeidis , Tunstall Oliver , Chan Jerry K. Y. , Choolani Mahesh , Bennett Phillip , Kumar Sailesh , Atkinson Deborah , Wyatt-Ashmead Josephine , Hu Ming , Stumpf Michael P. H. , Goudevenou Katerina , O'Connor David , Chou Stella T. , Weiss Mitchell J. , Karadimitris Anastasios , Jacobsen Sten Eirik , Vyas Paresh , Roberts Irene
Published: October 2012

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid–primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had
GATA1
mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.
Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy
Authors: Huang Yuhui , Yuan Jianping , Righi Elda , Kamoun Walid S. , Ancukiewicz Marek , Nezivar Jean , Santosuosso Michael , Martin John D. , Martin Margaret R. , Vianello Fabrizio , Leblanc Pierre , Munn Lance L. , Huang Peigen , Duda Dan G. , Fukumura Dai , Jain Rakesh K. , Poznansky Mark C.
Published: October 2012

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4
+
and CD8
+
T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8
+
T-cell–dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.
Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery
Authors: Walogorsky Michael , Mongeon Rebecca , Wen Hua , Nelson Nathan R. , Urban Jason M. , Ono Fumihito , Mandel Gail , Brehm Paul
Published: October 2012

Mutations in muscle ACh receptors cause slow-channel syndrome (SCS) and Escobar syndrome, two forms of congenital myasthenia. SCS is a dominant disorder with mutations reported for all receptor subunits except γ. Escobar syndrome is distinct, with mutations located exclusively in γ, and characterized by developmental improvement of muscle function. The zebrafish mutant line,
twister
, models SCS in terms of a dominant mutation in the α subunit (α
twi
) but shows the behavioral improvement associated with Escobar syndrome. Here, we present a unique electrophysiological study into developmental improvement for a myasthenic syndrome. The embryonic α
twi
βδγ receptor isoform produces slowly decaying synaptic currents typical of SCS that transit to a much faster decay upon the appearance of adult ε, despite the α
twi
mutation. Thus, the continued expression of α
twi
into adulthood is tolerated because of the ε expression and associated recovery, raising the likelihood of unappreciated myasthenic cases that benefit from the γ−ε switch.
The CORE‐10: A short measure of psychological distress for routine use in the psychological therapies
Authors: Barkham Michael , Bewick Bridgette , Mullin Tracy , Gilbody Simon , Connell Janice , Cahill Jane , Mellor-Clark John , Richards David , Unsworth Gisela , Evans Chris
Published: October 2012

Background: There is a need for a generic, short, and easy‐to‐use assessment measure for common presentations of psychological distress in UK primary care mental health settings. This paper sets out the development of the CORE‐10 in response to this need. Method: Items were drawn from the CORE‐OM and 10 items were selected according to a combination of usefulness, coverage of item clusters, and statistical procedures. Three CORE‐OM datasets were employed in the development phase: (1) a primary care sample, (2) a sample from an MRC platform trial of enhanced collaborative care of depression in primary care, and (3) a general population sample derived from the Office of National Statistics Psychiatric Morbidity Follow‐up survey. A fourth dataset comprising a sample from an occupational health setting was used to evaluate the CORE‐10 in its standalone format. Results: The internal reliability (alpha) of the CORE‐10 was .90 and the score for the CORE‐10 correlated with the CORE‐OM at .94 in a clinical sample and .92 in a non‐clinical sample. The clinical cut‐off score for general psychological distress was 11.0 with a reliable change index (90% CI) of 6. For depression, the cut‐off score for the CORE‐10 was 13 and yielded sensitivity and specificity values of .92 (CI=.83–1.0) and 0.72 (CI=.60–.83) respectively. Conclusion: The CORE‐10 is an acceptable and feasible instrument that has good psychometric properties and is practical to use with people presenting with common mental health problems in primary care settings.
Gaze transfer in remote cooperation: Is it always helpful to see what your partner is attending to?
Authors: Müller Romy , Helmert Jens R. , Pannasch Sebastian , Velichkovsky Boris M.
Published: October 2012

Establishing common ground in remote cooperation is challenging because nonverbal means of ambiguity resolution are limited. In such settings, information about a partner's gaze can support cooperative performance, but it is not yet clear whether and to what extent the abundance of information reflected in gaze comes at a cost. Specifically, in tasks that mainly rely on spatial referencing, gaze transfer might be distracting and leave the partner uncertain about the meaning of the gaze cursor. To examine this question, we let pairs of participants perform a joint puzzle task. One partner knew the solution and instructed the other partner's actions by (1) gaze, (2) speech, (3) gaze and speech, or (4) mouse and speech. Based on these instructions, the acting partner moved the pieces under conditions of high or low autonomy. Performance was better when using either gaze or mouse transfer compared to speech alone. However, in contrast to the mouse, gaze transfer induced uncertainty, evidenced in delayed responses to the cursor. Also, participants tried to resolve ambiguities by engaging in more verbal effort, formulating more explicit object descriptions and fewer deictic references. Thus, gaze transfer seems to increase uncertainty and ambiguity, thereby complicating grounding in this spatial referencing task. The results highlight the importance of closely examining task characteristics when considering gaze transfer as a means of support.
PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1
Authors: Pines Alex , Vrouwe Mischa G. , Marteijn Jurgen A. , Typas Dimitris , Luijsterburg Martijn S. , Cansoy Medine , Hensbergen Paul , Deelder André , de Groot Anton , Matsumoto Syota , Sugasawa Kaoru , Thoma Nicolas , Vermeulen Wim , Vrieling Harry , Mullenders Leon
Published: October 2012

The WD40-repeat protein DDB2 is essential for efficient recognition and subsequent removal of ultraviolet (UV)-induced DNA lesions by nucleotide excision repair (NER). However, how DDB2 promotes NER in chromatin is poorly understood. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a novel DDB2-associated factor. We demonstrate that DDB2 facilitated poly(ADP-ribosyl)ation of UV-damaged chromatin through the activity of PARP1, resulting in the recruitment of the chromatin-remodeling enzyme ALC1. Depletion of ALC1 rendered cells sensitive to UV and impaired repair of UV-induced DNA lesions. Additionally, DDB2 itself was targeted by poly(ADP-ribosyl)ation, resulting in increased protein stability and a prolonged chromatin retention time. Our in vitro and in vivo data support a model in which poly(ADP-ribosyl)ation of DDB2 suppresses DDB2 ubiquitylation and outline a molecular mechanism for PARP1-mediated regulation of NER through DDB2 stabilization and recruitment of the chromatin remodeler ALC1.
Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector
Authors: Wynne Joseph P. , Wu Jinhua , Su Wenjuan , Mor Adam , Patsoukis Nikolaos , Boussiotis Vassiliki A. , Hubbard Stevan R. , Philips Mark R.
Published: October 2012

Adaptive immunity depends on lymphocyte adhesion that is mediated by the integrin lymphocyte functional antigen 1 (LFA-1). The small guanosine triphosphatase Rap1 regulates LFA-1 adhesiveness through one of its effectors, Rap1-interacting adapter molecule (RIAM). We show that RIAM was recruited to the lymphocyte plasma membrane (PM) through its Ras association (RA) and pleckstrin homology (PH) domains, both of which were required for lymphocyte adhesion. The N terminus of RIAM inhibited membrane translocation. In vitro, the RA domain bound both Rap1 and H-Ras with equal but relatively low affinity, whereas in vivo only Rap1 was required for PM association. The PH domain bound phosphoinositol 4,5-bisphosphate (PI(4,5)P2) and was responsible for the spatial distribution of RIAM only at the PM of activated T cells. We determined the crystal structure of the RA and PH domains and found that, despite an intervening linker of 50 aa, the two domains were integrated into a single structural unit, which was critical for proper localization to the PM. Thus, the RA-PH domains of RIAM function as a proximity detector for activated Rap1 and PI(4,5)P2.
VIPR HMM: a hidden Markov model for detecting recombination with microbial detection microarrays
Authors: Allred Adam F. , Renshaw Hilary , Weaver Scott , Tesh Robert B. , Wang David
Published: October 2012

Motivation: Current methods in diagnostic microbiology typically focus on the detection of a single genomic locus or protein in a candidate agent. The presence of the entire microbe is then inferred from this isolated result. Problematically, the presence of recombination in microbial genomes would go undetected unless other genomic loci or protein components were specifically assayed. Microarrays lend themselves well to the detection of multiple loci from a given microbe; furthermore, the inherent nature of microarrays facilitates highly parallel interrogation of multiple microbes. However, none of the existing methods for analyzing diagnostic microarray data has the capacity to specifically identify recombinant microbes. In previous work, we developed a novel algorithm, VIPR, for analyzing diagnostic microarray data.

Results: We have expanded upon our previous implementation of VIPR by incorporating a hidden Markov model (HMM) to detect recombinant genomes. We trained our HMM on a set of non-recombinant parental viruses and applied our method to 11 recombinant alphaviruses and 4 recombinant flaviviruses hybridized to a diagnostic microarray in order to evaluate performance of the HMM. VIPR HMM correctly identified 95% of the 62 inter-species recombination breakpoints in the validation set and only two false-positive breakpoints were predicted. This study represents the first description and validation of an algorithm capable of detecting recombinant viruses based on diagnostic microarray hybridization patterns.

Availability: VIPR HMM is freely available for academic use and can be downloaded from http://ibridgenetwork.org/wustl/vipr.

Contact:  davewang@borcim.wustl.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
COPE: an accurate k-mer-based pair-end reads connection tool to facilitate genome assembly
Authors: Liu Binghang , Yuan Jianying , Yiu Siu-Ming , Li Zhenyu , Xie Yinlong , Chen Yanxiang , Shi Yujian , Zhang Hao , Li Yingrui , Lam Tak-Wah , Luo Ruibang
Published: October 2012

Motivation: The boost of next-generation sequencing technologies provides us with an unprecedented opportunity for elucidating genetic mysteries, yet the short-read length hinders us from better assembling the genome from scratch. New protocols now exist that can generate overlapping pair-end reads. By joining the 3′ ends of each read pair, one is able to construct longer reads for assembling. However, effectively joining two overlapped pair-end reads remains a challenging task.

Result: In this article, we present an efficient tool called Connecting Overlapped Pair-End (COPE) reads, to connect overlapping pair-end reads using k-mer frequencies. We evaluated our tool on 30× simulated pair-end reads from Arabidopsis thaliana with 1% base error. COPE connected over 99% of reads with 98.8% accuracy, which is, respectively, 10 and 2% higher than the recently published tool FLASH. When COPE is applied to real reads for genome assembly, the resulting contigs are found to have fewer errors and give a 14-fold improvement in the N50 measurement when compared with the contigs produced using unconnected reads.

Availability and implementation: COPE is implemented in C++ and is freely available as open-source code at ftp://ftp.genomics.org.cn/pub/cope.

Contact:  twlam@cs.hku.hk or luoruibang@genomics.org.cn
MesoRD 1.0: Stochastic reaction-diffusion simulations in the microscopic limit
Authors: Fange David , Mahmutovic Anel , Elf Johan
Published: October 2012

Summary: MesoRD is a tool for simulating stochastic reaction-diffusion systems as modeled by the reaction diffusion master equation. The simulated systems are defined in the Systems Biology Markup Language with additions to define compartment geometries. MesoRD 1.0 supports scale-dependent reaction rate constants and reactions between reactants in neighbouring subvolumes. These new features make it possible to construct physically consistent models of diffusion-controlled reactions also at fine spatial discretization.

Availability: MesoRD is written in C++ and licensed under the GNU general public license (GPL). MesoRD can be downloaded at http://mesord.sourceforge.net. The MesoRD homepage, http://mesord.sourceforge.net, contains detailed documentation and news about recently implemented features.

Contact:  johan.elf@icm.uu.se
ncPRO-seq: a tool for annotation and profiling of ncRNAs in sRNA-seq data
Authors: Chen Chong-Jian , Servant Nicolas , Toedling Joern , Sarazin Alexis , Marchais Antonin , Duvernois-Berthet Evelyne , Cognat Valérie , Colot Vincent , Voinnet Olivier , Heard Edith , Ciaudo Constance , Barillot Emmanuel
Published: October 2012

Summary: Non-coding RNA (ncRNA) PROfiling in small RNA (sRNA)-seq (ncPRO-seq) is a stand-alone, comprehensive and flexible ncRNA analysis pipeline. It can interrogate and perform detailed profiling analysis on sRNAs derived from annotated non-coding regions in miRBase, Rfam and RepeatMasker, as well as specific regions defined by users. The ncPRO-seq pipeline performs both gene-based and family-based analyses of sRNAs. It also has a module to identify regions significantly enriched with short reads, which cannot be classified under known ncRNA families, thus enabling the discovery of previously unknown ncRNA- or small interfering RNA (siRNA)-producing regions. The ncPRO-seq pipeline supports input read sequences in fastq, fasta and color space format, as well as alignment results in BAM format, meaning that sRNA raw data from the three current major platforms (Roche-454, Illumina-Solexa and Life technologies-SOLiD) can be analyzed with this pipeline. The ncPRO-seq pipeline can be used to analyze read and alignment data, based on any sequenced genome, including mammals and plants.

Availability: Source code, annotation files, manual and online version are available at http://ncpro.curie.fr/.

Contact:  bioinfo.ncproseq@curie.fr or cciaudo@ethz.ch

Supplementary information:  Supplementary data are available at Bioinformatics online.
Robust design of microbial strains
Authors: Costanza Jole , Carapezza Giovanni , Angione Claudio , Lió Pietro , Nicosia Giuseppe
Published: October 2012

Motivation: Metabolic engineering algorithms provide means to optimize a biological process leading to the improvement of a biotechnological interesting molecule. Therefore, it is important to understand how to act in a metabolic pathway in order to have the best results in terms of productions. In this work, we present a computational framework that searches for optimal and robust microbial strains that are able to produce target molecules. Our framework performs three tasks: it evaluates the parameter sensitivity of the microbial model, searches for the optimal genetic or fluxes design and finally calculates the robustness of the microbial strains. We are capable to combine the exploration of species, reactions, pathways and knockout parameter spaces with the Pareto-optimality principle.

Results: Our framework provides also theoretical and practical guidelines for design automation. The statistical cross comparison of our new optimization procedures, performed with respect to currently widely used algorithms for bacteria (e.g. Escherichia coli) over different multiple functions, reveals good performances over a variety of biotechnological products.

Availability:  http://www.dmi.unict.it/nicosia/pathDesign.html.

Contact:  nicosia@dmi.unict.it or pl219@cam.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Learning and Teaching with the RCGP Curriculum
Authors: Tulinius Charlotte , Hibble Arthur G. , Irving Greg J.
Published: October 2012

This article describes how to use the RCGP curriculum for learning and teaching in general practice, explaining why the revised curriculum is designed the way it is and how you can get the most out of it during your training and beyond.