bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurotrophic Factor-Laden Acellular Chondroitin Sulfate Scaffolds Promote Chronic Functional Recovery After Severe Traumatic Brain Injury
Authors: Latchoumane Charles-Francois V. , Betancur Martha I. , Simchick Gregory A. , Sun Min Kyoung , Forghani Rameen , Lenear Christopher E. , Ahmed Aws , Mohankumar Ramya , Balaji Nivedha , Mason Hannah D. , Holmes Philip V. , Zhao Qun , Bellamkonda Ravi V. , Karumbaiah Lohitash 
Published: June 2020

ABSTRACTSevere traumatic brain injury (sTBI) survivors experience permanent functional disabilities due to significant volume loss and the brain’s poor capacity to regenerate. Chondroitin sulfate glycosaminoglycans (CS-GAGs) are key regulators of growth factor signaling and neural stem cell homeostasis in the brain. However, the efficacy of engineered CS (eCS) matrices in mediating structural and functional recovery after sTBI has not been investigated. We report that neurotrophic factor functionalized acellular eCS matrices implanted into the rat M1 region acutely post-sTBI, significantly enhanced cellular repair and gross motor function recovery when compared to controls, 20 weeks post-sTBI. Animals subjected to M2 region injuries followed by eCS matrix implantations, demonstrated the significant recovery of ‘reach-to-grasp’ function. This was attributed to enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity. These findings indicate that eCS matrices implanted acutely post-sTBI can support complex cellular, vascular, and neuronal circuit repair, chronically after sTBI.
Dihydroxyacetone phosphate signals glucose availability to mTORC1
Authors: Orozco Jose M. , Krawczyk Patrycja A. , Scaria Sonia M. , Cangelosi Andrew L. , Chan Sze Ham , Kunchok Tenzin , Lewis Caroline A. , Sabatini David M. 
Published: June 2020

AbstractIn response to nutrients, the mTOR complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose, which provide the building blocks for the biosynthesis of most macromolecules. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells to identify glucose-derived metabolites required to activate mTORC1. We find that mTORC1 senses a metabolite downstream of the aldolase and upstream of the glyceraldehyde 3-phosphate dehydrogenase steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from dihydroxyacetone is sufficient to activate mTORC1 even in the absence of glucose. Genetic perturbations in the GATOR-Rag signaling axis abrogate glucose sensing by mTORC1. DHAP is the glycolytic metabolite along with glyceraldehyde 3-phosphate (GAP) that has the greatest fold-change between cells in high and low glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.
Development of zygotic and germline gene drives in mice
Authors: Pfitzner Chandran , Hughes James , White Melissa , Scherer Michaela , Piltz Sandra , Thomas Paul 
Published: June 2020

AbstractCRISPR-based synthetic gene drives have the potential to deliver a more effective and humane method of invasive vertebrate pest control than current strategies. Relatively efficient CRISPR gene drives have been developed in insects and yeast but not in mammals. Here we investigated the efficiency of CRISPR/Cas9-based gene drives in Mus musculus by constructing “split drive” systems with Cas9 under the control of zygotic (CAG) or germline (Vasa) promoters. While both systems generated double stranded breaks at their intended target site in vivo, no homing was detectable. Our data indicate that robust and specific Cas9 expression during meiosis is a critical requirement for the generation of efficient CRISPR-based synthetic gene drives in rodents.
Non-selective cation permeation in an AMPA-type glutamate receptor
Authors: Biedermann Johann , Braunbeck Sebastian , Plested Andrew J. R. , Sun Han 
Published: June 2020

AbstractFast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a non-selective cation channel which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamics (MD) simulations on a putative open state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+and Cs+permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+and K+in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a cone- shaped void that lacked major interactions with ions. We observed Cl-invasion of the upper pore, explaining anion permeation in the edited form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, non-selective cation permeation, and co-permeation by water. Simulations suggested Cs+uses two equally populated ion binding sites in the filter and we confirmed with electrophysiology of GluA2 that Cs+is more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.Significance StatementAMPA-type glutamate receptors (AMPARs) are key actors in neurotransmission, making the final step in a relay of excitability from one brain cell to another. The receptor contains an integral ion channel, which, when opened by neurotransmitter binding, permits sodium and other cations to cross the cell membrane. We investigated permeation of sodium, potassium and caesium in an AMPAR at the atomistic level using a computational molecular dynamics approach on a structure with the ion channel pore in a presumably open state. We determined that the region selecting between cations is the simplest of any channel of this type. Distinct from ion channels that select single ion species, cations are never fully dehydrated and have only one major ion binding site in the filter. Simulations suggested two similar binding sites for caesium, and studies of AMPARs in mammalian cell membranes showed that this makes caesium more permeant than sodium.
3D reconstruction of odontoblast processes of the mouse molar and incisor
Authors: Shuhaibar Ninna , Hand Arthur R. , Terasaki Mark 
Published: June 2020

AbstractOdontoblast processes are thin cytoplasmic projections that extend from the cell body at the periphery of the pulp toward the dentin-enamel junction. The odontoblast processes function in the secretion and assembly of dentin during development, participate in mechanosensation, and aid in dentin repair in mature teeth. Because they are small and densely arranged, their three-dimensional organization is not well documented. To gain further insight into how odontoblast processes contribute to odontogenesis, we used serial section electron microscopy to examine these processes in the predentin region of mouse molars and incisors. In molars, the odontoblast processes are tubular with a diameter of ~1.8 μm. The odontoblast processes near the incisor tip are similarly shaped, but those midway between the tip and apex are shaped like plates. The plates are radially aligned and longitudinally oriented with respect to the growth axis of the incisor. The thickness of the plates is approximately the same as the diameter of molar odontoblast processes. The plates have an irregular edge; the average ratio of width (midway in the predentin) to thickness is 2.3 on the labial side and 3.6 on the lingual side. The plate geometry seems likely to be related to the continuous growth of the incisor and may provide a clue as to the mechanisms by which the odontoblast processes are involved in tooth development.
Statistical Pitfalls in Brain Age Analyses
Authors: Butler Ellyn R. , Chen Andrew , Ramadan Rabie , Le Trang T. , Ruparel Kosha , Moore Tyler M. , Satterthwaite Theodore D. , Zhang Fengqing , Shou Haochang , Gur Ruben C. , Nichols Thomas E. , Shinohara Russell T. 
Published: June 2020

AbstractOver the past decade, there has been an abundance of research on the difference between age and age predicted using brain features, which is commonly referred to as the “brain age gap”. Researchers have identified that the brain age gap, as a linear transformation of an out-of-sample residual, is dependent on age. As such, any group differences on the brain age gap could simply be due to group differences on age. To mitigate the brain age gap’s dependence on age, it has been proposed that age be regressed out of the brain age gap. If this modified brain age gap (MBAG) is treated as a corrected deviation from age, model accuracy statistics such asR2will be artificially inflated. Given the limitations of proposed brain age analyses, further theoretical work is warranted to determine the best way to quantify deviation from normality.HighlightsThe brain age gap is an out-of-sample residual, and as such varies as a function of age.A recently proposed modification of the brain age gap, designed to mitigate the dependence on age, results in inflated model accuracy statistics if used incorrectly.Given these limitations, we suggest that new methods should be developed to quantify deviation from normal developmental and aging trajectories.
Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells
Authors: Neavin Drew , Nguyen Quan , Daniszewski Maciej S. , Liang Helena H. , Chiu Han Sheng , Senabouth Anne , Lukowski Samuel W , Crombie Duncan E. , Lidgerwood Grace E. , Hernández Damián , Vickers James C. , Cook Anthony L. , Palpant Nathan J. , Pébay Alice , Hewitt Alex W. , Powell Joseph E. 
Published: June 2020

AbstractThe discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) - cells that can be differentiated into any cell type of the three germ layers - has provided a foundation forin vitrohuman disease modelling1,2, drug development1,2, and population genetics studies3,4. In the majority of instances, the expression levels of genes, plays a critical role in contributing to disease risk, or the ability to identify therapeutic targets. However, while the effect of the genetic background of cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of individual cells. Differences in the effect of genetic variation on the gene expression of different cell-types, would provide significant resolution for in vitro research using preprogramed cells. By bringing together single cell RNA sequencing15–21and population genetics, we now have a framework in which to evaluate the cell-types specific effects of genetic variation on gene expression. Here, we performed single cell RNA-sequencing on 64,018 fibroblasts from 79 donors and we mapped expression quantitative trait loci (eQTL) at the level of individual cell types. We demonstrate that the large majority of eQTL detected in fibroblasts are specific to an individual sub-type of cells. To address if the allelic effects on gene expression are dynamic across cell reprogramming, we generated scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type specific eQTL in iPSCs, and show that that the eQTL in fibroblasts are almost entirely disappear during reprogramming. This work provides an atlas of how genetic variation influences gene expression across cell subtypes, and provided evidence for patterns of genetic architecture that lead to cell-types specific eQTL effects.
Exposure to artificial light at night accelerates but does not override latitude-dependent seasonal reproductive response in dark-eyed juncos
Authors: Singh D. , Montoure J. , Ketterson E.D. 
Published: June 2020

AbstractIn the modern era of industrialization, illuminated nights have become a common defining feature of human-occupied environments, particularly cities. Artificial light at night (ALAN) imposes several known negative impacts on the neuroendocrine system, metabolism, and seasonal reproduction of species living in the wild. However, we know little about the impact of ALAN on populations of birds that either live year-round in the same location or move to different latitudes across seasons. To test whether ALAN has differing impact on reproductive timing of the bird populations that winter in sympatry but breed at different latitudes, we monitored sedentary and migratory male dark-eyed juncos that were or were not exposed to low intensity (~2.5 ± 0.5 lux) ALAN. All groups were held in common conditions and day length was gradually increased to mimic natural day length changes (NDL). We assessed seasonal reproductive response from initiation to termination of the breeding cycle. As expected based on earlier research, the sedentary birds exhibited earlier gonadal recrudescence and terminated breeding later than the migratory birds. In addition, resident and migrant birds exposed to ALAN initiated gonadal recrudescence earlier and terminated reproduction sooner as compared to their conspecifics experiencing NDL. Importantly, the difference in the reproductive timing of sedentary and migratory populations was maintained even when exposed to ALAN. This variation in the seasonal reproductive timing may likely have a genetic ground or early developmental effects imposed due to different latitude of origin. This study reveals first that latitude-dependent variation in reproductive timing is maintained despite exposure to ALAN, and second that ALAN accelerated reproductive development across both migrants and residents. The results corroborating relationship between latitude, population, and ALAN impact on seasonal reproductive timing, may provide a potential mechanism to test the fitness of a population and its range expansion to exploit urban environment.
Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs
Authors: Ku Yongsuk , Park Joo-Hwan , Cho Ryeongeun , Lee Yongki , Park Hyoung-Min , Kim MinA , Hur Kyunghoon , Byun Soo Young , Liu Jun , Shum David , Shin Dong-Yeop , Koh Youngil , Cho Je-Yoel , Yoon Sung-Soo , Hong Junshik , Kim Yoosik 
Published: June 2020

SUMMARY5-Aza-2′-deoxycytidine, also known as decitabine, is a DNA-methyltransferase inhibitor (DNMTi) used to treat acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERV), which can induce an immune response by acting as cellular double-stranded RNAs (dsRNAs). Here, we employ an image-based screening platform to identify dsRNA-binding factors that mediate the downstream effect of ERV induction. We find that Staufen1 (Stau1) knockdown decreases the interferon signature and rescues decitabine-mediated cell death. Moreover, Stau1 directly binds to ERV RNAs and stabilizes them, together with a long non-coding RNA TINCR. We further show that TINCR enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that AML patients with low Stau1 and TINCR expressions exhibits inferior treatment outcomes to the DNMTi therapy. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA-binding proteins for access to their common dsRNA targets.HIGHLIHGTSImage-based RNAi screening reveals multiple dsRBPs regulate response to decitabineStau1 binds to ERV RNAs and affects their stability and subcellular localizationTINCR binds to Stau1 and enhances Stau1-ERV interactionsAML/MDS patients with low Stau1 and TINCR expressions show poor response to DNMTis
Statins attenuate antiviral IFN-β and ISG expression via inhibiting IRF3/JAK/STAT signaling in poly(I:C)-treated hyperlipidemic mice and macrophages
Authors: Koike Atsushi , Tsujinaka Kaito , Fujimori Ko 
Published: June 2020

AbstractViral infection is a significant burden to healthcare worldwide. Statins, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, are widely used as cholesterol-lowering drugs. Recently, long term statin therapy was shown to reduce the antiviral immune response; however, the underlying molecular mechanisms are unclear. Here, we found that simvastatin decreased polyinosinic-polycytidylic acid [poly(I:C)]-induced expression of antiviral interferon (IFN)-β and IFN-stimulated genes (ISGs) in the bronchoalveolar lavage fluid and lungs of mice with high-fat diet-induced hyperlipidemia. As macrophages were the dominant cell type in the bronchoalveolar lavage fluid of poly(I:C)-treated mice, we examined the molecular mechanisms of statin-mediated inhibition of antiviral gene expression using murine J774.1/JA-4 macrophages. Simvastatin and pitavastatin decreased poly(I:C)-induced expression of IFN-β and ISGs. Moreover, they repressed poly(I:C)-induced phosphorylation of IFN regulatory factor (IRF) 3 and signal transducers and activators of transcription (STAT) 1, which is involved in Janus kinase (JAK)/STAT signaling. Mevalonate and geranylgeranylpyrophosphate (GGPP), but not cholesterol, counteracted the negative effect of statins on IFN-β and ISG expression and phosphorylation of IRF3 and STAT1. These results suggest that statins suppressed the expression of IFN-β and ISGs in poly(I:C)-treated hyperlipidemic mice and murine macrophages, and that these effects occured through the inhibition of IRF3-mediated JAK/STAT signaling in macrophages. Furthermore, GGPP recovered the statin-suppressed IRF3/JAK/STAT signaling pathway in poly(I:C)-treated macrophages.
Absence of heme at the catalytic site of heme oxygenase-2 triggers its lysosomal degradation
Authors: Liu Liu , Dumbrepatil Arti B. , Fleischhacker Angela S. , Marsh E. Neil G. , Ragsdale Stephen W. 
Published: June 2020

ABSTRACTHeme oxygenase-2 (HO2) and −1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. While transcriptional control of HO1 expression has been well-studied, how the cellular levels and activity of HO2 are regulated remains unclear. Here, the mechanism of post-translational regulation of cellular HO2 level by heme is elucidated. Under heme deficient conditions, HO2 is destabilized and targeted for degradation. In HO2, three heme binding sites are potential targets of heme-dependent regulation: one at its catalytic site; the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, a HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared to the wild-type HO2. However, cellular heme overload does not affect HO2 stability. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2’s role in maintaining heme homeostasis, paving the way for future investigation into HO2’s pathophysiological role in heme deficiency response.
Universal Features of Epidemic Models Under Social Distancing Guidelines
Authors: Sadeghi Mahdiar , Greene James M. , Sontag Eduardo D. 
Published: June 2020

AbstractSocial distancing as a form of nonpharmaceutical intervention has been enacted in many countries as a form of mitigating the spread of COVID-19. There has been a large interest in mathematical modeling to aid in the prediction of both the total infected population and virus-related deaths, as well as to aid government agencies in decision making. As the virus continues to spread, there are both economic and sociological incentives to minimize time spent with strict distancing mandates enforced, and/or to adopt periodically relaxed distancing protocols, which allow for scheduled economic activity. The main objective of this study is to reduce the disease burden in a population, here measured as the peak of the infected population, while simultaneously minimizing the length of time the population is socially distanced, utilizing both a single period of social distancing as well as periodic relaxation. We derive a linear relationship among the optimal start time and duration of a single interval of social distancing from an approximation of the classic epidemicSIRmodel. Furthermore, we see a sharp phase transition region in start times for a single pulse of distancing, where the peak of the infected population changes rapidly; notably, this transition occurs wellbeforeone would intuitively expect. By numerical investigation of more sophisticated epidemiological models designed specifically to describe the COVID-19 pandemic, we see that all share remarkably similar dynamic characteristics when contact rates are subject to periodic or one-shot changes, and hence lead us to conclude that these features areuniversalin epidemic models. On the other hand, the nonlinearity of epidemic models leads to non-monotone behavior of the peak of infected population under periodic relaxation of social distancing policies. This observation led us to hypothesize that an additional single interval social distancing at aproper timecan significantly decrease the infected peak of periodic policies, and we verified this improvement numerically. While synchronous quarantine and social distancing mandates across populations effectively minimize the spread of an epidemic over the world, relaxation decisions should not be enacted at the same time for different populations.