bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction
Authors: Canchy Ludivine , Girardeau Paul , Durand Audrey , Vouillac-Mendoza Caroline , Ahmed Serge H. 
Published: May 2020

ABSTRACTCocaine is known to increase brain dopamine at supranormal levels in comparison to alternative nondrug rewards. According to the dopamine hypothesis of addiction, this difference would explain, at least in part, why the latter are eventually given up in favor of continued cocaine use during the transition to addiction. Though resting on solid neuroscientific foundations, this hypothesis has nevertheless proven difficult to reconcile with research on cocaine choice in experimental animals. When facing a choice between an intravenous bolus of cocaine and a nondrug alternative (e.g., sweet water), both delivered immediately after choice, rats do not choose the drug, as would be predicted, but instead develop a strong preference for the nondrug alternative, sometimes to the exclusion of continued drug use. Here we report converging evidence that reconciles this finding with the dopamine hypothesis of addiction. Briefly, our data suggest that cocaine is indeed supranormal in reward magnitude, as postulated by the dopamine hypothesis of addiction, but is less preferred during choice because its pharmacokinetics makes it an inherently more delayed reward than the alternative. Reframing previous drug choice studies in rats as intertemporal choice studies reveals that the discounting effects of delays spare no rewards, including supranormal ones, and that during choice, pharmacokinetics trumps pharmacodynamics. Finally, this study also reveals important gaps in our understanding of drug reward delays that need to be filled by future experimental and theoretical work.
Vein-to-blade ratio is an allometric indicator of climate-induced changes in grapevine leaf size and shape
Authors: Chitwood Daniel H. , Mullins Joey , Migicovsky Zoë , Frank Margaret , VanBuren Robert , Londo Jason P. 
Published: May 2020

ABSTRACTPremiseAs a leaf expands, its shape dynamically changes. Previously, we documented an allometric relationship between vein and blade area in grapevine leaves. Larger leaves have a smaller ratio of primary and secondary vein area relative to blade area compared to smaller leaves. We sought to use allometry as an indicator of leaf size to measure the environmental effects of climate on grapevine leaf morphology.MethodsWe measure the ratio of vein-to-blade area in 8,412 leaves from the same 208 vines across four growing seasons (2013, 2015, 2016, and 2017) using 21 homologous landmarks. Matching leaves by vine and node, we correlate size and shape of grapevine leaves with climate variables.Key resultsVein-to-blade ratio varies strongly between years in ways that blade or vein area do not. Maximum daily temperature and to a lesser degree precipitation are the most strongly correlated climate variables with vein-to-blade ratio, indicating that smaller leaves are associated with heat waves and drought. Leaf count and overall leaf area of shoots and the vineyard population studied also diminish with heat and drought. Grapevine leaf primordia initiate in buds the year prior to when they emerge, and we find that climate during the previous growing season exerts the largest statistical effects over these relationships.ConclusionsOur results demonstrate the profound effects of heat and drought on the vegetative morphology of grapevines and show that vein-to-blade ratio is a strong allometric indicator of the effects of climate on grapevine leaf morphology.
A systematic investigation of human DNA preservation in medieval skeletons
Authors: Parker Cody , Rohrlach Adam B. , Friederich Susanne , Nagel Sarah , Meyer Matthias , Krause Johannes , Bos Kirsten I. , Haak Wolfgang 
Published: May 2020

AbstractAncient DNA (aDNA) analyses necessitate the destructive sampling of archaeological material. Currently the dense inner portion of the petrous pyramid, the location of the skull that houses the inner ear, is the most sought after skeletal element for molecular analyses of ancient humans as it has been shown to yield high amounts of endogenous DNA. Destructive sampling of the petrous pyramid, assuming its recovery, is often not recommended for highly valued specimens. To investigate alternatives, we present a survey of human aDNA preservation for each of ten skeletal elements in a skeletal collection from Medieval Germany. Through comparison of human DNA content and quality we confirm best performance of the petrous pyramid and identify seven additional sampling locations across four skeletal elements that yield adequate aDNA for most applications in human palaeogenetics. Our study provides a better perspective on DNA preservation across the human skeleton and takes a further step toward the more responsible use of ancient materials in human aDNA studies.
The human SKI complex prevents DNA-RNA hybrid-associated telomere instability
Authors: Herrera-Moyano Emilia , Porreca Rosa Maria , Ranjha Lepakshi , Skourti Eleni , Gonzalez-Franco Roser , Sun Ying , Stylianakis Emmanouil , Montoya Alex , Kramer Holger , Vannier Jean-Baptiste 
Published: May 2020

AbstractSuper killer (SKI) complex is a well-known cytoplasmic 3′ to 5′ mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs. Recently, SKIV2L, the 3′ to 5′ RNA helicase of the human SKI (hSKI) complex has been implicated in the degradation of nuclear non-coding RNAs escaping to the cytoplasm. Here, we show that hSKI is present in the nucleus, on chromatin and in particular at telomeres during the G2 cell cycle phase. In cells, SKIV2L prevents telomeric loss, and DNA damage response activation, and its absence leads to DNA-RNA hybrid-mediated telomere fragility. Moreover, we demonstrate that purified hSKI complex preferentially unwinds telomeric DNA-RNA hybridsin vitro. Taken together, our results provide a nuclear function of the hSKI complex in overcoming replication stress caused by aberrant processing of telomeric DNA-RNA hybrids and thus maintaining telomere stability.
MARK4 with an Alzheimer’s disease-related mutation promotes tau hyperphosphorylation directly and indirectly and exacerbates neurodegeneration
Authors: Oba Toshiya , Saito Taro , Asada Akiko , Shimizu Sawako , Iijima Koichi M. , Ando Kanae 
Published: May 2020

AbstractAccumulation of the microtubule-associated protein tau is associated with Alzheimer’s disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser262 and Ser356 play critical roles in tau accumulation and toxicity. Microtubule-affinity regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a doublede novomutation in the linker region of MARK4, ΔG316E317InsD, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317Dincreases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser262/356-dependent and -independent mechanisms. Using transgenicDrosophilaexpressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that co-expression of MARK4wtand MARK4ΔG316E317Dincreased total tau levels and enhanced tau-induced neurodegeneration, and that MARK4ΔG316E317Dhad more potent effects than MARK4wt. Interestingly, thein vitrokinase activities of MARK4wtand MARK4ΔG316E317Dwere similar. Blocking tau phosphorylation at Ser262 and Ser356 by alanine substitutions protected tau from the effects of MARK4wt, but not from MARK4ΔG316E317D. While both MARK4wtand MARK4ΔG316E317Dincreased the levels of oligomeric forms of tau, MARK4ΔG316E317Dfurther boosted the levels of tau phosphorylated at several sites other than Ser262/356 and increased the detergent insolubility of tauin vivo. Together, these findings suggest that MARK4ΔG316E317Dincreases tau levels and exacerbates tau toxicity via an additional gain-of-function mechanism, and that modification in this region of MARK4 may impact disease pathogenesis.
Networks of Splice Factor Regulation by Unproductive Splicing Coupled With Nonsense Mediated mRNA Decay
Authors: Desai Anna , Hu Zhiqiang , French Courtney E. , Lloyd James P. B. , Brenner Steven E. 
Published: May 2020

AbstractBackgroundNonsense mediated mRNA decay (NMD) is an RNA surveillance pathway that degrades aberrant transcripts harboring premature termination codons. This pathway, in conjunction with alternative splicing, regulates gene expression post-transcriptionally. Nearly all serine and arginine-rich (SR) proteins and many heterogeneous nuclear ribonucleoproteins (hnRNPs) produce isoforms that can be degraded by the NMD pathway. Many splicing factors have been reported to be regulated via alternative splicing coupled to NMD. However, it is still uncharacterized that to what extent NMD contributes to the regulation of splicing factors.ResultsHere, we characterized a regulatory network of splicing factors through alternative splicing coupled to NMD. Based upon an extensive literature search, we first assembled a network that encompasses the current knowledge of splice factors repressing or activating the expression of other splicing factors through alternative splicing coupled to NMD. This regulatory network is limited, including just a handful of well-studied splicing factors. To gain a more global and less biased overview, we examined the splicing factor-mRNA interactions from public crosslinking-immunoprecipitation (CLIP)-seq data, which provides information about protein–RNA interactions. A network view of these interactions reveals extensive binding among splicing regulators. We also found that splicing factors bind more frequently to transcripts of other splicing factors than to other genes. In addition, many splicing factors are targets of NMD, and might be regulated via alternative splicing coupled to NMD, which is demonstrated by the significant overlap between the experimental network and eCLIP-network. We found that hierarchy of the splicing-factor interaction network differs from the hierarchy observed for transcription factors.ConclusionThe extensive interaction between splicing factors and transcripts of other splicing factors suggests that the potential regulation via alternative splicing coupled with NMD is widespread. The splicing factor regulation is fundamentally different from that of transcription factors.
Convalescent plasma treatment of severe COVID-19: A matched control study
Authors: Liu Sean T. H. , Lin Hung-Mo , Baine Ian , Wajnberg Ania , Gumprecht Jeffrey P. , Rahman Farah , Rodriguez Denise , Tandon Pranai , Bassily-Marcus Adel , Bander Jeffrey , Sanky Charles , Dupper Amy , Zheng Allen , Altman Deena R. , Chen Benjamin K. , Krammer Florian , Mendu Damodara Rao , Firpo-Betancourt Adolfo , Levin Matthew A. , Bagiella Emilia , Casadevall Arturo , Cordon-Cardo Carlos , Jhang Jeffrey S. , Arinsburg Suzanne A. , Reich David L. , Aberg Judith A. , Bouvier Nicole M. 
Published: May 2020

Background
Since December 2019, Coronavirus Disease 2019 (COVID-19) has become a global pandemic, causing mass morbidity and mortality. Prior studies in other respiratory infections suggest that convalescent plasma transfusion may offer benefit to some patients. Here, the outcomes of thirty-nine hospitalized patients with severe to life-threatening COVID-19 who received convalescent plasma transfusion were compared against a cohort of retrospectively matched controls.
Methods
Plasma recipients were selected based on supplemental oxygen needs at the time of enrollment and the time elapsed since the onset of symptoms. Recipients were transfused with convalescent plasma from donors with a SARS-CoV-2 (severe acute respiratory disease coronavirus 2) anti-spike antibody titer of	≥1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls.
Results
Convalescent plasma recipients were more likely than control patients to remain the same or have improvements in their supplemental oxygen requirements by post-transfusion day 14, with an odds ratio of 0.86 (95% CI: 0.75~0.98; p=0.028). Plasma recipients also demonstrated improved survival, compared to control patients (log-rank test: p=0.039). In a covariates-adjusted Cox model, convalescent plasma transfusion improved survival for non-intubated patients (hazard ratio 0.19 (95% CI: 0.05 ~0.72); p=0.015), but not for intubated patients (1.24 (0.33~4.67); p=0.752).
Conclusions
Convalescent plasma transfusion is a potentially efficacious treatment option for patients hospitalized with COVID-19; however, these data suggest that non-intubated patients may benefit more than those requiring mechanical ventilation.
Quantifying Effects, Forecasting Releases, and Herd Immunity of the Covid-19 Epidemic in S. Paulo – Brazil
Authors: Celaschi S. 
Published: May 2020

AbstractA simple and well known epidemiological deterministic model was selected to estimate the main results for the basic dynamics of the Covid-19 epidemic breakout in the city of São Paulo – Brazil. The methodology employed the SEIR Model to characterize the epidemics outbreak and future outcomes. A time-dependent incidence weight on the SEIR reproductive basic number accounts for local Mitigation Policies (MP). The insights gained from analysis of these successful interventions were used to quantify shifts and reductions on active cases, casualties, and estimatives on required medical facilities (ITU). This knowledge can be applied to other Brazilian areas. The analysis was applied to forecast the consequences of releasing the MP over specific periods of time. Herd Immunity (HI) analysis allowed estimating how far we are from reaching the HI threshold value, and the price to be paid.
Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1
Authors: Chopra Ravi , Bushart David D , Cooper John P , Yellajoshyula Dhananjay , Morrison Logan M , Huang Haoran , Scoles Daniel R , Pulst Stefan M , Orr Harry T , Shakkottai Vikram G 
Published: May 2020

AbstractSelective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 corepressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.
Comparison of analytical methods for rapid & reliable quantification of plant-based carbohydrates for the quintessential bioenergy educator
Authors: Chundawat Shishir P. S. 
Published: May 2020

AbstractBiochemical conversion of plant-based insoluble carbohydrate polymers, such as starch from corn grains or cellulose-hemicellulose from corn stover, into soluble fermentable sugars (e.g., glucose and xylose) for bioenergy production has seen tremendous research activity and commercial-scale biorefineries deployment over the last three decades, particularly in regions around the world that have a dominant agricultural-based economy. Therefore, educators in schools and universities have developed various hands-on experimental activities to engage the general public and students either in outreach events or lab/classroom-based settings to instruct students on various inter-disciplinary concepts relevant to bioenergy and biochemicals production. One of the limitations of most available protocols is the lack of systematic and comprehensive comparison of educator-friendly analytical tools and protocols for quantitative analysis of water-soluble carbohydrates commonly encountered in a biorefinery backdrop during the biochemical conversion of lignocellulosic biomass to biofuels/biochemicals. Here, we systematically compare and validate findings from four leading analytical approaches for detection and quantification of lignocellulosic biomass derived soluble carbohydrates. We compare these assay methods based on the overall ease of use, detection accuracy/sensitivity, commercial availability, analytical cost per assay run, and suitability for use by instructors in biorefining specific hands-on activity protocols. Next, we provide a detailed instructional protocol that utilizes one of these validated soluble sugar assays as part of a ∼90 min hands-on bioenergy focused activity (called ‘Grass-to-Gas!’) conducted at Rutgers University with pre-university high school students. ‘Grass-to-Gas!’ activity involves students running biochemical assays that helps them understand the various facets of cellulosic biomass hydrolysis by commercial cellulase enzymes and monitoring the total glucose product released using our validated sugar assays to finally estimate the fractional conversion of cellulose-to-glucose. Lastly, we further demonstrate how such carbohydrate-based analytical methods can be used by instructors to help university students explore and understand various chemistry, biochemistry, and chemical engineering concepts relevant to other advanced operations involved in lignocellulose biorefining. These activity protocols would greatly aid educators teaching interdisciplinary science and engineering concepts to students in the backdrop of lignocellulose biorefining.
Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia
Authors: Rivera Osvaldo D. , Mallory Michael J. , Quesnel-Vallières Mathieu , Schultz David C. , Carroll Martin , Barash Yoseph , Cherry Sara , Lynch Kristen W. 
Published: May 2020

AbstractMost genes associated with Acute Myeloid Leukemia (AML) are mutated in less than 10% of patients, suggesting alternative mechanisms for gene disruption contribute to this disease. Here we find a set of splicing events that disrupt the expression of a subset of AML-associated genes, including EZH2 and ZRSR2, independent of known somatic mutations. Most strikingly, in at least one cohort, aberrant splicing triples the number of patients with a reduction in functional EZH2 as compared to that predicted by somatic mutation of EZH2 alone. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlights the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.
Integrative Analysis of Metabolomic and Transcriptomic Profiles Uncovers Biological Mechanism of Feed Efficiency in Pigs
Authors: Banerjee Priyanka , Okstoft Carmelo Victor Adriano , Kadarmideen Haja N 
Published: May 2020

ABSTRACTFeed efficiency (FE) is an economically important trait. Thus, reliable predictors would help to reduce the production cost and provide sustainability to the pig industry. We carried out metabolome-transcriptome integration analysis on 40 purebred Duroc and Landrace male uncastrated pigs to identify potential gene-metabolite interactions and explore the molecular mechanism underlying FE. To this end, we applied untargeted metabolomics and RNA-seq approaches to the same animals. After data quality control, we used a linear model approach to integrate the data and find significant differently correlated gene-metabolite pairs separately for the breeds (Duroc and Landrace) and FE groups (low and high FE) followed by a pathway over-representation analysis. We identified 21 and 12 significant gene-metabolite pairs for each group. The valine-leucine-isoleucine biosynthesis/degradation and arginine-proline metabolism pathways were associated with unique metabolites. The unique genes obtained from significant metabolite-gene pairs were associated with sphingolipid catabolism, multicellular organismal process, cGMP, and purine metabolic processes. While some of the genes and metabolites identified were known for their association with FE, others are novel and provide new avenues for further research. Further validation of genes, metabolites, and gene-metabolite interactions in larger cohorts will help us to elucidate the regulatory mechanisms and pathways underlying FE.
Does the motor cortex want the full story? The influence of sentence context on corticospinal excitability in action language processing
Authors: Dupont W , Papaxanthis C , Lebon F , Madden-Lombardi C 
Published: May 2020

AbstractThe reading of action verbs has been shown to activate motor areas, whereby sentence context may serve to either globally strengthen this activation or to selectively sharpen it. To investigate this issue, we manipulated the presence of manual actions and sentence context, assessing the level of corticospinal excitability by means of transcranial magnetic stimulation. We hypothesized that context would serve to sharpen the neural representation of the described actions in the motor cortex, reflected in context-specific modulation of corticospinal excitability.Participants silently read manual action verbs and non-manual verbs, preceded by a full sentence (rich context) or not (minimal context). Transcranial magnetic stimulation pulses were delivered at rest or shortly after verb presentation. The coil was positioned over the cortical representation of the right first dorsal interosseous (pointer finger).We observed a general increase of corticospinal excitability while reading both manual action and non-manual verbs in minimal context, whereas the modulation was action-specific in rich context: corticospinal excitability increased while reading manual verbs, but did not differ from baseline for non-manual verbs. These findings suggest that sentence context sharpens motor representations, activating the motor cortex when relevant and eliminating any residual motor activation when no action is present.