bluuebunny/crossref_metadata_2025_split huggingface dataset:
Purification, identification, and characterization of two benzophenanthridine alkaloids fromCorydalis longicalcaratarhizomes with anti-mitotic and polyploidy-inducing activities
Authors: Li Jinhua , Yan Ziqi , Li Hongmei , Shi Qiong , Huang Linfang , Allen Thaddeus D. , Yang Dun , Zhang Jing 
Published: November 2019

ABSTRACTMitosis has long been a therapeutic target for the treatment of cancer. After conducting a phenotypic screen for anti-mitotic activity in a crude extract library of more than 2000 medicinal plants, we identified the rhizomes ofCorydalis longicalcarata. Guided by the bioactivity-based assay, two benzophenanthridine alkaloids were purified and subsequently identified as corynoline and its close analog acetylcorynoline. This study uncovers a previously unknown antimitotic activity for these two phytochemicals, discovers their potential to be developed as anticancer drugs, and highlights their pleiotropic effects on cell division, including prevention of chromosome congression, compromise of spindle checkpoint response, and blockage of cytokinesis.
Molecules to Mankind: Bridging Laboratory and Population Training
Authors: Burke Rachel M. , Gazmararian Julie A. , McCarty Nael A. , Rambo-Martin Benjamin L. , Shaw Kelly A. 
Published: November 2019

ABSTRACTAim/PurposeToday’s biomedical researchers are expected to apply understanding of basic biology to improve human health. Meeting this goal requires mastery of both laboratory and population sciences, each of which has its own knowledge base, techniques, and training paradigms.BackgroundEmory University’s “Molecules-to-Mankind” (M2M) doctoral pathway was established in 2009 to be an evolving model of interdisciplinary PhD education. M2M supplements fellows’ home programs, ensuring they receive training in both population and laboratory sciences.MethodologyThe present paper describes the M2M program in detail. Surveys of faculty and fellows were also carried out, and the results are presented herein.ContributionThe M2M program follows a unique model by which doctoral students receive training in both population and laboratory sciences. The present paper describes this model, such that the information can be disseminated to other educational institutions interested in implementing similar programs.FindingsThis unique model facilitates engagement of stakeholders including the fellow’s home program, dissertation advisor, and Emory’s professional schools. Recruited across biomedical PhD and MD/PhD programs, fellows have diverse research experiences and represent “spokes” bound together by the M2M “hub.” This hub’s central feature is a weekly seminar class where fellows and faculty members gather for open discussion with interdisciplinary speakers with successful research careers, emphasizing speakers who have tied laboratory and population sciences in their own work. This forum provides an encouraging environment for dialogue on all aspects of biomedical research from the science itself, to the speaker’s career path, and the logistics of garnering institutional support and building transdisciplinary collaborations. A decade since its inception, M2M has a proven track record of shaping early-stage careers for its 49 alumni to date.Recommendations for PractitionersEngaging trainees outside their home doctoral programs can have positive implications on overall quality of education.Recommendation for ResearchersAs interdisciplinary models grow ever more important in biomedical sciences, it is important to further examine the best teaching methods for training the next generation of scientists.Impact on SocietyInterdisciplinary training at the doctoral level is important to produce future cohorts of engaged and versatile scientific leaders.Future ResearchFuture research should continue to explore novel methods of training graduate students at the doctoral level.
Calling differential DNA methylation at cell-type resolution: an objective status-quo
Authors: Jing Han , Zheng Shijie C. , Breeze Charles E. , Beck Stephan , Teschendorff Andrew E. 
Published: November 2019

AbstractDue to cost and logistical reasons, Epigenome-Wide-Association Studies (EWAS) are normally performed in complex tissues, resulting in average DNA methylation profiles over potentially many different cell-types, which can obscure important cell-type specific associations with disease. Identifying the specific cell-types that are altered is a key hurdle for elucidating causal pathways to disease, and consequently statistical algorithms have recently emerged that aim to address this challenge. Comparisons between these algorithms are of great interest, yet here we find that the main comparative study so far was substantially biased and potentially misleading. By using this study as an example, we highlight some of the key issues that need to be considered to ensure that future assessments between methods are more objective.
Notes on the threatened lowland forests of Mt Cameroon and their endemics including Drypetes njonji sp. nov., with a key to species of Drypetes sect. Stipulares (Putranjivaceae)
Authors: Cheek Martin , Ndam Nouhou , Budden Andrew 
Published: November 2019

ABSTRACTBackground and aimsThis paper reports a further discovery of a new endemic threatened species to science in the context of long-term botanical surveys in the lowland coastal forests of Mount Cameroon specifically and generally in the Cross River-Sanaga interval of west-central Africa. These studies focus on species discovery and conservation through the Tropical Important Plant Areas programme.MethodsNormal practices of herbarium taxonomy have been applied to study the material collected. The relevant collections are stored in the Herbarium of the Royal Botanic Gardens, Kew, London and at the Limbe Botanic Garden, Limbe, and the Institute of Research in Agronomic Development – National Herbarium of Cameroon, Yaoundé.Key resultsNew species to science continue to be discovered from Mt Cameroon. Most of these species are rare, highly localised, and threatened by habitat destruction. These discoveries increase the justification for improved conservation management of surviving habitat. Drypetes njonji is described as an additional species new to science and appears to be endemic to the lowland coastal forests at the foot of Mt Cameroon. It is placed in and keyed out in Sect. Stipulares, a group confined to Lower Guinea. The conservation status of Drypetes njonji is assessed as Endangered (EN B1+2ab(iii)) according to the 2012 criteria of IUCN. An updated overview of the lowland plant endemics of Mt Cameroon is presented.
From plant populations to communities: using hierarchical trait environment relationships to reveal within ecosystem filtering
Authors: Deschamps Lucas , Proulx Raphaël , Gross Nicolas , Rheault Guillaume , Maire Vincent 
Published: November 2019

AbstractExplaining the existence of highly diverse plant communities under strong abiotic filtering is a long-standing challenge in ecology. Hierarchical aspects of abiotic and biotic filters are rarely taken into account and studies focus mainly on community-level aggregated patterns. Because variations in biotic conditions might take place in short abiotic gradient and within the tolerance of species in regional pool, it is likely that biotic filtering will select individuals within species and adjust population characteristics. To challenge this idea, we replicated a diversity gradient in four highly contrasted wetlands with an almost complete species turn-over, sampling individuals in communities irrespective of their taxonomic identities or status. Using hierarchical distributional modelling, we analyzed the variation of the mean and dispersion of functional trait space at the ecosystem, community and species level. We found that the abiotic differences between ecosystems filtered species contrasted in their growth/nutrient conservation trade-off, while within ecosystems community variation were mainly due to the partitioning of canopy and leaf adaptations to light conditions. We found strong species-specific functional and demographic responses of dominant species along the diversity gradient, especially for traits linked to biomass and space occupation. Two contrasted strategies emerged, with species using plasticity to maintain equally dense populations, while others used plasticity to become overwhelmingly abundant when in favorable conditions. Our results demonstrate that within ecosystems, variation in biotic conditions selects individuals within populations, revealing the importance of phenotypic variation for a species to be maintained in more or less diverse communities. Because phenotypic variations are related to demographic responses, it offers a way to link the study of species diversity and eco-evolutionary dynamics.
Structures of three MORN repeat proteins and a re-evaluation of the proposed lipid-binding properties of MORN repeats
Authors: Sajko Sara , Grishkovskaya Irina , Kostan Julius , Graewert Melissa , Setiawan Kim , Trübestein Linda , Niedermüller Korbinian , Gehin Charlotte , Sponga Antonio , Puchinger Martin , Gavin Anne-Claude , Leonard Thomas , Svergun Dimitri , Smith Terry K. , Morriswood Brooke , Djinovic-Carugo Kristina 
Published: November 2019

ABSTRACTMORN (Membrane Occupation and Recognition Nexus) repeat proteins have a wide taxonomic distribution, being found in both prokaryotes and eukaryotes. Despite this ubiquity, they remain poorly characterised at both a structural and a functional level compared to other common repeats. In functional terms, they are often assumed to be lipid-binding modules that mediate membrane targeting. We addressed this putative activity by focusing on a protein composed solely of MORN repeats –Trypanosoma bruceiMORN1. Surprisingly, no evidence for binding to membranes or lipid vesicles by TbMORN1 could be obtained either in vivo or in vitro. Conversely, TbMORN1 did interact with individual phospholipids. High- and low-resolution structures of the MORN1 protein fromTrypanosoma bruceiand homologous proteins from the parasitesToxoplasma gondiiandPlasmodium falciparumwere obtained using a combination of macromolecular crystallography, small-angle X-ray scattering, and electron microscopy. This enabled a first structure-based definition of the MORN repeat itself. Furthermore, all three structures dimerised via their C-termini in an antiparallel configuration. The dimers could form extended or V-shaped quaternary structures depending on the presence of specific interface residues. This work provides a new perspective on MORN repeats, showing that they are protein-protein interaction modules capable of mediating both dimerisation and oligomerisation.
A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology
Authors: Cavanagh Sean E. , Lam Norman H. , Murray John D. , Hunt Laurence T. , Kennerley Steven W. 
Published: November 2019

AbstractDecision-making biases can be systematic features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases in health and disease. Monkeys performed an evidence integration task in which they showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a neural mechanism for this behaviour. Because NMDA receptor (NMDA-R) hypofunction is a leading hypothesis for neuropathology in schizophrenia, we simulated behavioural effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were tested experimentally using the NMDA-R antagonist ketamine, yielding changes in decision-making consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent.SignificancePeople can make apparently irrational decisions because of underlying features in their decision circuitry. Deficits in the same neural circuits may also underlie debilitating cognitive symptoms of neuropsychiatric patients. Here, we reveal a neural circuit mechanism explaining an irrationality frequently observed in healthy humans making binary choices – the pro-variance bias. Our circuit model could be perturbed by introducing deficits in either excitatory or inhibitory neuron function. These two perturbations made specific, dissociable predictions for the types of irrational decisionmaking behaviour produced. We used the NMDA-R antagonist ketamine, an experimental model for schizophrenia, to test if these predictions were relevant to neuropsychiatric pathophysiology. The results were consistent with impaired excitatory neuron function, providing important new insights into the pathophysiology of schizophrenia.
Aversion of the invasive Asian longhorned tick to the white-footed mouse, the dominant reservoir of tick-borne pathogens in the United States
Authors: Ronai Isobel , Tufts Danielle M. , Diuk-Wasser Maria A. 
Published: November 2019

AbstractThe Asian longhorned tick (Haemaphysalis longicornis) was reported for the first time in the United States of America in 2017 and has now spread across 12 states. The potential of this invasive tick vector to transmit pathogens will be determined through its association to native hosts, such as the white-footed mouse (Peromyscus leucopus) which is the primary reservoir for the causative agent of Lyme disease (Borrelia burgdorferi) and other zoonotic pathogens. We placed larval H. longicornis on P. leucopus, 65% of the larvae (n = 40) moved off the host within a short period of time and none engorged. In contrast, larval black-legged ticks (Ixodes scapularis) did not move from where they were placed in the ear of the mouse. We then conducted a laboratory behavioural assay to assess the interaction of H. longicornis with the hair of potential mammalian host species in the United States of America. H. longicornis larvae were less likely to enter the hair zone of P. leucopus and humans compared to the hair of domestic cats, domestic dogs, and white-tailed deer. Our study identifies a tick-host hair interaction behaviour, which can be quantified in a laboratory assay to predict tick-host associations and provides insights into how ticks select a host.
Landscape structure shapes tree seedlings’ diversity at multiple spatial scales in a fragmented tropical rainforest
Authors: Nicasio-Arzeta Sergio , Zermeño-Hernández Isela E. , Maza-Villalobos Susana , Benítez-Malvido Julieta 
Published: November 2019

AbstractBiotic-dispersed tree seedling species are fundamental for the maintenance of the structure and function of forest patches in fragmented rainforest landscapes. Nonetheless, the effects of landscape structure and the spatial scale at which operates on seedling α- and β-diversity is unknown. Using a multi-scale approach, we assessed the relative effect of landscape composition (i.e., percentage of old-growth/secondary forest cover), configuration (i.e., aggregation/density of forest patches) and connectivity (i.e., structural and functional) on α- and β-diversity of biotic-dispersed seedlings in 16 forest patches in the Lacandona rainforest, Mexico. We assessed these effects at 13 spatial scales (from 300 to 1500 m radius, at 100 m intervals) for three α- and β-diversity orders (rare, common and dominant species). We found that patch aggregation increased species richness and reduced β-diversity of common and dominant species at similar spatial scales (500 to 600 m). Additionally, functional connectivity had a positive effect on the β-diversity of rare species in the 800 m spatial extent. These effects suggest that landscape configuration and functional connectivity sustain seedling diversity by preserving seed rain richness and the presence of large terrestrial herbivorous mammals. In contrast, the percentage of secondary forest matrix was detrimental for all α-diversity orders and the β-diversity of common and dominant species. Forthcoming conservation strategies should prevent deforestation, increase habitat amount and promote functional connectivity of forest-dependent fauna through matrix management actions.
Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation
Authors: Aslam Muhammad Assad , Alemdehy Mir Farshid , Kwesi-Maliepaard Eliza Mari , Caganova Marieta , Pardieck Iris N. , van den Brand Teun , Muhaimin Fitriari Izzatunnisa , van Welsem Tibor , de Rink Iris , Song Ji-Ying , de Wit Elzo , Arens Ramon , Rajewsky Klaus , Jacobs Heinz , van Leeuwen Fred 
Published: November 2019

AbstractDifferentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Murine B cells lackingDot1Lfailed to establish germinal centers (GC) and normal humoral immune responsesin vivo.In vitro, activated B cells showed aberrant differentiation and prematurely acquired plasma cell features. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L supports the repression of an anti-proliferative, plasma cell differentiation program by maintaining expression of the H3K27 methyltransferaseEzh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Our findings show that DOT1L is a central modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B cell naivety and GC B cell differentiation.
Oceans apart: Heterogeneous patterns of parallel evolution in sticklebacks
Authors: Fang Bohao , Kemppainen Petri , Momigliano Paolo , Feng Xueyun , Merilä Juha 
Published: November 2019

AbstractAn important model system for the study of genomic mechanisms underlying parallel ecological adaptation in the wild is the three-spined stickleback (Gasterosteus aculeatus), which has repeatedly colonized and adapted to freshwater from the sea throughout the northern hemisphere. Previous studies have identified numerous genomic regions showing consistent genetic differentiation between freshwater and marine ecotypes, but these are typically based on limited geographic sampling and are biased towards studies in the Eastern Pacific. We analysed population genomic data from marine and freshwater ecotypes of three-spined sticklebacks with from a comprehensive global collection of marine and freshwater ecotypes to detect loci involved in parallel evolution at different geographic scales. Our findings highlight that most signatures of parallel evolution were unique to the Eastern Pacific. Trans-oceanic marine and freshwater differentiation was only found in a very limited number of genomic regions, including three chromosomal inversions. Using both simulations and empirical data, we demonstrate that this is likely due to both the stochastic loss of freshwater-adapted alleles during founder events during the invasion of the Atlantic basin and selection against freshwater-adapted variants in the sea, both of which have reduced the amount of standing genetic variation available for freshwater adaptation outside the Eastern Pacific region. Moreover, the existence of highly elevated linkage disequilibrium associated with marine-freshwater differentiation in the Eastern Pacific is also consistent with a secondary contact scenario between marine and freshwater populations that have evolved in isolation from each other during past glacial periods. Thus, contrary to what earlier studies focused on Eastern Pacific populations have led us to believe, parallel marine-freshwater differentiation in sticklebacks is far less prevalent and pronounced in all other parts of the species global distribution range.
Inhibiting endoplasmic reticulum stress decreases tumor burden in a mouse model for hepatocellular carcinoma
Authors: Pavlovic Natasa , Calitz Carlemi , Thanapirom Kessarin , Mazza Giuseppe , Rombouts Krista , Gerwins Pär , Heindryckx Femke 
Published: November 2019

ABSTRACTHepatocellular carcinoma (HCC) is a liver tumor that arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells induce ER-stress in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which inhibited tumor cell proliferation and migration in different in vitro 2D and 3D co-cultures. Our results suggest that IRE1α is an important mediator in the communication between stellate cells and cancer cells and components of the ER-stress pathway may be therapeutically relevant for HCC-patients.Impact statementIRE1α is an important mediator in the communication between stellate cells and cancer cells and components of the ER-stress pathway may be therapeutically relevant for liver cancer.
Cortisol-induced signatures of stress in the fish microbiome
Authors: Webster Tamsyn M. Uren , Rodriguez-Barreto Deiene , Consuegra Sofia , Garcia de Leaniz Carlos 
Published: November 2019

AbstractStress experienced in intensive aquaculture can compromise fish growth, condition and immunity. Microbiome disruption may contribute to these adverse health effects, but little is known about how stress affects fish microbial communities. Here, we specifically examined the effects of stress-induced cortisol production on the fish microbiome. We exposed juvenile Atlantic salmon to a mild confinement stressor for two weeks. We then measured cortisol in the plasma, skin-mucus and faeces, and characterised the skin and faecal microbiome. Faecal and skin cortisol concentrations increased in fish exposed to confinement stress, and were positively correlated with plasma cortisol. Elevated faecal cortisol was associated with pronounced changes in the diversity and structure of the faecal microbiome. In particular, we identified a marked decline in probiotic Lactobacillales (Carnobacteriumsp.) and an increase in pro-inflammatory and pathogenic taxa within the classes Clostridia and Gammaproteobacteria. In contrast, skin-mucus cortisol concentrations were lower and not associated with any detectable changes in the skin microbiome. Our results demonstrate that cortisol disrupts the gut microbiome, which may, in turn, contribute to the adverse effects of stress on fish health. They also highlight the value of using non-invasive faecal samples to monitor stress, including simultaneous determination of cortisol and stress-responsive bacteria.