bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression
Authors: Ruscica Vincenzo , Bawankar Praveen , Peter Daniel , Helms Sigrun , Igreja Cátia , Izaurralde Elisa 
Published: May 2019

Abstract
The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5′-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4–NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP–GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.
Highly efficient single-stranded DNA ligation technique improves low-input whole-genome bisulfite sequencing by post-bisulfite adaptor tagging
Authors: Miura Fumihito , Shibata Yukiko , Miura Miki , Sangatsuda Yuhei , Hisano Osamu , Araki Hiromitsu , Ito Takashi 
Published: May 2019

Abstract
Whole-genome bisulfite sequencing (WGBS) is the current gold standard of methylome analysis. Post-bisulfite adaptor tagging (PBAT) is an increasingly popular WGBS protocol because of high sensitivity and low bias. PBAT originally relied on two rounds of random priming for adaptor-tagging of single-stranded DNA (ssDNA) to attain high efficiency but at a cost of library insert length. To overcome this limitation, we developed terminal deoxyribonucleotidyl transferase (TdT)-assisted adenylate connector-mediated ssDNA (TACS) ligation as an alternative to random priming. In this method, TdT attaches adenylates to the 3′-end of input ssDNA, which are then utilized by RNA ligase as an efficient connector to the ssDNA adaptor. A protocol that uses TACS ligation instead of the second random priming step substantially increased the lengths of PBAT library fragments. Moreover, we devised a dual-library strategy that splits the input DNA to prepare two libraries with reciprocal adaptor polarity, combining them prior to sequencing. This strategy ensured an ideal base–color balance to eliminate the need for DNA spike-in for color compensation, further improving the throughput and quality of WGBS. Adopting the above strategies to the HiSeq X Ten and NovaSeq 6000 platforms, we established a cost-effective, high-quality WGBS, which should accelerate various methylome analyses.
A Cost-effectiveness Analysis of an Adjuvanted Subunit Vaccine for the Prevention of Herpes Zoster and Post-herpetic Neuralgia
Authors: Carpenter Christopher F , Aljassem Annas , Stassinopoulos Jerry , Pisacreta Giovanni , Hutton David 
Published: May 2019

Abstract

Background
Herpes zoster (HZ) develops in up to 50% of unvaccinated individuals, accounting for &gt;1 million cases annually in the United States. A live attenuated HZ vaccine (LAV) is Food and Drug Administration approved for those age 50 years or older, though Advisory Committee on Immunization Practices recommendations are only for those age 60 years or older. LAV efficacy is ~70% for persons 50–59 years of age, with lower efficacy in older adults. A new 2-dose adjuvanted subunit vaccine (SUV) has &gt;95% efficacy in persons 50–69 years of age and remains ~90% efficacious in persons vaccinated at age 70 years.

Methods
To estimate the relative cost-effectiveness of SUV, LAV, and no vaccination (NoV) strategies, a Markov model was developed based on published data on vaccine efficacy, durability of protection, quality of life, resource utilization, costs, and disease epidemiology. The perspective was US societal, and the cycle length was 1 year with a lifelong time horizon. SUV efficacy was estimated to wane at the same rate as LAV. Outcomes evaluated included lifetime costs, discounted life expectancy, and incremental cost-effectiveness ratios (ICERs).

Results
For individuals vaccinated at age 50 years, the ICER for LAV vs NoV was $118 535 per quality-adjusted life-year (QALY); at age 60 years, the ICER dropped to $42 712/QALY. SUV was more expensive but had better ICERs than LAV. At age 50, the ICER was $91 156/QALY, and it dropped to $19 300/QALY at age 60.

Conclusions
Vaccination with SUV was more cost-effective than LAV in all age groups studied. Vaccination with SUV at age 50 years appears cost-effective, with an ICER &lt;$100 000/QALY.
Religious Faith and the Fallibility of Public Reasons
Authors: Bespalov Andrei 
Published: May 2019

Abstract
Rawlsian liberals define legitimacy in terms of the public justification principle (PJP): the exercise of political power is legitimate only if it is justified on the grounds of reasons that all may reasonably be expected to accept. Does PJP exclude religious reasons from public justification of legal provisions? I argue that the requirement of ‘reasonable acceptability’ is not clear enough to answer this question. Furthermore, it fails to address the problematic fact that justification on the grounds of religious faith involves non-negotiable claims, which is incompatible with respect for fellow citizens as co-legislators. Accordingly, I reformulate PJP in fallibilistic terms: the exercise of political power is legitimate only if it is justified on the grounds of reasons that can be subject to reasonable criticism. I show that reasons based on religious faith do not meet this principle, just like any other reasons that involve claims about final values.
Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment
Authors: Carrion-Castillo Amaia , Pepe Antonietta , Kong Xiang-Zhen , Fisher Simon E , Mazoyer Bernard , Tzourio-Mazoyer Nathalie , Crivello Fabrice , Francks Clyde 
Published: May 2019

AbstractPrevious studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10-15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.
A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination
Authors: Pardo José V. , Sheikh Sohail A. , Schwindt Graeme , Lee Joel T. , Adson David E. , Rittberg Barry , Abuzzahab Faruk S. 
Published: May 2019

AbstractTreatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism similar to those seen in treatment-responsive major depression.
Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia
Authors: Louka Eleni , Povinelli Benjamin , Meira Alba Rodriguez , Buck Gemma , Ashley Neil , Hamblin Angela , Booth Christopher A.G. , Sousos Nikolaos , Roy Anindita , Elliott Natalina , Iskander Deena , de la Fuente Josu , Fordham Nicholas , O’Byrne Sorcha , Inglott Sarah , Rao Anupama , Roberts Irene , Mead Adam J. 
Published: May 2019

AbstractJuvenile Myelomonocytic Leukemia (JMML) is a poor prognosis childhood leukemia usually caused by germline or somatic RAS-activating mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA-sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment with RAS-activating mutations as a “first hit”, (2) mutations are acquired with both linear and branching patterns of clonal evolution and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal inter-patient heterogeneity of JMML-LSCs which are present in, but not confined to, the phenotypic HSC compartment. RNA-sequencing of JMML-LSCs reveals upregulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, CD96) paving the way for LSC-directed disease monitoring and therapy in this disease.
Quantitative insights into age-associated DNA-repair inefficiency in single cells
Authors: Young Thomas Z. , Liu Ping , Acar Murat 
Published: May 2019

ABSTRACTThe double strand break (DSB) is a highly toxic form of DNA damage that is thought to be both a driver and consequence of age-related dysfunction. Although DSB repair is essential for a cell’s survival, little is known about how DSB repair mechanisms are affected by cellular age. Here we characterize the impact of cellular aging on the efficiency of single-strand annealing (SSA), a repair mechanism for DSBs occurring between direct repeats. Using a single-cell reporter of SSA repair, we measure SSA repair efficiency in young and old cells, and report a 23.4% decline in repair efficiency. This decline is not due to increased usage of non-homologous end joining (NHEJ). Instead, we identify increased G1-phase duration in old cells as a factor responsible for the decreased SSA repair efficiency. We further explore how SSA repair efficiency is affected by sequence heterology and find that heteroduplex rejection remains high in old cells. Our work provides novel quantitative insights into the links between cellular aging and DSB repair efficiency at single-cell resolution in replicatively aging cells.
Protein and Lipid Mass Concentration Measurement in Tissues by Stimulated Raman Scattering Microscopy
Authors: Oh Seungeun , Lee ChangHee , Yang Wenlong , Li Ang , Mukherjee Avik , Basan Markus , Ran Chongzhao , Yin Wei , Tabin Clifford J. , Fu Dan , Sunney Xie X. , Kirschner Marc W. 
Published: May 2019

AbstractCell mass and its chemical composition are important aggregate cellular variables for physiological processes including growth control and tissue homeostasis. Despite their central importance, it has been difficult to quantitatively measure these quantities from single cells in intact tissue. Here, we introduce Normalized Raman Imaging (NoRI), a Stimulated Raman Scattering (SRS) microscopy method that provides the local concentrations of protein, lipid and water from live or fixed tissue samples with high spatial resolution. Using NoRI, we demonstrate that single cell protein, lipid and water concentrations are maintained in a tight range in cells under same physiological conditions and are altered in different physiological states such as cell cycle stages, attachment to substrates of different stiffness, or by entering senescence. In animal tissues, protein and lipid concentration varies with cell types, yet an unexpected cell-to-cell heterogeneity was found in cerebellar Purkinje cells. Protein and lipid concentration profile provides a new means to quantitatively compare disease-related pathology as demonstrated using models of Alzheimer’s disease. Our demonstration shows that NoRI is a broadly applicable tool for probing the biological regulation of protein mass, lipid mass and water in cellular and tissue growth, homeostasis, and disease.
Neural correlates of cardiac interoceptive accuracy across development: implications for social symptoms in autism spectrum disorders
Authors: Failla Michelle D. , Bryant Lauren K. , Heflin Brynna H. , Mash Lisa E. , Schauder Kim , Davis Samona , Gerdes Madison B. , Weitlauf Amy , Rogers Baxter P. , Cascio Carissa J. 
Published: May 2019

AbstractBackgroundInteroception involves the processing of sensory information relevant to physiological functioning and is integral to building self-awareness, emotional states, and modulating social behaviors. With the role of interoception in emotional processing and social functioning, there is growing interest in characterizing interoception in autism spectrum disorder (ASD), yet, there are mixed results regarding cardiac interoceptive accuracy in ASD.MethodsIn this study, we explored the neural basis of cardiac interoception using an fMRI heartbeat counting task in order to assess neural correlates of primary interoception. We predicted that interoceptive-specific response in the insula, a “hub” for interoception, would be related to ASD symptomatology. We investigated the relationship of insula responses during cardiac interoceptive accuracy and a self/caregiver-reported autism-related symptom scale (Social Responsiveness Scale-2 (SRS)). Participants included 46 individuals with autism spectrum disorder (ASD) (age 8-54, mean= 19.43±10.68 years) and 54 individuals with typical development for comparison (TC, age 8-53, mean= 21.43±10.41 years).ResultsWe found no significant difference in cardiac interoceptive accuracy or neural response to cardiac interoception in ASD. Several insula sudivisons had a curvilinear relationship to age, peaking in early adulthood. Interoceptive-specific insula response was associated with adult self-report SRS scores; this association differed by diagnostic group and self/other report.ConclusionsThis work suggests that 1) there is no global deficit in interoception in ASD, but that integrating interoceptive cues with social information may distinguish individuals with ASD, and 2) there is a developmental trajectory for interoceptive processing in the insula that may be relevant for socio-emotional health.
Basis for discrimination by engineered CRISPR/Cas9 enzymes
Authors: Liu Mu-Sen , Gong Shanzhong , Yu Helen-Hong , Jung Kyungseok , Johnson Kenneth A. , Taylor David W. 
Published: May 2019

AbstractCRISPR/Cas9 is a programmable genome editing tool that has been widely used for biological applications. While engineered Cas9s have been reported to increase discrimination against off-target cleavage compared with wild type Streptococcus pyogenes (SpCas9) in vivo, the mechanism for enhanced specificity has not been extensively characterized. To understand the basis for improved discrimination against off-target DNA containing important mismatches at the distal end of the guide RNA, we performed kinetic analyses on the high-fidelity (Cas9-HF1) and hyper-accurate (HypaCas9) engineered Cas9 variants. While DNA unwinding is the rate-limiting step for on-target cleavage by SpCas9, we show that chemistry is seriously impaired by more than 100-fold for the high-fidelity variants. The high-fidelity variants improve discrimination by slowing the rate of chemistry without increasing the rate of DNA rewinding—the kinetic partitioning favors release rather than cleavage of a bound off-target substrate because chemistry is slow. Further improvement in discrimination may require engineering increased rates of dissociation of off-target DNA.
A Temporal Transcriptional Map of Human Natural Killer Cell Differentiation
Authors: Pfefferle Aline , Netskar Herman , Ask Eivind Heggernes , Lorenz Susanne , Goodridge Jodie P. , Sohlberg Ebba , Clancy Trevor , Malmberg Karl-Johan 
Published: May 2019

AbstractNatural killer cell repertoires are functionally diversified as a result of differentiation, homeostatic receptor-ligand interactions and adaptive responses to viral infections. However, the regulatory gene-circuits that define the manifold cell states and drive NK cell differentiation have not been clearly resolved. Here, we performed single-cell RNA sequencing of 26,506 cells derived from sorted phenotypically-defined human NK cell subsets to delineate a tightly coordinated differentiation process from a small population of CD56brightprecursors to adaptive NKG2C+CD56dimNK cells. RNA velocity analysis identified a clear directionality in the transition from CD56brightto CD56dimNK cells, which was dominated by genes involved in transcription and translation as well as acquisition of NK cell effector function. Gene expression trends mapped to pseudotime, defined by increasing entropy, identified three distinct transcriptional checkpoints, reflecting important changes in regulatory gene-circuits. The CD56brightNK cell population dominated pseudotime with two distinct checkpoints separating precursors from intermediate states that gradually took on transcriptional signatures similar to CD56dimNK cells. The final checkpoint occurred during late terminal differentiation of CD56dimNK cells and was associated with unique divergent gene-expression trends. Furthermore, we utilized this single-cell RNA sequencing resource to decipher the regulation of genes involved in lysosomal biogenesis and found a coordinated gradual increase in theRAB4andBLOC1Sgene families with differentiation into CD56dimNK cells. These results identify important gene programs driving functional diversification and specialization during NK cell differentiation and hold potential to guide new strategies for NK cell-based cancer immunotherapy.
Clustering of the structures by using “snakes-&-dragons” approach, or correlation matrix as a signal
Authors: Andreev Victor P. , Liu Gang , Zee Jarcy , Henn Lisa , Flores Gilberto E. , Merion Robert M. 
Published: May 2019

AbstractBiological, ecological, social, and technological systems are complex structures with multiple interacting parts, often represented by networks. Correlation matrices describing interdependency of the variables in such structures provide key information for comparison and classification of such systems. Classification based on correlation matrices could supplement or improve classification based on variable values, since the former reveals similarities in system structures, while the latter relies on the similarities in system states. Importantly, this approach of clustering correlation matrices is different from clustering elements of the correlation matrices, because our goal is to compare and cluster multiple networks – not the nodes within the networks. A novel approach for clustering correlation matrices, named “snakes-&-dragons,” is introduced and illustrated by examples from neuroscience, human microbiome, and macroeconomics.
Reconciling Base-Pair Resolution 5-methylcytosine and 5-hydroxymethylcytosine Data in Neuroepigenetics
Authors: Kochmanski Joseph , Savonen Candace , Bernstein Alison I. 
Published: May 2019

AbstractEpigenetic marks operate at multiple chromosomal levels to regulate gene expression, from direct covalent modification of DNA to 3D chromosomal structure. Research has shown that 5-methylcytosine (5-mC) and its oxidized form, 5-hydroxymethylcytosine (5-hmC), are stable epigenetic marks with distinct genomic distributions and separate regulatory functions. In addition, recent data indicate that 5-hmC plays a critical regulatory role in the mammalian brain, emphasizing the importance of considering this alternative DNA modification in the context of neuroepigenetics. Traditional bisulfite (BS) treatment-based methods to measure the methylome are not able to distinguish between 5-mC and 5-hmC, meaning much of the existing literature does not differentiate these two DNA modifications. Recently developed methods, including Tet-assisted bisulfite (TAB) treatment and oxidative bisulfite (oxBS) treatment, allow for differentiation of 5-hmC and/or 5-mC levels at base-pair resolution when combined with next-generation sequencing or methylation arrays. Despite these technological advances, there remains a lack of clarity regarding the appropriate statistical methods for integration of 5-mC and 5-hmC data. As a result, it can be difficult to determine the effects of an experimental treatment on 5-mC and 5-hmC dynamics. Here, we propose a statistical approach involving mixed effects to simultaneously model paired 5-mC and 5-hmC data as repeated measures. Using this approach, it will be possible to determine the effects of an experimental treatment on both 5-mC and 5-hmC at the base-pair level.