bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypes of Chronic Hepatitis B in Children From a Large North American Cohort
Authors: Schwarz Kathleen B. , Lombardero Manuel , Di Bisceglie Adrian M. , Murray Karen F. , Rosenthal Philip , Ling Simon C. , Cloonan Yona Keich , Rodriguez‐Baez Norberto , Schwarzenberg Sarah Jane , Hoofnagle Jay H. , Teckman Jeffrey ,   Hepatitis B Research Network (HBRN)
Published: August 2019

ABSTRACTObjective:The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population‐based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors.Background:Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy.Methods:Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg‐negative with low HBV DNA and normal ALT levels; immune‐tolerant: HBeAg‐positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg‐positive or ‐negative with high HBV DNA and abnormal ALT levels.Results:Three hundred seventy‐one participants were analyzed of whom 274 were HBeAg‐positive (74%). Younger participants were more likely be HBeAg‐positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg‐negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg‐negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg‐positive infection.Conclusions:Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.
Photo-Integrated Conversation Moderated by Robots for Cognitive Health in Older Adults: A Randomized Controlled Trial
Authors: Otake-Matsuura Mihoko , Tokunaga Seiki , Watanabe Kumi , Abe Masato S. , Sekiguchi Takuya , Sugimoto Hikaru , Kishimoto Taishiro , Kudo Takashi 
Published: August 2019

AbstractBackground and ObjectivesSocial interaction might prevent or delay dementia, but little is known about the specific effects of various social activity interventions on cognition. This study conducted a single-site randomized controlled trial (RCT) of Photo-Integrated Conversation moderated by a Robot (PICMOR), a group conversation intervention program for resilience against cognitive decline and dementia.Research Design and MethodsIn the RCT, PICMOR was compared to an unstructured group conversation condition. Sixty-five community-living older adults participated in this study. The intervention was provided once a week for 12 weeks. Primary outcome measures were the cognitive functions; process outcome measures included the linguistic characteristics of speech to estimate interaction quality. Baseline and post-intervention data were collected. PICMOR contains two key features: (i) photos taken by the participants are displayed and discussed sequentially; and (ii) a robotic moderator manages turn-taking to make sure that participants are allocated the same amount of time.ResultsAmong the primary outcome measures (i.e., cognitive functions), verbal fluency significantly improved in the intervention group. Among the process outcome measures (i.e., linguistic characteristics of speech), the amount of speech and richness of words were larger for the intervention group.Discussion and ImplicationsThis study demonstrated for the first time the positive effects of a robotic social activity intervention on cognitive function in healthy older adults via RCT. The group conversation generated by PICMOR may improve participants’ cognitive function controlling the amount of speech produced to make it equal. PICMOR is available and accessible to community-living older adults.
Social Media Surveillance for Perceived Therapeutic Effects of Cannabidiol (CBD) Products
Authors: Tran Tung , Kavuluru Ramakanth 
Published: August 2019

AbstractBackgroundCBD products have risen in popularity given CBD’s therapeutic potential and lack of legal oversight, despite lacking conclusive scientific evidence for widespread over-the-counter usage for many of its perceived benefits. While medical evidence is being generated, social media surveillance offers a fast and inexpensive alternative to traditional surveys in ascertaining perceived therapeutic purposes and modes of consumption for CBD products.MethodsWe collected all comments from the CBD subreddit posted between January 1 and April 30, 2019 as well as comments submitted to the FDA regarding regulation of cannabis-derived products and analyzed them using a rule-based language processing method. A relative ranking of popular therapeutic uses and product groups for CBD is obtained based on frequency of pattern matches including precise queries that entail identifying mentions of the condition, a CBD product, and some “trigger” phrase indicating therapeutic use. We validated the social media-based findings using a similar analysis on comments to the U.S. Food and Drug Administration’s (FDA) 2019 request-for-comments on cannabis-derived products.ResultsCBD is mostly discussed as a remedy for anxiety disorders and pain and this is consistent across both comment sources. Of comments posted to the CBD subreddit during the monitored time span, 6.19% mentioned anxiety at least once with at least 6.02% of these comments specifically mentioning CBD as a treatment for anxiety (i.e., 0.37% of total comments). The most popular CBD product group is oil and tinctures.ConclusionSocial media surveillance of CBD usage has the potential to surface new therapeutic use-cases as they are posted. Contemporary social media data indicate, for example, that stress and nausea are frequently mentioned as therapeutic use cases for CBD without corresponding evidence, that affirms or denies, in the research literature. However, the abundance of anecdotal claims warrants serious scientific exploration moving forward. Meanwhile, as FDA ponders regulation, our effort demonstrates that social data offers a convenient affordance to surveil for CBD usage patterns in a way that is fast and inexpensive and can inform conventional electronic surveys.
Deformable mirror-based two-photon microscopy for axial mammalian brain imaging
Authors: Peinado Alba , Bendek Eduardo , Yokoyama Sae , Poskanzer Kira E. 
Published: August 2019

AbstractThis work presents the design and implementation of an enhanced version of a traditional two-photon (2P) microscope with the addition of high-speed axial scanning for live mammalian brain imaging. Our implementation utilizes a deformable mirror (DM) that can rapidly apply different defocus shapes to manipulate the laser beam divergence and consequently control the axial position of the beam focus in the sample. We provide a mathematical model describing the DM curvature, then experimentally characterize the radius of curvature as well as the Zernike terms of the DM surface for a given set of defocuses. A description of the optical setup of the 2P microscope is detailed. We conduct a thorough calibration of the system, determining the point spread function, the total scanning range, the axial step size, and the intensity curvature as a function of depth. Finally, the instrument is used for imaging different neurobiological samples, including fixed brain slices and in vivo mouse cerebral cortex.
Enhancing sensitivity and controlling false discovery rate in somatic indel discovery
Authors: Köster Johannes , Dijkstra Louis J. , Marschall Tobias , Schönhuth Alexander 
Published: August 2019

AbstractAs witnessed by various population-scale cancer genome sequencing projects, accurate discovery of somatic variants has become of central importance in modern cancer research. However, count statistics on somatic insertions and deletions (indels) discovered so far point out that large amounts of discoveries must have been missed. The reason is that the combination of uncertainties relating to, for example, gap and alignment ambiguities, twilight zone indels, cancer heterogeneity, sample purity, sampling and strand bias are hard to accurately quantify. Here, a unifying statistical model is provided whose dependency structures enable to accurately quantify all inherent uncertainties in short time. As major consequence, false discovery rate (FDR) in somatic indel discovery can now be controlled at utmost accuracy. As demonstrated on simulated and real data, this enables to dramatically increase the amount of true discoveries while safely suppressing the FDR. Specifically supported by workflow design, our approach can be integrated as a post-processing step in large-scale projects.The software is publicly available at https://varlociraptor.github.io and can be easily installed via Bioconda1 [Grüning et al., 2018].
BMP-signalling inhibition inDrosophilasecondary cells remodels the seminal proteome, and self and rival ejaculate functions
Authors: Hopkins Ben R. , Sepil Irem , Bonham Sarah , Miller Thomas , Charles Philip D. , Fischer Roman , Kessler Benedikt M. , Wilson Clive , Wigby Stuart 
Published: August 2019

ABSTRACTSeminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. InDrosophila melanogaster, most SFPs are produced in the accessory glands, which are composed of ∼1000 fertility-enhancing ‘main cells’ and ∼40, more functionally cryptic, ‘secondary cells’. Inhibition of BMP-signalling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female post-mating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary cell secretions might therefore make a highly specific contribution to the seminal proteome and ejaculate function; alternatively, they might regulate more global – but hitherto-undiscovered – SFP functions and proteome composition. Here, we present data that supports the latter model. We show that in addition to previously reported phenotypes, secondary cell-specific BMP-signalling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a novel constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal a mix of specific and widespread changes to the seminal proteome that surprisingly encompass alterations to main cell-derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell-types suggesting that modification to the cellular make-up of seminal fluid-producing tissues is an important factor in ejaculate evolution.
Metabolic cofactors act as initiating substrates for primase and affect replication primer processing
Authors: Julius Christina , Yuzenkova Yulia 
Published: August 2019

AbstractRecently a new, non-canonical type of 5’-RNA capping with cellular metabolic cofactors was discovered in bacteria and eukaryotes. This type of capping is performed by RNA polymerases, the main enzymes of transcription, which initiate RNA synthesis with cofactors. Here we show that primase, the enzyme of replication which primes synthesis of DNA by making short RNA primers, initiates synthesis of replication primers using the number of metabolic cofactors. Primase DnaG ofE. colistarts synthesis of RNA with cofactors NAD+/NADH, FAD and DP-CoAin vitro. This activity does not affect primase specificity of initiation. ppGpp, the global starvation response regulator, strongly inhibits the non-canonical initiation by DnaG. Amino acid residues of a “basic ridge” define the binding determinant of cofactors to DnaG. Likewise, the human primase catalytic subunit P49 can use modified substrate m7GTP for synthesis initiation.For correct genome duplication, the RNA primer needs to be removed and Okazaki fragments ligated. We show that the efficiency of primer processing by DNA polymerase I is strongly affected by cofactors on the 5’-end of RNA. Overall our results suggest that cofactors at the 5’ position of the primer influence regulation of initiation and Okazaki fragments processing.Visual abstractA. Non-canonical capping of RNA by RNA polymerase.RNA polymerase uses cellular cofactor as initiating substrate for RNA synthesis, instead of NTP. Then RNA chain grows, while cofactor remains attached and serves as cap.B. Proposed mechanism of non-canonical initiation of RNA primer synthesis by DnaG primase during replication.DnaG primase initiates synthesis of the primer for DNA replication using cellular cofactor. Primer stays annealed with the DNA template. DNApolI encounters cofactor, which affects the removal of primer.
Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A
Authors: Sen Dilara , Voulgaropoulos Alexis , Drobna Zuzana , Keung Albert J. 
Published: August 2019

SUMMARYHuman neurodevelopment and its associated diseases are complex and challenging to study. This has driven recent excitement for human cerebral organoids (hCOs) as research and screening tools. These models are steadily proving their utility; however, it remains unclear what limits they will face in recapitulating the complexities of neurodevelopment and disease. Here we show that their utility extends to key (epi)genetic and disease processes that are complex in space and time. Specifically, hCOs capture UBE3A’s dynamically imprinted expression and subcellular localization patterns. Furthermore, given UBE3A’s direct links to Angelman Syndrome and Autism Spectrum Disorder, we show that hCOs respond to candidate small molecule therapeutics. This work demonstrates that hCOs can provide important insights to focus the scope of mechanistic and therapeutic strategies including revealing difficult to access prenatal developmental time windows and cell types key to disease etiology.
Aquila_stLFR: diploid genome assembly based structural variant calling package for stLFR linked-read
Authors: Liu Yichen Henry , Grubbs Griffin L. , Zhang Lu , Fang Xiaodong , Dill David L. , Sidow Arend , Zhou Xin 
Published: August 2019

AbstractMotivationIdentifying structural variants (SVs) is of critical importance in health and disease, however, detecting them remains a scientific and computing challenge. Several linked-read sequencing technologies, including 10X linked-read, TELL-Seq, and single tube long fragment read (stLFR), have been recently developed as cost-effective approaches to reconstruct multi-megabase haplotypes (phase blocks) from sequence data of a single sample. These technologies provide an optimal sequencing platform to characterize SVs, though few computational algorithms can utilize them. Thus, we developed Aquila_stLFR, an approach that resolves SVs through haplotype-based assembly of stLFR linked-reads.ResultsAquila_stLFR first partitions LFRs into two haplotype-specific blocks, by taking advantage of the potential phasing ability of the linked-read itself. Each haplotype is then assembled independently, to achieve a complete diploid assembly to finally reconstruct the genome-wide SVs. We benchmarked Aquila_stLFR on a well-studied sample, NA24385, and showed Aquila_stLFR can detect medium to large size (50bp – 10kb) deletions with a high sensitivity and insertions with a high specificity.AvailabilitySource code and documentation are available onhttps://github.com/maiziex/Aquila_stLFR.Contactmaizie.zhou@vanderbilt.eduSupplementary informationSupplementary data are available atBioinformaticsonline.
The Clinical Significance and Biological Function ofDPEP1in B-cell Acute Lymphoblastic Leukemia
Authors: Zhang Jia-Min , Xu Yan , Gale Robert Peter , Wu Li-Xin , Zhang Jing , Feng Yong-Huai , Qin Ya-Zhen , Jiang Hao , Jiang Qian , Jiang Bin , Liu Yan-Rong , Chen Yu-Hong , Wang Yu , Zhang Xiao-Hui , Xu Lan-Ping , Huang Xiao-Jun , Liu Kai-Yan , Ruan Guo-Rui 
Published: August 2019

AbstractDehydropeptidase-1 (DPEP1) is a zinc-dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B-cell acute lymphoblastic leukaemia (ALL) is unknown.We found that in adults with common-B-cell ALL highDPEP1transcript levels at diagnosis was independently-associated with an increased CIR and worse RFS compared with subjects with low transcript levels. We show an increased proliferation and pro-survival role ofDPEP1in B-cell ALL cellsviaregulation of phosphCREB and p53 which may be the biological basis of the clinical correlation we report. Our data implicateDPEP1expression in the biology of common B-cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analyzingDPEP1transcript levels at diagnosis could help predict therapy-outcomes. Moreover, regulation ofDPEP1expression could be a therapy target in B-cell ALL.
Self-reported health behaviors and longitudinal cognitive performance: Results from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Mueller Kimberly D. , Koscik Rebecca L. , Norton Derek , Morris Martha C. , Jonaitis Erin M. , Clark Lindsay R. , Fields Taylor , Allison Samantha , Berman Sara , Kraning Sarah , Zuelsdorff Megan , Okonkwo Ozioma , Chin Nathaniel , Carlsson Cynthia , Bendlin Barbara B. , Hermann Bruce , Johnson Sterling C. 
Published: August 2019

AbstractBackgroundStudies have suggested associations between self-reported engagement in health behaviors and reduced risk of cognitive decline. Most studies explore these relationships using one health behavior, often cross-sectionally or with dementia as the outcome. In this study, we explored whether several individual self-reported health behaviors were associated with cognitive decline when considered simultaneously, using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), an Alzheimer’s disease risk-enriched cohort who were non-demented and in late midlife at baseline.MethodWe analyzed longitudinal cognitive data from 828 participants in WRAP, with a mean age at baseline cognitive assessment of 57 (range = 36-78, sd = 6.8) and an average of 6.3 years (standard deviation = 1.9, range = 2-10) of follow-up. The primary outcome was a multi-domain cognitive composite, and secondary outcomes were immediate/delayed memory and executive function composites. Predictors of interest were self-reported measures of physical activity, cognitive activity, adherence to a Mediterranean-style diet (MIND), and interactions with each other and age. We conducted linear mixed effects analyses within an Information-theoretic (IT) model averaging (MA) approach on a set of models including covariates and combinations of these 2- and 3-way interactions. The IT approach was selected due to the large number of interactions of interest and to avoid pitfalls of traditional model selection approaches.ResultsModel-averaged results identified no significant modifiable behavior*age interactions in relationship to the primary composite outcome. In secondary outcomes, higher MIND diet scores associated with slower decline in executive function. Men showed faster decline than women on delayed memory, independent of health behaviors. There were no other significant interactions among any other health behaviors and cognitive trajectories.ConclusionsWhen multiple covariates and health behaviors were considered simultaneously, there were limited weak associations with cognitive decline in this age range. These results may be explained alone or in combination by three alternative explanations: 1) the range of cognitive decline is in middle age is too small to observe relationships with health behaviors, 2) the putative associations of these health behaviors on cognition may not be robust in this age range, or 3) the self-reported measures of the health behaviors may not be optimal for predicting cognitive decline. More study may be needed that incorporates sensitive measures of health behaviors, AD biomarker profiles, and/or other disease comorbidities.
Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study
Authors: Liu Shue , Yi Hyun , Gu Jun , Ikegami Daigo , Hayashi Kentaro , Hao Shuanglin 
Published: August 2019

AbstractOpioid use disorder (OUD) is a significant clinical and social problem, inducing dependence/addiction and over-dose death. Opioid dependence/withdrawal contributes to the addiction vulnerability. Limited understanding of the exact mechanisms of morphine withdrawal leads to failure to adequately manage opioid withdrawal symptoms. Determining new molecular mechanisms of morphine withdrawal (MW) may allow development of novel therapeutic strategies for treating this disorder. Chronic morphine with naloxone precipitation induces MW behavioral response. Sirt3 (one member of sirtuins family) as a mitochondrial fidelity, plays an important role in mitochondrial homeostasis through the direct regulation of mitochondrial energy metabolism, ATP synthesis, detoxification of mitochondrial ROS, etc. In the pilot study, we found that (1) cultured neurons infected with lentiviral vector expressing Sirt3 induced over-expression of Sirt3, (2) microinjection of LV-Sirt3 into the vlPAG increased Sirt3 protein expression in rats, (3) MW lowered the expression of Sirt3 in the vlPAG, and (4) microinjection of LV-Sirt3 into the vlPAG decreased the MW behavioral response. Current preliminary study demonstrates that complement of Sirt3 in the PAG suppressed MW, providing a novel therapeutic approach to morphine physical withdrawal symptoms. The exact up-and/or down-stream factors of Sirt3 in the model are under the investigation.
Distinct neuronal subtypes of the lateral habenula differentially target ventral tegmental area dopamine neurons
Authors: Wallace Michael L. , Huang Kee Wui , Hochbaum Daniel , Hyun Minsuk , Radeljic Gianna , Sabatini Bernardo L. 
Published: August 2019

ABSTRACTThe lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find 5 subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb we describe 4 neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit.