bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early-life Temperature Exposure Affects Thyroid Hormone Receptor Signaling and Epigenetic Regulation of the Paraventricular Nucleus in Female Rat Pups
Authors: Lauby Samantha C. , McGowan Patrick O. 
Published: May 2020

AbstractEarly-life maternal care received has a profound effect on later-life behaviour in adult offspring and previous studies have suggested epigenetic mechanisms (e.g., DNA methylation) are involved. Changes in thyroid hormone receptor signaling might be related to differences in maternal care received and DNA methylation modifications. We investigated the effects of two factors in the maternal environment, temperature exposure (a proxy of maternal contact) and licking-like tactile stimulation, on these processes in week-old female rat pups. We assessed thyroid hormone receptor signaling by measuring circulating triiodothyronine and transcript abundance of thyroid hormone receptors and the thyroid hormone-responsive genes DNA methyltransferase 3a and oxytocin in the paraventricular nucleus of the hypothalamus. DNA methylation of the oxytocin promoter was assessed in relation to changes in thyroid hormone receptor binding. Repeated room temperature exposure was associated with a decrease in thyroid hormone receptor signaling measures relative to nest temperature exposure, while acute room temperature exposure was associated with an increase. Repeated room temperature exposure also increased thyroid hormone receptor binding and DNA methylation at the oxytocin promoter. These findings suggest that repeated room temperature exposure may affect DNA methylation levels as a consequence of alterations in thyroid hormone receptor signaling.
Enhanced meningeal lymphatic drainage ameliorates neuroinflammation and hepatic encephalopathy in cirrhotic rats
Authors: Hsu Shao-Jung , Zhang Chihao , Jeong Jain , Lee Seong-il , McConnell Matthew , Utsumi Teruo , Iwakiri Yasuko 
Published: May 2020

AbstractBackground and aimsHepatic encephalopathy (HE) is a serious neurological complication in patients with liver cirrhosis. Nothing is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE.MethodsA 4-week bile duct ligation (BDL) model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated using archived GSE41919. Motor function of rats was assessed by the rotarod test. AAV8-VEGF-C was injected into the cisterna magna of BDL rats one day after surgery to induce meningeal lymphangiogenesis.ResultsCirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (p<0.001) as well as increased neuroinflammation as indicated by significant increases in IL-1β, INFγ, TNFα and Iba1 expression in at least one of the three regions of the cortex. Motor function was also impaired in rats with HE (p<0.05). Human brains of cirrhotic patients with HE also exhibited upregulation of pro-inflammatory genes (NF-κβ, Iba1, TNFα and IL-1β) (n=6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (p=0.035) and tracer dye uptake in the anterior and middle regions of the cortex (p=0.006 & 0.003, respectively), their corresponding meninges (p=0.086 & 0.006, respectively) and the draining lymph nodes (p=0.02). Further, AAV8-VEGF-C decreased microglia activation (p<0.001) and neuroinflammation, and ameliorated motor dysfunction (p=0.024).ConclusionPromoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.
Gliding motility ofPlasmodiummerozoites
Authors: Yahata Kazuhide , Hart Melissa N. , Davies Heledd , Asada Masahito , Wassmer Samuel C. , Templeton Thomas J. , Treeck Moritz , Moon Robert W. , Kaneko Osamu 
Published: May 2020

AbstractPlasmodiummalaria parasites are obligate intracellular protozoans that use a unique form of locomotion, termed gliding motility, to move through host tissues and invade cells. The process is substrate-dependent and powered by an actomyosin motor that drives the posterior translocation of extracellular adhesins which in turn propel the parasite forward. Gliding motility is essential for tissue translocation in the sporozoite and ookinete stages; however, the short-lived erythrocyte-invading merozoite stage has never been observed to undergo gliding movement. Here we showPlasmodiummerozoites possess the ability to undergo gliding motility and that this mechanism is likely an important precursor step for successful parasite invasion. We demonstrate that two human infective species,P. falciparumandP. knowlesi, have distinct merozoite motility profiles which may reflect distinct invasion strategies. Additionally, we develop and validate a higher throughput assay to evaluate the effects of genetic and pharmacological perturbations on both the molecular motor and complex signaling cascade that regulates motility in merozoites. The discovery of merozoite motility provides a new model to study the glideosome and may facilitate the pursuit of new targets for malaria treatment.Significance statementPlasmodiummalaria parasites use a unique substrate-dependent locomotion termed gliding motility to translocate through tissues and invade cells. Dogma has suggested that the small labile invasive stages that invade erythrocytes, merozoites, use this motility solely to penetrate target erythrocytes. Here we reveal that merozoites use gliding motility for translocation across host cells prior to invasion. This forms an important pre-invasion step that is powered by a conserved actomyosin motor and is regulated by a complex signaling pathway. This work fundamentally changes our understanding of the role of gliding motility and invasion in the blood and will have a significant impact on our understanding of blood stage host-pathogen interactions, parasite biology, and could have implications for vaccine development.
DNA methylation covariation in human whole blood and sperm: implications for studies of intergenerational epigenetic effects
Authors: Åsenius Fredrika , Gorrie-Stone Tyler J. , Brew Ama , Panchbaya Yasmin , Williamson Elizabeth , Schalkwyk Leonard C. , Rakyan Vardhman K. , Holland Michelle L. , Marzi Sarah J. , Williams David J. 
Published: May 2020

AbstractBackgroundEpidemiological studies suggest that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals suggest that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in matched human blood and sperm from lean (discovery n=47; replication n=21) and obese (n=22) males to analyse tissue covariation of DNA methylation, and identify whether this covariation is influenced by obesity.ResultsDNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (∼1%). While at the majority of these sites, DNA methylation appears to be influenced by genetic variation, obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity did not influence covariation patterns. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884;P=8.95 × 10−8; beta=0.02) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n=5,917), spermatozoa displayed differential DNA methylation in pathways enriched in transcriptional regulation.ConclusionsHuman sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. Obesity only nominally influences sperm DNA methylation, making it an unlikely mediator of intergenerational effects of metabolic traits.
A statistical framework for assessing pharmacological response and biomarkers using uncertainty estimates
Authors: Wang Dennis , Hensman James , Kutkaite Ginte , Toh Tzen S. ,   GDSC Screening Team, Dry Jonathan R , Saez-Rodriguez Julio , Garnett Mathew J. , Menden Michael P. , Dondelinger Frank 
Published: May 2020

AbstractDrug high-throughput screenings across large molecular-characterised cancer cell line panels enable the discovery of biomarkers, and thereby, cancer precision medicine. The ability to experimentally generate drug response data has accelerated. However, this data is typically quantified by a summary statistic from a best-fit dose response curve, whilst neglecting the uncertainty of the curve fit and the potential variability in the raw readouts. Here, we model the experimental variance using Gaussian Processes, and subsequently, leverage this uncertainty for identifying associated biomarkers with a new statistical framework based on Bayesian testing. Applied to the Genomics of Drug Sensitivity in Cancer,in vitroscreening data on 265 compounds across 1,074 cell lines, our uncertainty models identified 24 clinically established drug response biomarkers, and in addition provided evidence for 6 novel biomarkers. We validated our uncertainty estimates with an additional drug screen of 26 drugs, 10 cell lines with 8 to 9 replicates. Our method is applicable to drug high-throughput screens without replicates, and enables robust biomarker discovery for new cancer therapies.
Functional profiling of COVID-19 respiratory tract microbiomes
Authors: Haiminen Niina , Utro Filippo , Seabolt Ed , Parida Laxmi 
Published: May 2020

ABSTRACTIn response to the ongoing global pandemic, progress has been made in understanding the molecular-level host interactions of the new coronavirus SARS-CoV-2 responsible for COVID-19. However, when the virus enters the body it interacts not only with the host but also with the micro-organisms already inhabiting the host. Understanding the virus-host-microbiome interactions can yield additional insights into the biological processes perturbed by viral invasion. With this aim we carry out a functional analysis of previously published RNA sequencing data of bronchoalveolar lavage fluid from eight COVID-19 patients, twenty-five community-acquired pneumonia patients, and twenty healthy controls. The resulting microbiome functional profiles and their top differentiating features clearly separate the cohorts. By examining the functional features in connection with their associated metabolic pathways, differentially abundant pathways are indicated, compared to both the community-acquired pneumonia and healthy cohorts. From this analysis, distinguishing signatures in COVID-19 respiratory tract microbiomes are identified, including decreased lipid and glycan metabolism pathways, and increased carbohydrate metabolism pathways. Here we present a framework for comparative functional analysis of microbiomes, the results from which can lead to new hypotheses on the host-microbiome interactions in healthy versus afflicted cohorts. The findings from this analysis call for further research on microbial functions and host-microbiome interactions during SARS-CoV-2 infection.
Obesity-induced astrocyte dysfunction impairs heterosynaptic plasticity in the orbitofrontal cortex
Authors: Lau Benjamin K. , Murphy-Royal Ciaran , Kaur Manpreet , Qiao Min , Bains Jaideep S. , Gordon Grant R. , Borgland Stephanie L. 
Published: May 2020

SummaryOverconsumption of highly palatable, energy dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here we show that extended access to a cafeteria diet impairs astrocyte glutamate clearance, which leads to a heterosynaptic depression of GABA transmission onto pyramidal neurons of the OFC. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which acts via metabotropic glutamate receptors to liberate endocannabinoids. This impaired the induction of endocannabinoid-mediated long-term plasticity. In obese rats, this cascade of synaptic impairments was rescued by restoring astrocyte glutamate transport with the nutritional supplement, N-acetylcysteine. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the OFC.HighlightsDiet-induced obesity induces hypertrophy of astrocytes and impairs their ability to transport glutamate.Failure of astrocytes to clear extrasynaptic glutamate drives endocannabinoid-mediated inhibitory long-term depression of principal output neurons in the OFC.Astrocytic glutamate transporter function is restored with NAC, which rescues the synaptic deficits.
Long-TUC-seq is a robust method for quantification of metabolically labeled full-length isoforms
Authors: Rahmanian Sorena , Balderrama-Gutierrez Gabriela , Wyman Dana , McGill Cassandra Joan , Nguyen Kim , Spitale Robert , Mortazavi Ali 
Published: May 2020

ABSTRACTThe steady state expression of each gene is the result of a dynamic transcription and degradation of that gene. While regular RNA-seq methods only measure steady state expression levels, RNA-seq of metabolically labeled RNA identifies transcripts that were transcribed during the window of metabolic labeling. Whereas short-read RNA sequencing can identify metabolically labeled RNA at the gene level, long-read sequencing provides much better resolution of isoform-level transcription. Here we combine thiouridine-to-cytosine conversion (TUC) with PacBio long-read sequencing to study the dynamics of mRNA transcription in the GM12878 cell line. We show that using long-TUC-seq, we can detect metabolically labeled mRNA of distinct isoforms more reliably than using short reads. Long-TUC-seq holds the promise of capturing isoform dynamics robustly and without the need for enrichment.
Culturing of ‘Unculturable’ Subsurface Microbes: Natural Organic Carbon Source Fuels the Growth of Diverse and Distinct Bacteria from Groundwater
Authors: Wu Xiaoqin , Spencer Sarah , Gushgari-Doyle Sara , Yee Mon Oo , Voriskova Jana , Li Yifan , Alm Eric J. , Chakraborty Romy 
Published: May 2020

ABSTRACTThe recovery and cultivation of diverse field-related microorganisms from the terrestrial subsurface environment remains a challenge despite recent advances in modern molecular technology. Here we applied natural organic carbon (C), i.e., sediment-derived natural organic matter (NOM) and bacterial cell lysate, to groundwater microbial communities for a 30-day enrichment incubation, followed by conventional direct-plating for isolation. The groundwater was collected from a background well at the Oak Ridge Reservation Field Research Center, Tennessee. As a comparison, we also included enrichments amended with simple organic C sources, including glucose, acetate, benzoate, oleic acid, cellulose, and mixed vitamins. Our results demonstrate that complex natural organic C sources are more effective in enriching diverse bacterial species from groundwater than simple organic C sources. Microcosms amended with simple organic C (glucose, acetate, benzoate, or oleic acid) show significantly lower biodiversity than unamended control and are dominated by only few phyla such asProteobacteriaandBacteroidetes. In contrast, microcosms amended with complex natural organic C (sediment NOM or bacterial cell lysate) display significantly higher biodiversity, and enrich distinct species from the phyla that are poorly represented in published culture collections (e.g.,Verrucomicrobia, Planctomycetes, andArmatimonadetes). Our subsequent isolation efforts from natural organic C-amended enrichments led to 222 purified bacterial isolates representing 5 phyla, 16 orders, and 54 distinct species including candidate novel, rarely cultivated, and undescribed organisms.ImportanceInnovative strategies for recovering bacterial strains representing the true diversity of microbial communities in the terrestrial subsurface would significantly advance the understanding of ecologically critical taxa residing in these ecosystems. In this study, we demonstrate that complex natural organic C that mimic the naturally available resources for microbes encourages the growth of diverse bacteria much more robustly than traditional simplistic organic C sources. Results from this study will substantially advance and improve the design of strategies to effectively cultivate and isolate diverse and novel subsurface microorganisms in the laboratory. Obtaining axenic cultures of the ‘once-unculturable’ microorganisms will greatly enhance our understanding of microbial physiology, function, and roles in different biogeochemical niches in terrestrial subsurface ecosystems.
The mitotic protein NuMA plays a spindle-independent role in nuclear formation and mechanics
Authors: Serra-Marques Andrea , Houtekamer Ronja , Hintzen Dorine , Canty John T. , Yildiz Ahmet , Dumont Sophie 
Published: May 2020

AbstractEukaryotic cells typically form a single, round nucleus after mitosis, and failures to do so can compromise genomic integrity. How mammalian cells form such a nucleus remains incompletely understood. NuMA is a spindle protein whose disruption results in nuclear fragmentation. What role NuMA plays in nuclear integrity, or whether its perceived role stems from its spindle function, is unclear. Here, we use live imaging to demonstrate that NuMA plays a spindle-independent role in forming a single, round nucleus. NuMA keeps the decondensing chromosome mass compact at mitotic exit, and promotes a mechanically robust nucleus. NuMA’s C-terminus binds DNA in vitro and chromosomes in interphase, while its coiled-coil acts as a regulatory and structural hub: it prevents NuMA from binding chromosomes at mitosis, regulates its nuclear mobility and is essential for nuclear formation. Thus, NuMA plays a long-range structural role in building and maintaining an intact nucleus, as it does for the spindle, playing a protective role over the cell cycle.
Mutational landscape and in silico structure models of SARS-CoV-2 Spike Receptor Binding Domain reveal key molecular determinants for virus-host interaction
Authors: Nelson-Sathi Shijulal , Umasankar PK , Sreekumar E , Radhakrishnan Nair R , Joseph Iype , Nori Sai Ravi Chandra , Philip Jamiema Sara , Prasad Roshny , Navyasree KV , Ramesh Shikha , Pillai Heera , Ghosh Sanu , Santosh Kumar TR , Radhakrishna Pillai M. 
Published: May 2020

AbstractProtein-protein interactions between virus and host are crucial for infection. SARS-CoV-2, the causative agent of COVID-19 pandemic is an RNA virus prone to mutations. Formation of a stable binding interface between the Spike (S) protein Receptor Binding Domain (RBD) of SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) of host actuates viral entry. Yet, how this binding interface evolves as virus acquires mutations during pandemic remains elusive. Here, using a high fidelity bioinformatics pipeline, we analysed 31,403 SARS-CoV-2 genomes across the globe, and identified 444 non-synonymous mutations that cause 49 distinct amino acid substitutions in the RBD. Molecular phylogenetic analysis suggested independent emergence of these RBD mutants during pandemic. In silico structure modelling of interfaces induced by mutations on residues which directly engage ACE2 or lie in the near vicinity revealed molecular rearrangements and binding energies unique to each RBD mutant. Comparative structure analysis using binding interface from mouse that prevents SARS-CoV-2 entry uncovered minimal molecular determinants in RBD necessary for the formation of stable interface. We identified that interfacial interaction involving amino acid residues N487 and G496 on either ends of the binding scaffold are indispensable to anchor RBD and are well conserved in all SARS-like corona viruses. All other interactions appear to be required to locally remodel binding interface with varying affinities and thus may decide extent of viral transmission and disease outcome. Together, our findings propose the modalities and variations in RBD-ACE2 interface formation exploited by SARS-CoV-2 for endurance.ImportanceCOVID-19, so far the worst hit pandemic to mankind, started in January 2020 and is still prevailing globally. Our study identified key molecular arrangements in RBD-ACE2 interface that help virus to tolerate mutations and prevail. In addition, RBD mutations identified in this study can serve as a molecular directory for experimental biologists to perform functional validation experiments. The minimal molecular requirements for the formation of RBD-ACE2 interface predicted using in silico structure models may help precisely design neutralizing antibodies, vaccines and therapeutics. Our study also proposes the significance of understanding evolution of protein interfaces during pandemic.
Oral pyruvate prevents glaucomatous neurodegeneration
Authors: Williams Pete A , Harder Jeffrey M , Guymer Chelsea , Wood John P M , Daskalaki Evangelia , Chidlow Glyn , Cardozo Brynn H , Foxworth Nicole E , Cochran Kelly E , Ouellette Tionna B , Wheelock Craig E , Casson Robert J , John Simon W M 
Published: May 2020

AbstractIntraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.FundingVetenskapsrådet 2018-02124 and StratNeuro StartUp grant (PAW). Pete Williams is supported by the Karolinska Institutet in the form of a Board of Research Faculty Funded Career Position and by St. Erik Eye Hospital philanthropic donations. EY011721 and the Barbra and Joseph Cohen Foundation and startup funds from Columbia University (SWMJ). Simon John is an Investigator of HHMI.
Effective Dynamics of Nucleosome Configurations at the YeastPHO5Promoter
Authors: Wolff Michael Roland , Schmid Andrea , Korber Philipp , Gerland Ulrich 
Published: May 2020

AbstractChromatin dynamics are mediated by remodeling enzymes and play crucial roles in gene regulation, as established in a paradigmatic model, the yeastPHO5promoter. However, effective nucleosome dynamics, i.e. trajectories of promoter nucleosome configurations, remain elusive. Here, we infer such dynamics from the integration of published single-molecule data that capture multi-nucleosome configurations for repressed to fully activePHO5promoter states with other existing histone turnover and new chromatin accessibility data. We devised and systematically investigated a new class of “regulated on-off-slide” models simulating global and local nucleosome (dis)assembly and sliding. Only seven of 68 145 models agreed well with all data. All seven models involve sliding and the known central role of the N-2 nucleosome, but regulate promoter state transitions by modulating just one assembly rather than disassembly process. This is consistent with but challenges common interpretations of previous observations at thePHO5promoter and suggests chromatin opening by binding competitions.