bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem cell derived human microglia transplanted in mouse brain to study genetic risk of Alzheimer’s Disease
Authors: Mancuso Renzo , Van Den Daele Johanna , Fattorelli Nicola , Wolfs Leen , Balusu Sriram , Burton Oliver , Sierksma Annerieke , Fourne Yannick , Poovathingal Suresh , Arranz-Mendiguren Amaia , Sala Frigerio Carlo , Claes Christel , Serneels Lutgarde , Theys Tom , Hugh Perry V. , Verfaillie Catherine , Fiers Mark , De Strooper Bart 
Published: February 2019

Summary paragraphGenetics highlight the central role of microglia in Alzheimer’s disease but at least 36% of AD-risk genes lack good mouse orthologues. Here, we show that embryonic stem cell (ESC)-derived human microglia successfully engraft the mouse brain and recapitulate transcriptionally primary human microglia derived from human surgical samples. Upon exposure to oligomeric Aβ a wide range of AD-risk genes are expressed that are not readily studied in current mouse models for AD. This work provides a unique humanized animal model that will allow elucidating the role of genetic risk in the pathogenesis of AD.
LD scores are associated with differences in allele frequencies between populations but LD score regression can still distinguish confounding from polygenicity
Authors: Alexander Mason , Curtis David 
Published: February 2019

SummaryThe LD score regression method tests whether there is an association between the LD score and allele frequency differences between cases and controls. It makes the assumption that there is no association between LD score and allele frequency differences between populations and hence that any observed association is due to a polygenic effect rather than population stratification. This assumption has not previously been tested. In comparisons between HapMap populations we observe that there is indeed an association between the LD score and allele frequency differences. However this effect is small and when we carry out simulations of large case-control samples the effect becomes negligible. We conclude that if the intercept is small then any increase in mean chi-squared does indeed reflect a polygenic effect rather than population stratification.
Field validation of an eDNA assay for the endangered white-clawed crayfishAustropotamobius pallipes
Authors: Atkinson Siobhán , Carlsson Jeanette E.L. , Ball Bernard , Kelly-Quinn Mary , Carlsson Jens 
Published: February 2019

AbstractThe white-clawed crayfishAustropotamobius pallipeshas undergone extensive declines within its native range in the last century. Because of its threatened status, European legislation requires the species to be regularly monitored and that Special Areas of Conservation (SACs) be designated for it. Knowledge on the distribution of this species is vital for addressing these needs. This study presents an environmental (e)DNA assay to detectA. pallipesin water samples, based on the mitochondrial cytochrome oxidase I (COI) gene, utilizing species-specific primers, a minor groove binding (MGB) probe and quantitative PCR. The results of this study indicate that eDNA is an effective tool for detectingA. pallipesin a lotic system, and could provide a valuable, non-invasive method for determining the distribution of this species.
Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors
Authors: Kitson Sarah J. , Rosser Matthew , Fischer Deborah P. , Marshall Kay M. , Clarke Robert B. , Crosbie Emma J. 
Published: February 2019

Translational relevanceEndometrial cancer stem cells are reported to drive metastasis and disease relapse and are resistant to commonly used chemotherapeutic drugs. Here, we characterise ALDHhighand CD133+veendometrial cancer stem cells with differing levels of cancer stem cell activity and stem cell and epithelial-mesenchymal transition (EMT) gene expression. Their proportions and activity are reduced following treatment with metformin at a lower concentration than that required to affect bulk tumour cell proliferation, establishing a selective and specific effect on endometrial cancer stem cells. We demonstrate that this effect is abrogated when endometrial cancer cells are pre-treated with adipocyte conditioned media, indicating adipokine-mediated resistance to metformin. These results support future studies of metformin as an adjuvant therapy to reduce the risk of disease recurrence but should also investigate the impact of obesity on treatment response.AbstractPurposeAdvanced endometrial cancer continues to have a poor prognosis due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+veendometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity.Experimental designIshikawa and Hec-1a cell lines were used to characterise ALDHhighand CD133+veendometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media.ResultsALDHhighcells demonstrated greater endometrial cancer stem cell activity than CD133+vecells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5-1mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p≤0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media.ConclusionsThese results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.
Flowering behaviour inArabis alpinaensures the maintenance of a perennating dormant bud bank
Authors: Vayssières Alice , Mishra Priyanka , Roggen Adrian , Ponraj Udhaya , Neumann Ulla , Theres Klaus , Ljung Karin , Albani Maria C. 
Published: February 2019

ABSTRACTArabis alpina, similar to woody perennials, has a complex architecture with a zone of axillary vegetative branches and a zone of dormant buds that serve as perennating organs. We show that floral development during vernalization is the key for shaping the dormant bud zone by facilitating a synchronized and rapid growth after vernalization and thereby causing an increase in auxin response and transport and endogenous indole-3-acetic acid (IAA) levels in the stem. Floral development during vernalization is associated with the development of axillary buds in subapical nodes. Our transcriptome analysis indicated that these buds are not dormant during vernalization but only attain sustained growth after the return to warm temperatures. Floral and subapical vegetative branches grow after vernalization and inhibit the development of the buds below. Dormancy in these buds is regulated across theA. alpinalife cycle by low temperatures and by apical dominance in a BRANCHED 1-dependent mechanism.
The effect of drought and intercropping on chicory nutrient uptake from below 2 m studied in a multiple tracer setup
Authors: Rasmussen Camilla Ruø , Thorup-Kristensen Kristian , Dresbøll Dorte Bodin 
Published: February 2019

AbstractAimsWe tested if chicory acquires nutrients from soil layers down to 3.5 m depth and whether the deep nutrient uptake increases as a result of topsoil drought or topsoil resource competition. We also tested whether application of the trace elements Cs, Li, Rb, Sr, and Se, as tracers result in similar uptake rates.MethodsThe methodological tests were primarily carried out in a pilot experiment where the five tracers were applied to 1 m depth in lucerne and red beet grown in tube rhizotrons. The dynamics of deep nutrient uptake in chicory was studied in large 4 m deep rhizoboxes. A drought was imposed when roots had reached around 2 m depth.ResultsChicory acquired tracers applied to 3.5 m depth, but we found no compensatory tracer uptake with depth during drought. We found some indications of a compensatory tracer uptake from 2.3 and 2.9 m depth in intercropped chicory. Application of equimolar amounts of trace elements resulted in similar excess tracer concentrations within species.ConclusionChicory acquires nutrients from below 3 m but does not increase deep nutrient uptake as a response to limited topsoil nutrient availability.
The Ps and Qs of alarmone synthesis inStaphylococcus aureus
Authors: Yang Ning , Xie Shujie , Tang Nga-Yeung , Choi Mei Y. , Wang Ying , Watt Rory M. 
Published: February 2019

AbstractDuring the stringent response, bacteria synthesize guanosine-3’,5’-bis(diphosphate) (ppGpp) and guanosine-5’-triphosphate 3’-diphosphate (pppGpp), which act as secondary messengers to promote cellular survival and adaptation. (p)ppGpp ‘alarmones’ are synthesized and/or hydrolyzed by proteins belonging to the RelA/SpoT Homologue (RSH) family. Many bacteria also encode ‘small alarmone synthetase’ (SAS) proteins (e.g. RelP, RelQ) which may also be capable of synthesizing a third alarmone: guanosine-5’-phosphate 3’-diphosphate (pGpp). Here, we report the biochemical properties of the Rel (RSH), RelP and RelQ proteins fromStaphylococcus aureus(Sa-Rel, Sa-RelP, Sa-RelQ, respectively). Sa-Rel synthesized pppGpp more efficiently than ppGpp, but lacked the ability to produce pGpp. However, Sa-Rel efficiently hydrolyzed all three alarmones in a Mn(II) ion-dependent manner. The removal of the C-terminal regulatory domain of Sa-Rel increased its rate of (p)ppGpp synthesisca. 10-fold, but had negligible effects on its rate of (pp)pGpp hydrolysis. Sa-RelP and Sa-RelQ efficiently synthesized pGpp in addition to pppGpp and ppGpp. The alarmone-synthesizing abilities of Sa-RelQ, but not Sa-RelP, were allosterically-stimulated by the addition of pppGpp, ppGpp or pGpp. The respective (pp)pGpp-synthesizing activities of Sa-RelP/Sa-RelQ were compared and contrasted with SAS homologues fromEnterococcus faecalis(Ef-RelQ) andStreptococcus mutans(Sm-RelQ, Sm-RelP). Results indicated that EF-RelQ, Sm-RelQ and Sa-RelQ were functionally-equivalent; but exhibited considerable variations in their respective biochemical properties, and the degrees to which alarmones and single-stranded RNA molecules allosterically stimulated their respective alarmone-synthesizing activities. The respective (pp)pGpp-synthesizing capabilities of Sa-RelP and Sm-RelP proteins were inhibited by pGpp, ppGpp and pppGpp. Our results support the premise that RelP and RelQ proteins may synthesize pGpp in addition to (p)ppGpp withinS. aureusand other Gram-positive bacterial species.
Can we predict which species win when new habitat becomes available?
Authors: Nomura Miki , Ohlemüller Ralf , Lee William G. , Lloyd Kelvin M. , Anderson Barbara J. 
Published: February 2019

AbstractLand cover change is a key component of anthropogenic global environmental change, contributing to changes in environmental conditions of habitats. These changes can lead to the redistribution of species and shifts in the functional composition and properties of ecosystems. Deforestation is globally the most widespread anthropogenically driven land cover change leading to conversion from closed forest to open non-forest habitat. The consequences of these functional habitat changes on species distributions are only poorly understood. This study investigates the relative roles of geographic features, species climatic niche characteristics and species traits in determining the ability of open-habitat plant species to take advantage of recently opened habitats. We use current occurrence records of 18 herbaceous, predominantly open-habitat species of the genus Acaena (Rosaceae) to determine their prevalence in recently opened habitat. Geographic features of the spatial distribution of open habitat, species’ climatic niche characteristics, and species traits related to dispersal were tested their correlation with species’ prevalence in anthropogenically opened habitat. While primary open habitat (naturally open) was characterised by cold climates, secondary open habitat (naturally closed but anthropogenically opened) is characterised by warmer and wetter conditions. We found high levels of variation in the prevalence of secondary open habitat among the investigated species indicating differences between species in their ability to colonise newly opened habitat. For the species investigated, geographical and climatic niche factors showed generally stronger relationships with species’ prevalence in secondary open habitat than functional traits did. For small herbaceous species, geographical and environmental factors appear to be more important than species functional traits for facilitating expansion into secondary open habitats. Our results suggested that the land cover change might have triggered the shifts of factors controlling open-habitat plant distributions from the competition with forest trees to current environmental constraints.
Comparison of different orders of Legendre polynomials in random regression model for estimation of genetic parameters and breeding values of milk yield in the Chinese Holstein population
Authors: Li Jianbin , Gao Hongding , Madsen Per , Liu Wenhao , Bao Peng , Xue Guanghui , Yang Jun , Gao Yundong , Su Guosheng 
Published: February 2019

AbstractRandom regression test-day model has become the most commonly adopted model for routine genetic evaluations for different dairy populations, which allows accurately accounting for genetic and environmental effects at different periods during lactation. The objective of this study was to explore appropriate random regression test-day model for genetic evaluation of milk yield in Chinese Holstein population. Data included 419,567 test-day records from 54,417 cows in the first lactation. Variance components and breeding values were estimated using random regression test-day model with different order (first order to fifth order) of Legendre polynomials, and accounted for homogeneous or heterogeneous residual variance across the lactation. The goodness of fit of the models was evaluated by total residual variance (TRV) and − 2logL. Further, the predictive ability of the models was assessed by Spearman’s rank correlation between estimated breeding values for 305d milk yield (EBV305) from the full data set and reduced data set in which the records from the last calving year were masked. The results showed that random regression models using third order Legendre polynomials (LP3) with heterogeneous residual variance achieved the lower TRV and − 2logL value and the highest correlation for EBV305 between full data and reduced data. Heritability estimated by this model was 0.250 for 305d milk yield and ranged from 0.163 to 0.304 for test-day milk yield. We suggest random regression model with Legendre polynomial of order 3 and accounting for heterogeneous residual variances could be an appropriate model to be used for genetic evaluation of milk yield for Chinese Holstein population.
Photoperiod-induced neurotransmitter plasticity declines with aging: an epigenetic regulation?
Authors: Pritchard Rory , Chen Helene , Romoli Ben , Spitzer Nicholas C. , Dulcis Davide 
Published: February 2019

ABSTRACTNeuroplasticity has classically been understood to arise through changes in synaptic strength or synaptic connectivity. A newly discovered form of neuroplasticity, neurotransmitter switching, involves changes in neurotransmitter identity. Chronic exposure to different photoperiods alters the number of dopamine (tyrosine hydroxylase, TH+) and somatostatin (SST+) neurons in the paraventricular nucleus (PaVN) of the hypothalamus of adult rats and results in discrete behavioral changes. Here we investigate whether photoperiod-induced neurotransmitter switching persists during aging and whether epigenetic mechanisms of histone acetylation and DNA methylation may contribute to this neurotransmitter plasticity. We show that this plasticity is robust at 1 and at 3 months but reduced in TH+ neurons at 12 months and completely abolished in both TH+ and SST+ neurons by 18 months. De novo methylation and histone 3 acetylation were observed following short-day photoperiod exposure in both TH+ and SST+ neurons at 1 and 3 months while an overall increase in methylation of SST+ neurons paralleled neuroplasticity reduction at 12 and 18 months. Histone acetylation increased in TH+ neurons and decreased in SST+ neurons following short-day exposure at 3 months while the total number of acetylated PaVN neurons remained constant. Reciprocal histone acetylation in TH+ and SST+ neurons suggests the importance of studying epigenetic regulation at the circuit level for identified cell phenotypes. The association of age-dependent reduction in neurotransmitter plasticity and changes in DNA methylation and acetylation patterns in two neuronal phenotypes known to switch transmitter identity suggests mechanistic insights into transmitter plasticity in the aging brain.SIGNIFICANCENeurotransmitter switching, like changes in synaptic strength, formation of new synapses and synapse remodeling, declines with age. This age-dependent reduction in transmitter plasticity is associated with changes in levels of DNA methylase and histone deacetylase that imply epigenetic regulation of transcription. A reciprocal pattern of histone acetylation in a single population of neurons that depends on the transmitter expressed emphasizes the value of studying epigenetic mechanisms at the level of cell phenotypes rather than cell genotypes or whole tissue. The findings may be useful for developing approaches for non-invasive treatment of disorders characterized by neurotransmitter dysfunction.
Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma
Authors: Lin Yu-Hsiu T. , Way Gregory P. , Barwick Benjamin G. , Mariano Margarette C. , Marcoulis Makeba , Ferguson Ian D. , Driessen Christoph , Boise Lawrence H. , Greene Casey S. , Wiita Arun P. 
Published: February 2019

ABSTRACTA major driver of multiple myeloma is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employ an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in multiple myeloma to inform precision medicine strategies. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between NRAS and KRAS mutants invisible to the genomic landscape. Transcriptional analysis suggests that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs. WT RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes whereas RAS mutations overall carry no survival impact. We further develop an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. These results may lead to improved stratification of MM patients in clinical trials while also revealing unexplored modes of Ras biology.
Altered Cell-Substrate Behavior on Microporous Membranes is a Result of Disruption and Grip
Authors: Allahyari Zahra , Gholizadeh Shayan , Chung Henry H. , Delgadillo Luis F. , Gaborski Thomas R. 
Published: February 2019

ABSTRACTPorous membranes are ubiquitous in cell co-culture and tissue-on-a-chip studies. These materials are predominantly chosen for their semi-permeable and size exclusion properties to restrict or permit transmigration and cell-cell communication. However, previous studies have shown pore size, spacing and orientation affect cell behavior including extracellular matrix production and migration. The mechanism behind this behavior is not fully understood. In this study, we fabricated micropatterned non-fouling polyethylene glycol (PEG) islands to mimic pores in order to decouple the effect of surface discontinuity from grip provided by pore wall edges. Similar to porous membranes, we found that the PEG islands hindered fibronectin fibrillogenesis with cells on patterned substrates producing shorter fibrils. Additionally, cell migration speed over micropatterned PEG islands was greater than unpatterned controls, suggesting that disruption of cell-substrate interactions by PEG islands promoted a more dynamic and migratory behavior, similarly to cells migrating on microporous membranes. Preferred cellular directionality during migration was nearly identical between substrates with identically patterned PEG islands and micropores, further confirming disruption of cell-substrate interactions as a common mechanism behind the cellular responses on these substrates. Interestingly, cell spreading and the magnitude of migration speed was significantly greater on porous membranes compared to PEG islands with identical feature size and spacing, suggesting pore edges enhanced cellular grip. These results provide a more complete picture on how porous membranes affect cells which are grown on them in an increasing number of cellular barrier and co-culture studies.
Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation
Authors: Stratton Matthew S. , Bagchi Rushita A. , Hirsch Rachel A. , Riching Andrew S. , Felisbino Marina B. , Enyart Blake Y. , Koch Keith A. , Cavasin Maria A. , Alexanian Michael , Song Kunhua , Qi Jun , Lemieux Madeleine E. , Lam Maggie P.Y. , Haldar Saptarsi M. , Lin Charles Y. , McKinsey Timothy A. 
Published: February 2019

AbstractSmall molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-β signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-β-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.