bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian model selection favors parametric over categorical fMRI subsequent memory models in young and older adults
Authors: Soch Joram , Richter Anni , Schütze Hartmut , Kizilirmak Jasmin M. , Assmann Anne , Knopf Lea , Raschick Matthias , Schult Annika , Maass Anne , Ziegler Gabriel , Richardson-Klavehn Alan , Düzel Emrah , Schott Björn H. 
Published: July 2020

AbstractSubsequent memory paradigms allow to identify neural correlates of successful encoding by separating brain responses as a function of memory performance during later retrieval. In functional magnetic resonance imaging (fMRI), the paradigm typically elicits activations of medial temporal lobe, prefrontal and parietal cortical structures in young, healthy participants. This categorical approach is, however, limited by insufficient memory performance in older and particularly memory-impaired individuals. A parametric modulation of encoding-related activations with memory confidence could overcome this limitation. Here, we applied cross-validated Bayesian model selection (cvBMS) for first-level fMRI models to a visual subsequent memory paradigm in young (18-35 years) and older (51-80 years) adults. Nested cvBMS revealed that parametric models, especially with non-linear transformations of memory confidence ratings, outperformed categorical models in explaining the fMRI signal variance during encoding. We thereby provide a framework for improving the modeling of encoding-related activations and for applying subsequent memory paradigms to memory-impaired individuals.
Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution
Authors: Higgs M. J. , Hill M. J. , John R. M. , Isles A. R. 
Published: July 2020

ABSTRACTBackgroundAlthough a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels.ResultsWe established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examined brain-wide datasets to test enrichment within distinct brain regions and neuron subpopulations and demonstrated over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we identified hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression.ConclusionsThese analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted gene expression converges. Our findings indicate the neuronal regulation of motivated behaviours such as feeding and sleep, alongside the regulation of pituitary function as functional hotspots for imprinting, thus adding statistical rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.
ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma
Authors: Sheybani Natasha D. , Paul Soumen , McCauley Katelyenn S. , Breza Victoria R. , Berr Stuart S. , Miller G. Wilson , Neumann Kiel D. , Price Richard J. 
Published: July 2020

AbstractPhagocytic immunotherapies such as CD47 blockade have emerged as promising strategies for glioblastoma (GB) therapy, but the blood brain/tumor barriers (BBB/BTB) pose a persistent challenge for mCD47 delivery that can be overcome by focused ultrasound (FUS)-mediated BBB/BTB disruption. We here leverage immuno-PET imaging to determine how timing of [89Zr]-mCD47 injection relative to FUS impacts antibody penetrance into orthotopic murine gliomas. We then design and implement a rational paradigm for combining FUS and mCD47 for glioma therapy. We demonstrate that timing of antibody injection relative to FUS BBB/BTB disruption is a critical determinant of mCD47 access, with post-FUS injection conferring superlative antibody delivery to gliomas. We also show that mCD47 delivery across the BBB/BTB with repeat sessions of FUS can significantly constrain tumor outgrowth and extend survival in glioma-bearing mice. This study generates provocative insights for ongoing pre-clinical and clinical evaluations of FUS-mediated antibody delivery to brain tumors. Moreover, our results confirm that mCD47 delivery with FUS is a promising therapeutic strategy for GB therapy.
Hello darkness, my old friend: 3-Ketoacyl-Coenzyme A Synthase4 is a branch point in the regulation of triacylglycerol synthesis inArabidopsis thaliana
Authors: Luzarowska Urszula , Ruß Anne-Kathrin , Joubès Jérôme , Batsale Marguerite , Szymański Jędrzej , Thirumalaikumar Venkatesh Periyakavanam , Luzarowski Marcin , Wu Si , Zhu Feng , Endres Niklas , Khedhayir Sarah , Schumacher Julia , Jasinska Weronika , Xu Ke , Correa Cordoba Sandra Marcela , Weil Simy , Skirycz Aleksandra , Fernie Alisdair Robert , Li-Beisson Yonghua , Fusari Corina Mariana , Brotman Yariv 
Published: July 2020

AbstractDue to their sessile lifestyle, plants have evolved unique mechanisms to deal with environmental challenges. Under stress, plant lipids are important as alternative sources of carbon and energy when sugars or starch are limited. Here, we applied combined heat and darkness and extended darkness to a panel of ∼ 300 Arabidopsis accessions to study lipid remodeling under carbon starvation. Natural allelic variation at3-KETOACYL-COENZYME A SYNTHASE4(KCS4), a gene encoding for an enzyme involved in very long chain fatty-acid (VLCFA) synthesis, underlies a differential accumulation of polyunsaturated triacylglycerols (puTAGs) under stress. Ectopic expression in yeast and plants proved that KCS4 is a functional enzyme localized in the ER with specificity for C22 and C24 saturated acyl-CoA. Allelic mutants and transient overexpressionin plantarevealed the differential role ofKCS4alleles in VLCFA synthesis and wax coverage, puTAG accumulation and biomass. Moreover, the region harboringKCS4is under high selective pressure and allelic variation atKCS4correlated with environmental parameters from the locales of Arabidopsis accessions. Our results provide evidence that KCS4 plays a decisive role in the subsequent fate of fatty acids released from chloroplast-membrane lipids under carbon starvation. This work sheds light on both plant response mechanisms and the evolutionary events shaping the lipidome under carbon starvation.One sentence summaryNatural variation atKCS4underlies a differential accumulation of polyunsaturated triacylglycerols under carbon starvation, by acting as a regulatory branch point in the fate of fatty acids.
Mutagenicity of folic acid deficiency and supplementation is tissue-specific and results in distinct mutation profiles
Authors: Diaz G. Stephanie , LeBlanc Danielle P. , Gagné Remi , Behan Nathalie A. , Wong Alex , Marchetti Francesco , MacFarlane Amanda J. 
Published: July 2020

AbstractCancer incidence varies by tissue due to differences in environmental risk factor exposure, gene variant inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia. Conversely, high folic acid (FA) intake has been associated with higher CRC risk. However, the mutagenic potential of FA intake in different tissues has not been characterized. Here we quantified mutations in folate-susceptible somatic tissues, namely bone marrow and colon, from the same MutaMouse mice and determined the FA-induced mutation profiles of both tissues using next generation sequencing. FA-induced mutagenesis was tissue- and dose-specific: FA deficiency increased mutant frequency (MF) in bone marrow while FA supplementation increased MF in colon. Analyses of mutation profiles suggested that FA interacted with mutagenic mechanisms that are unique to each tissue. These data illuminate potential mechanisms underpinning differences in susceptibility to FA-related cancers.
DehydratedCaenorhabditis elegansstocks are resistant to multiple freeze-thaw cycles
Authors: McClanahan Patrick D. , McCloskey Richard J. , Hing Melanie Ng Tung , Raizen David M. , Fang-Yen Christopher 
Published: July 2020

ABSTRACTUltracold preservation is widely used for storage of genetic stocks ofCaenorhabditis elegans. Current cryopreservation protocols are vulnerable to refrigeration failures, which can result in the loss of stock viability due to damage during re-freezing. Here we present a method for preserving worms in a dehydrated and frozen form that retains viability after multiple freeze/thaw cycles. After dehydration in the presence of trehalose or glycerol,C. elegansstocks can be frozen and thawed multiple times while maintaining viability. While both dauer and non-dauer larvae survive desiccation and freezing, the dauer defective mutantdaf-16does not survive desiccation. Our technique is useful for storing stocks in a manner robust to freezer failures, and potentially for shipping strains between laboratories.
High resolution mouse subventricular zone stem cell niche transcriptome reveals features of lineage, anatomy, and aging
Authors: Xie Xuanhua P. , Laks Dan R. , Sun Daochun , Poran Asaf , Laughney Ashley M. , Wang Zilai , Sam Jessica , Belenguer German , Fariñas Isabel , Elemento Olivier , Zhou Xiuping , Parada Luis F. 
Published: July 2020

AbstractAdult neural stem cells (NSC) serve as a reservoir for brain plasticity and origin for certain gliomas. Lineage tracing and genomic approaches have portrayed complex underlying heterogeneity within the major anatomical location for NSC, the subventricular zone (SVZ). To gain a comprehensive profile of NSC heterogeneity, we utilized a well validated stem/progenitor specific reporter transgene in concert with single cell RNA sequencing to achieve unbiased analysis of SVZ cells from infancy to advanced age. The magnitude and high specificity of the resulting transcriptional data sets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia), and non-central nervous system cells (endothelial, immune). Initial mining of the data delineates four quiescent NSC and three progenitor cell subpopulations formed in a linear progression. Further evidence indicates that distinct stem and progenitor populations reside in different regions of the SVZ. As stem/progenitor populations progress from neonatal to advanced age, they acquire a deficiency in transition from quiescence to proliferation. Further data mining identifies stage specific biological processes, transcription factor networks, and cell surface markers for investigation of cellular identities, lineage relationships, and key regulatory pathways in adult NSC maintenance and neurogenesis.Significance StatementAdult neural stem cells (NSC) are closely related to multiple neurological disorders and brain tumors. Comprehensive investigation of their composition, lineage, and aging will provide new insights that may lead to enhanced patient treatment. This study applies a novel transgene to label and manipulate neural stem/progenitor cells, and monitor their evolution during aging. Together with high-throughput single cell RNA sequencing, we are able to analyze the subventricular zone (SVZ) cells from infancy to advanced age with unprecedented granularity. Diverse new cell states are identified in the stem cell niche, and an aging related NSC deficiency in transition from quiescence to proliferation is identified. The related biological features provide rich resources to inspect adult NSC maintenance and neurogenesis.
CelLEVITAS: Label-free rapid sorting and enrichment of live cells via magnetic levitation
Authors: Chin Elliot K. , Grant Colin A. , Ogut Mehmet Giray , Cai Bocheng , Durmus Naside Gozde 
Published: July 2020

AbstractSorting methods that remove non-viable cells and debris, while retaining a high yield of viable cells, are crucial for many applications in biotechnology, genomics, tissue engineering and medicine. However, a significant challenge is gentle sorting of these different cell states based on very minute differences in density and magnetic signatures, without relying on any labels, tags or markers. Here, a new magnetic levitation-based technology, CelLEVITAS, is developed for the label-free sorting and enrichment of live cells. This work reports the first use of magnetic levitation for sorting of viable and non-viable cells within a microfluidic device and demonstrates extremely effective removal of dead cells and debris from heterogeneous samples. First, the levitation conditions for separating viable and non-viable cells under a magnetic field were fine-tuned. Levitation trajectories of live and dead cell states were then monitored in real-time, as cells magnetically focused to their corresponding levitation bands. CelLEVITAS successfully sorted and enriched live cells from a variety of input cell concentrations (100-200,000 cells/mL) and a variety of input purities (10-50%) into consistently high output purities (>80%). This method is sensitive, does not impair cell viability during sorting, and significantly increases the input sample viability up to 7-fold. Overall, this new magnetic levitation-based sorting strategy drastically reduces the processing time to a single-step, 30-minute sorting protocol and eliminates the manual pre-processing and labeling steps that are required for traditional flow cytometry techniques.
Insights into the catalytic properties of the mitochondrial rhomboid protease PARL
Authors: Lysyk Laine , Brassard Raelynn , Arutyunova Elena , Siebert Verena , Jiang Zhenze , Takyi Emmanuella , Morrison Melissa , Young Howard S. , Lemberg Marius K. , O’Donoghue Anthony J. , Lemieux M. Joanne 
Published: July 2020

AbstractThe rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac, which have crucial roles in mitochondrial quality control and apoptosis. To gain insight into the catalytic properties of the PARL protease, we expressed human PARL in yeast and used FRET-based kinetic assays to measure proteolytic activityin vitro. We show PARL activity in detergent is enhanced by cardiolipin. Significantly higher turnover rates are observed for PARL reconstituted in proteoliposomes, with Smac being cleaved most rapidly at a rate of 1 min−1. PGAM5 is cleaved with the highest efficiency compared to PINK1 and Smac. In proteoliposomes, a truncated β-cleavage form of PARL is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5 and Smac. Multiplex substrate profiling reveals a substrate preference for PARL with a bulky side chain Phe in P1, which is distinct from small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences.
Low Dose Lead Exposure Induces Alterations on Heterochromatin Hallmarks Persisting Through SH-SY5Y Cell Differentiation
Authors: Lin Li , Xie Junkai , Sanchez Oscar F. , Bryan Chris , Freeman Jennifer , Yuan Chongli 
Published: July 2020

ABSTRACTLead (Pb) is a commonly found heavy metal due to its historical applications. Recent studies have associated the early-life Pb exposure with the onset of various neurodegenerative disease. The molecular mechanisms of Pb conferring long-term neurotoxicity, however, is yet to be elucidated. In this study, we explored the persistency of alteration in epigenetic marks that arise from exposure to low dose of Pb using a combination of image-based and gene expression analysis. Using SH-SY5Y as a model cell line, we observed significant alterations in global 5-methycytosine (5mC) and histone 3 lysine 27 tri-methylation (H3K27me3) and histone 3 lysine 9 tri-methylation (H3K9me3) levels in a dose-dependent manner immediately after Pb exposure. The changes are partially associated with alterations in epigenetic enzyme expression levels. Long term culturing (14 days) after cease of exposure revealed persistent changes in 5mC, partial recovery in H3K9me3 and overcompensation in H3K27me3 levels. The observed alterations in H3K9me3 and H3K27me3 are reversed after neuronal differentiation, while reduction in 5mC levels are amplified with significant changes in patterns as identified via texture clustering analysis. Moreover, correlation analysis demonstrates a strong positive correlation between trends of 5mC alteration after differentiation and neuronal morphology. Collectively, our results suggest that exposure to low dose of Pb prior to differentiation can result in persistent epigenome alterations that can potentially be responsible for observed phenotypic changes.
The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-biofilm Drugs
Authors: Hall Donald C. , Król Jarosław E. , Cahill John P. , Ji Hai-Feng , Ehrlich Garth D. 
Published: July 2020

AbstractBiofilm infections have no effective medical treatments and can only be disrupted via physical means. This means that any biofilm infection that is not addressable surgically can never be eliminated and can only be managed as a chronic disease. Therefore, there is an urgent need for the development of new classes of drugs that can target the metabolic mechanisms within biofilms which render them recalcitrant to traditional antibiotics. This antibiotic recalcitrance of bacterial biofilms can be attributed largely to the formation of persister cells within the biofilm structure. These biofilm persister cells can be resistant to up to 1000 times the minimal inhibitory concentrations of many antibiotics as compared to their planktonic envirovars; they are thought to be the prokaryotic equivalent of metazoan stem cells. Their metabolic resistance has been demonstrated to be an active process induced by the stringent response that is triggered by the ribosomally-associated enzyme RelA in response to amino acid starvation. This 84-kD pyrophosphokinase produces the “magic spot” alarmones, collectively called (p)ppGpp. These alarmones act by directly regulating transcription by binding to RNA polymerase. These transcriptional changes lead to a major shift in cellular function to both upregulate oxidative stress-combating enzymes and down regulate major cellular functions associated with growth and replication. These changes in gene expression produce the quiescent persister cells. In this work, we describe a hybridin silico-laboratory pipeline for identifying and validating small-molecule inhibitors of RelA for use in the combinatorial treatment of bacterial biofilms as re-potentiators of classical antibiotics.
Mechanistic modelling of coronavirus infections and the impact of confined neighbourhoods on a short time scale
Authors: Ahmed Danish A , Ansari Ali R , Imran Mudassar , Dingle Kamaludin , Ahmed Naveed , Bonsall Michael B 
Published: July 2020

AbstractBackgroundTo mitigate the spread of the COVID-19 coronavirus, some countries have adopted more stringent non-pharmaceutical interventions in contrast to those widely used (for e.g. the state of Kuwait). In addition to standard practices such as enforcing curfews, social distancing, and closure of non-essential service industries, other non-conventional policies such as the total confinement of highly populated areas has also been implemented.MethodsIn this paper, we model the movement of a host population using a mechanistic approach based on random walks, which are either diffusive or super-diffusive. Infections are realised through a contact process, whereby a susceptible host may be infected if in close spatial proximity of the infectious host. Our focus is only on the short-time scale prior to the infectious period, so that no further transmission is assumed.ResultsWe find that the level of infection depends heavily on the population dynamics, and increases in the case of slow population diffusion, but remains stable for a high or super-diffusive population. Also, we find that the confinement of homogeneous or overcrowded sub-populations has minimal impact in the short term.ConclusionsOur results indicate that on a short time scale, confinement restrictions or complete lock down of whole residential areas may not be effective. Finally, we discuss the possible implications of our findings for total confinement in the context of the current situation in Kuwait.
Multimorbidity patterns among COVID-19 deaths: considerations for a better medical practice
Authors: Fernández-Niño Julián A. , Guerra-Gómez John A. , Idrovo Alvaro J. 
Published: July 2020

AbstractMedical care of individuals diagnosed with severe COVID-19 is complex, especially when patients are older adults with multimorbidity. The objective of this study was to describe patterns of multimorbidity among fatal cases of COVID-19. Data of Colombian confirmed deaths of COVID-19 until June 11, 2020, were included in this analysis (1488 deaths). Relationships between COVID-19, combinations of health conditions and age were explored using locally weighted polynomial regressions. Some multimorbidity patterns increase probability of death among older individuals, whereas other patterns are not age-related, or decreases the probability of death among older people. Consider multimorbidity in the medical management of COVID-19 patients is important to determine the more adequate medical interventions. In addition to the co-occurrence of COVID-19 with diseases of high prevalence in the world, in Colombia there are cases more complex with COVID-19 co-occur with endemic and orphan tropical diseases. In these cases, although its occurrence may be low, clinical management requires adjusting to its complex clinical condition.