bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host identity and symbiotic association affects the genetic and functional diversity of the clownfish-hosting sea anemone microbiome
Authors: Titus Benjamin M. , Laroche Robert , Rodríguez Estefanía , Wirshing Herman , Meyer Christopher P. 
Published: August 2019

AbstractAll eukaryotic life engages in symbioses with a diverse community of bacteria that are essential for performing basic life functions. In many cases, eukaryotic organisms form additional symbioses with other macroscopic eukaryotes. The tightly-linked physical interactions that characterize many macroscopic symbioses creates opportunities for microbial transfer, which likely affects the diversity and function of individual microbiomes, and may ultimately lead to microbiome convergence between distantly related taxa. Here, we sequence the microbiomes of five species of clownfish-hosting sea anemones that co-occur on coral reefs in the Maldives. We test the importance of evolutionary history, clownfish symbiont association, and habitat on the genetic and predicted functional diversity of the microbiome, and explore signals of microbiome convergence in anemone taxa that have evolved symbioses with clownfishes independently. Our data indicate that host identity shapes the majority of the genetic diversity of the clownfish-hosting sea anemone microbiome, but predicted functional microbial diversity analyses demonstrate a convergence among host anemone microbiomes, which reflect increased functional diversity over individuals that do not host clownfishes. Further, we identify up-regulated microbial functions in host anemones that are likely affected by clownfish presence. Taken together our study reveals an even deeper metabolic coupling between clownfishes and their host anemones, and what could be a previously unknown mutualistic benefit to anemones that are symbiotic with clownfishes.
Inference of Gene Regulatory Network Uncovers the Linkage Between Circadian Clock and Crassulacean Acid Metabolism in Kalanchoë fedtschenkoi
Authors: Moseley Robert C. , Motta Francis , Tuskan Gerald A. , Haase Steve , Yang Xiaohan 
Published: August 2019

AbstractThe circadian clock drives time-specific gene expression, allowing for associated biological processes to be active during certain times of the 24 h day. Crassulacean acid metabolism (CAM) photosynthetic plants represent an interesting case of circadian regulation of gene expression as CO2 fixation and stomatal movement in CAM plants display strong circadian dynamics. The molecular mechanisms behind how the circadian clock enabled these physiological differences is not well understood. Therefore, we set out to investigate whether core circadian elements in CAM plants were re-phased during evolution, or whether networks of phase-specific genes were simply connected to different core elements. We utilized a new metric for identifying candidate core genes of a periodic gene network and then applied the Local Edge Machine (LEM) algorithm to infer regulatory relationships between the candidate core clock genes and orthologs of known core clock genes in K. fedtschenkoi. We also used LEM to identify stomata-related gene targets for K. fedtschenkoi core clock genes and constructed a subsequent gene regulatory network. Our results provide new insights into the mechanism of circadian control of CAM-related genes in K. fedtschenkoi, facilitating the engineering of CAM machinery into non-CAM plants for sustainable crop production in water-limited environments.
Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease
Authors: Purvis Gareth S. D. , Collino Massimo , Tavio Haidee M. A. , Chiazza Fausto , O’Riodan Caroline E. , Zeboudj Lynda , Guisot Nick , Bunyard Peter , Greaves David R. , Thiemermann Christoph 
Published: August 2019

AbstractActivation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Bruton’s tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3β pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-κB and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the pro-inflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1β and TNFα after LPS stimulation. In the present study we provide ‘proof of concept’ evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D.
Electrophysiological correlates of the flexible allocation of visual working memory resources
Authors: Salahub Christine , Lockhart Holly A. , Dube Blaire , Al-Aidroos Naseem , Emrich Stephen M. 
Published: August 2019

AbstractVisual working memory is a brief, capacity-limited store of visual information that is involved in a large number of cognitive functions. To guide one’s behavior effectively, one must efficiently allocate these limited memory resources across memory items. Previous research has suggested that items are either stored in memory or completely blocked from memory access. However, recent behavioral work proposes that memory resources can be flexibly split across items based on their level of task importance. Here, we investigated the electrophysiological correlates of flexible resource allocation by manipulating the distribution of resources amongst systematically lateralized memory items. We examined the contralateral delay activity (CDA), a waveform typically associated with the number of items held in memory. Across three experiments, we found that, in addition to memory load, the CDA flexibly tracks memory resource allocation. This allocation occurred as early as attentional selection, as indicated by the N2pc. Additionally, CDA amplitude was better-described when fit with a continuous model predicted by load and resources together than when fit with either alone. Our findings show that electrophysiological markers of attentional selection and memory maintenance not only track memory load, but also the proportion of memory resources those items receive.
Galanin inhibits visceral afferent responses to noxious mechanical and inflammatory stimuli
Authors: Taylor Toni S. , Konda Parvesh , John Sarah S. , Bulmer David C. , Hockley James R.F. , Smith Ewan St. John 
Published: August 2019

AbstractGalanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signalling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent inhibition of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, inhibits mechanosensitivity. The inhibitory effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulphate-induced colitis. We conclude that galanin has a marked inhibitory effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediator, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception from the bowel and the therapeutic potential of targeting galaninergic signalling to treat visceral hypersensitivity.Key point summaryGalanin inhibits visceral afferent mechanosensitivity to noxious phasic distension of the colon via GalR1.Galanin attenuates afferent mechanical hypersensitivity induced by the application of inflammatory mediators.Inhibition of afferent mechanosensitivity by galanin is not observed in tissues isolated from mice undergoing DSS-induced colitisGalanin inhibits the transmission of noxious mechanical stimuli by colonic afferents and its sensitisation by inflammatory mediators highlighting an antinociceptive role for galanin in the colon.
The enteric nervous system of the human and mouse colon at a single-cell resolution
Authors: Drokhlyansky Eugene , Smillie Christopher S. , Van Wittenberghe Nicholas , Ericsson Maria , Griffin Gabriel K. , Dionne Danielle , Cuoco Michael S. , Goder-Reiser Max N. , Sharova Tatyana , Aguirre Andrew J. , Boland Genevieve M. , Graham Daniel , Rozenblatt-Rosen Orit , Xavier Ramnik J. , Regev Aviv 
Published: August 2019

AbstractAs the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.
Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology
Authors: Naikawadi Ram P. , Green Gary , Jones Kirk D. , Achtar-Zadeh Natalia , Mieleszko Julia E. , Kukreja Jasleen , Greenland John , Wolters Paul J. 
Published: August 2019

ABSTRACTRationaleTelomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology.ObjectiveOur objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD.Methods and ResultsHistopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1F/F) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4-fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescence-associated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells.ConclusionsThese findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.
Disome-seq reveals widespread ribosome collisions that recruit co-translational chaperones
Authors: Zhao Taolan , Chen Yan-Ming , Li Yu , Wang Jia , Chen Siyu , Gao Ning , Qian Wenfeng 
Published: August 2019

ABSTRACTRegulation of translation elongation plays a crucial role in determining absolute protein levels and ensuring the correct localization and folding of proteins. Much of our knowledge regarding translation elongation comes from the sequencing of mRNA fragments protected by single ribosomes (ribo-seq). However, larger protected mRNA fragments have been observed, suggesting the existence of an alternative and previously hidden layer of regulation. In this study, we performed disome-seq to sequence mRNA fragments protected by two stacked ribosomes — a product of translational pauses during which the 5′-ribosome collides with the 3′-paused one. We detected widespread ribosome collisions that are missed in traditional ribo-seq. These collisions are due to 1) slow ribosome release when stop codons are at the A-site, 2) slow peptide bond formation from proline, glycine, asparagine, and cysteine when they are at the P-site, and 3) slow leaving of polylysine from the exit tunnel of ribosomes. The paused ribosomes can continue translating after collisions, as suggested by the structure of disomes obtained by cryo-electron microscopy (cryo-EM). Collided ribosomes recruit chaperones, which can aid in the co-translational folding of the nascent peptides. Therefore, cells use regulated ribosome collisions to ensure protein homeostasis.
Spatial Patterns for Discriminative Estimation
Authors: Llera Alberto , Chauvin Roselyne , Mulders Peter , Naaijen Jilly , Mennes Maarten , Beckmann Christian F. 
Published: August 2019

AbstractFunctional connectivity between brain regions is modulated by cognitive states or experimental conditions. A multivariate methodology that can capture fMRI connectivity maps in light of different experimental conditions would be of primary importance to learn about the specific roles of the different brain areas involved in the observed connectivity variations. Here we detail, adapt, optimize and evaluate a supervised dimensionality reduction model to fMRI timeseries. We demonstrate the strength of such an approach for fMRI data using data from the Human Connectome Project to show that the model provides close to perfect discrimination between different fMRI tasks at low dimensionality. The straightforward interpretability and relevance of the model results is demonstrated by the obtained linear filters relating to anatomical areas well known to be involved on each considered task, and its robustness by testing discriminatory generalization and spatial reproducibility with respect to the number of subjects and fMRI time-points acquired. We additionally suggest how such approach can provide a complementary view to traditional task fMRI analyses by looking at changes in the covariance structure as a substitute to changes in the mean signal. We conclude that the presented methodology provides a robust tool to investigate brain connectivity alterations across induced cognitive changes and has the potential to be used in pathological or pharmacological cohort studies. A publicly available toolbox is provided to facilitate the end use and further development of this methodology to extract Spatial Patterns for Discriminative Estimation (SP♠DE).
Genetic screens reveal a central role for heme biosynthesis in artemisinin susceptibility
Authors: Harding Clare R. , Sidik Saima M. , Petrova Boryana , Gnädig Nina F. , Okombo John , Ward Kurt E. , Markus Benedikt M. , Fidock David A. , Lourido Sebastian 
Published: August 2019

ABSTRACTArtemisinins have revolutionized the treatment ofPlasmodium falciparummalaria, however, resistance threatens to undermine global control efforts. To explore artemisinin resistance in apicomplexan parasites broadly, we used genome-scale CRISPR screens recently developed forToxoplasma gondiito discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncovered the putative porphyrin transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provided evidence that mitochondrial metabolism can modulate resistance. We show that disruption of a top candidate from the screens, the mitochondrial protease DegP2, lowered levels of free heme and decreased DHA susceptibility, without significantly altering fitness in culture. Deletion of the homologous gene inP. falciparum, PfDegP, similarly lowered heme levels and DHA susceptibility. These results expose the vulnerability of the heme biosynthetic pathway for genetic perturbations that can lead to survival in the presence of DHA. We go on to show that chemically reducing heme biosynthesis can decrease the sensitivity of bothT. gondiiandP. falciparumto DHA, suggesting guidelines for developing combination therapies.
Meiotic budding yeast assemble bundled triple helices but not ladders
Authors: Ma Olivia X. , Chong Wen Guan , Lee Joy K.E. , Cai Shujun , Siebert C. Alistair , Howe Andrew , Zhang Peijun , Shi Jian , Surana Uttam , Gan Lu 
Published: August 2019

AbstractIn meiosis, cells undergo two sequential rounds of cell division, termed meiosis I and meiosis II. Textbook models of the meiosis I substage called pachytene show that nuclei have conspicuous 100-nm-wide, ladder-like synaptonemal complexes (SC), which form between homologous chromosomes. It remains unknown if cells have any other large, meiosis-specific nuclear structures. Here we present cryo-ET analysis of frozen-hydrated budding yeast cells before, during, and after pachytene. We found no evidence for the dense ladder-like structures expected of the SC or the ordered chromatin loops expected to project from their sides. Instead, we found large quantities of 12-nm-wide triple-helices that pack into crystalline bundles. These structures are present in meiotic cells, but not in interphase cells, so we call them meiotic triple helices (MTHs). MTHs are enriched in the nucleus but not enriched in the cytoplasm. Bundles of MTHs form at the same time as SCs in wild-type cells and also in mutant cells that are unable to form SCs. These results suggest that in yeast, SCs are not crystalline and that they coexist with large, previously unreported meiotic machines.
NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression
Authors: Peñalosa-Ruiz Georgina , Mulder Klaas W. , Veenstra Gert Jan C. 
Published: August 2019

ABSTRACTReprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OSKM) in somatic cells such as mouse embryonic fibroblasts (MEFs). OSKM bind chromatin, silencing the somatic identity and starting the stepwise reactivation of the pluripotency program. However, inefficient suppression of the somatic lineage leads to unwanted epigenetic memory from the tissue of origin, even in successfully generated iPSCs. Thus, it is essential to shed more light on chromatin regulators and processes involved in dissolving the somatic identity. Recent work characterized the role of transcriptional co-repressors NCOR1 and NCOR2 (also known as NCoR and SMRT), showing that they cooperate with c-MYC to silence pluripotency genes during late reprogramming stages. NCOR1/NCOR2 were also proposed to be involved in silencing fibroblast identity, however it is unclear how this happens. Here, we shed light on the role of NCOR1 in early reprogramming. We show that siRNA-mediated ablation of NCOR1 and OCT4 results in very similar phenotypes, including transcriptomic changes and highly correlated high content colony phenotypes.. Both NCOR1 and OCT4 bind to promoters co-occupied by c-MYC in MEFs. During early reprogramming, downregulation of one group of somatic MEF-expressed genes requires both NCOR1 and OCT4, whereas another group of MEF-expressed genes is downregulated by NCOR1 but not OCT4. Our data suggest that NCOR1, assisted by OCT4 and c-MYC, facilitates transcriptional inactivation of genes with high expression in MEFs, which need to be suppressed to bypass an early reprogramming block. This way, NCOR1 facilitates early reprogramming progression.
Biphasic Response of Protein Kinase A to Cyclic Adenosine Monophosphate Triggers Distinct Epithelial Phenotypes
Authors: Fonseca João Pedro , Weinberg Zara Y. , Aslankoohi Elham , El-Samad Hana 
Published: August 2019

AbstractDespite the large diversity of the proteins involved in cellular signaling, many intracellular signaling pathways converge onto one of only dozens of small molecule second messengers. Cyclic adenosine monophosphate (cAMP), one of these second messengers, is known to regulate activity of both Protein Kinase A (PKA) and the Extracellular Regulated Kinase (ERK), among other signaling pathways. In its role as an important cellular signaling hub, intracellular cAMP concentration has long been assumed to monotonically regulate its known effectors.Using an optogenetictool that can introduce precise amounts of cAMP in MDCKI cells, we identify genes whose expression changes biphasically with monotonically increasing cAMP levels. By examining the behavior of PKA and ERK1/2 in the same dose regime, we find that these kinases also respond biphasically to increasing cAMP levels, with opposite phases. We reveal that this behavior results from an elaborate integration by PKA of many cellular signals triggered by cAMP. In addition to the direct activation of PKA, cAMP also modulates the activity of p38 and ERK, which then converge to inhibit PKA. These interactions and their ensuing biphasic PKA profile have important physiological repercussions, influencing the ability of MDCKI cells to proliferate and form acini. Our data, supported by computational modeling, synthesize a set of network interconnections involving PKA and other important signaling pathways into a model that demonstrates how cells can capitalize on signal integration to create a diverse set of responses to cAMP concentration and produce complex input-output relationships.