bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinally Measured Changes in Somnolence Severity With a Visual Analog Scale in a Randomized Lithium Versus Quetiapine-IR Study in Bipolar Disorder
Authors: Gao Keming , Su Meilei , Ganocy Stephen J. , Goto Toyomi , Yuan Chengmei , Fang Fang , Conroy Carla , Brownrigg Brittany , Serrano Mary Beth , Calabrese Joseph R. 
Published: March 2019

Abstract

Objective
The aim of this study was to use a visual analog scale (VAS) longitudinally measuring somnolence severity in patients with bipolar disorder.

Methods
A data set of patients with bipolar spectrum disorders who were randomized to lithium or quetiapine-IR for 16 weeks was used. The somnolence severity was measured with a VAS from 0 to 100 (VAS based), and somnolence frequency was recorded according to incident report (incidence based) at each visit. The rates of VAS-based and incidence-based somnolence and changes in somnolence severity from baseline to the end of study were compared between the lithium and quetiapine groups. Longitudinal changes in somnolence severity were analyzed with linear regression analysis.

Results
Of 42 patients randomized, only 3 scored 0 on the VAS at baseline. The rates of incidence-based and VAS-based somnolence were similar in the lithium and quetiapine-IR groups. The VAS change scores from baseline to each visit varied in both groups with significant decreases at weeks 6 and 12 in the quetiapine-IR group only. The decrease at week 6 in the quetiapine-IR group was significantly different from that in the lithium group. Patterns of changes in somnolence severity were inconsistent in both groups. A significant interaction between time course and the decrease in VAS scores was observed in the quetiapine-IR group, but not in the lithium group.

Conclusions
Baseline somnolence was highly prevalent in patients with bipolar disorder. The change in somnolence severity was different between lithium-treated and quetiapine-treated patients. Quantifying somnolence longitudinally is important in clinical trials and practice.
Proprotein convertase subtilisin/kexin type 9 and lipid metabolism
Authors: Spolitu Stefano , Dai Wen , Zadroga John A. , Ozcan Lale 
Published: March 2019

Purpose of review
The purpose of this review is to highlight the recent findings of one of the most promising therapeutic targets in LDL cholesterol (LDL-C) management, proprotein convertase subtilisin/kexin type 9 (PCSK9).

Recent findings
Endoplasmic reticulum cargo receptor, surfeit locus protein 4 interacts with PCSK9 and regulates its exit from endoplasmic reticulum and its secretion. Once secreted, PCSK9 binds to heparin sulfate proteoglycans on the hepatocyte surface and this binding is required for PCSK9–LDL receptor (LDLR) complex formation and LDLR degradation. Posttranscriptionally, recent work has shown that PCSK9 gets degraded in lysosomes by activation of the glucagon receptor signaling, providing more data on the hormonal regulation of PCSK9. Finally, human studies with PCSK9 inhibitors offered more evidence on their benefits and safe use.

Summary
Recent work on the regulation of PCSK9 has enhanced our understanding of its biology, which may provide important information for future PCSK9-based therapies.
Ethics in the PED
Authors: Dreisinger Naomi , Moore David 
Published: March 2019

Abstract
Death is an uncommon event in the pediatric emergency department. The sudden end of a young life is always an undesirable event. Staff and family members are never prepared. Although staff in the emergency department can become routinized to caring for acutely ill and dying patients, family members may become shocked by this novel and terrible experience. Whether the patient is old or young, previously sick or healthy, it is important to stop and consider how hard it must be for the assembled family. As frontline clinicians, we all deeply care about the outcome of our patients and their families, yet for them to feel they have been understood and well cared for, it is recognized that clinicians must attend to health care conversations on a deeper and more relational level. Consideration that these events happen and reinforcing that it is difficult for all involved ensure staff that their challenges are recognized.
The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis
Authors: Magyari Melinda , Sorensen Per Soelberg 
Published: March 2019

Purpose of review
This review provides a brief update of new research findings on the changing epidemiology, disease course, and prognosis of multiple sclerosis (MS).

Recent findings
Evidence not only continues to support the female predominance in incidence and prevalence of the disease but also supports an increase in incidence of MS in geographic areas that were previously considered to be low incidence for the disease.

Summary
An increased interest in population-based registries and databases will provide more valid epidemiological measures and observational studies conducted in well-defined study populations. Such studies are crucial for an accurate description of both changing prognosis of MS and differential characteristics of the various MS phenotypes.
Title: Intergenerational effects of early adversity on survival in wild baboons
Authors: Zipple Matthew N. , Archie Elizabeth A. , Tung Jenny , Altmann Jeanne , Alberts Susan C. 
Published: March 2019

AbstractIn humans and nonhuman animals, early life adversity can affect an individual’s health, survival, and fertility for many years after the adverse experience. However, whether early life adversity also imposes intergenerational effects on the exposed individual’s offspring is not well understood. Here, we fill this gap by leveraging prospective, longitudinal data on a wild, long-lived primate. We find that juveniles whose mothers experienced early life adversity exhibit high mortality before age 4, and this effect is independent of the juvenile’s own experience of early adversity. Furthermore, our results point towards a strong role for classic parental effects in driving these effects: mothers that experienced early life adversity displayed reduced viability in adulthood, which in turn led to reductions in offspring survival. Importantly, these mothers’ juvenile offspring often preceded them in death by 1 to 2 years, indicating that, for high adversity mothers, the quality of maternal care declines near the end of life. While we cannot exclude direct effects of a parent’s environment on offspring quality (e.g., transgenerational epigenetic changes), our results are most consistent with a classic parental effect, in which the environment experienced by a parent affects its future phenotype and therefore its offspring’s phenotype. Together, our findings demonstrate that adversity experienced by individuals in one generation can have strong effects on the survival of offspring in the next generation, even if those offspring did not themselves experience early adversity.
Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression
Authors: Courtney David G. , Chalem Andrea , Bogerd Hal P. , Law Brittany A. , Kennedy Edward M. , Holley Christopher L. , Cullen Bryan R. 
Published: March 2019

AbstractWhile it has been known for several years that viral RNAs are subject to the addition of several distinct covalent modifications to individual nucleotides, collectively referred to as epitranscriptomic modifications, the effect of these editing events on viral gene expression has been controversial. Here, we report the purification of murine leukemia virus (MLV) genomic RNA to homogeneity and show that this viral RNA contains levels ofN6-methyladenosine (m6A), 5-methylcytosine (m5C) and 2’O-methylated (Nm) ribonucleotides that are an order of magnitude higher than detected on bulk cellular mRNAs. Mapping of m6A and m5C residues on MLV transcripts identified multiple discrete editing sites and allowed the construction of MLV variants bearing silent mutations that removed a subset of these sites. Analysis of the replication potential of these mutants revealed a modest but significant attenuation in viral replication in 3T3 cells in culture. Consistent with a positive role for m6A and m5C in viral replication, we also demonstrate that overexpression of the key m6A reader protein YTHDF2 enhances MLV replication, while downregulation of the m5C writer NSUN2 inhibits MLV replication.ImportanceThe data presented in this manuscript demonstrate that MLV RNAs bear an exceptionally high level of the epitranscriptomic modifications m6A, m5C and Nm, thus suggesting that these each facilitate some aspect of the viral replication cycle. Consistent with this hypothesis, we demonstrate that mutational removal of a subset of these m6A or m5C modifications from MLV transcripts inhibits MLV replication incisand a similar result was also observed upon manipulation of the level of expression of key cellular epitranscriptomic cofactors intrans. Together, these results argue that the addition of several different epitranscriptomic modifications to viral transcripts stimulates viral gene expression and suggest that MLV has therefore evolved to maximize the level of these modifications that are added to viral RNAs.
Driving the scalability of DNA-based information storage systems
Authors: Tomek Kyle J. , Volkel Kevin , Simpson Alexander , Hass Austin G. , Indermaur Elaine W. , Tuck James , Keung Albert J. 
Published: March 2019

ABSTRACTThe extreme density of DNA presents a compelling advantage over current storage media; however, in order to reach practical capacities, new approaches for organizing and accessing information are needed. Here we use chemical handles to selectively extract unique files from a complex database of DNA mimicking 5 TB of data and design and implement a nested file address system that increases the theoretical maximum capacity of DNA storage systems by five orders of magnitude. These advancements enable the development and future scaling of DNA-based data storage systems with reasonable modern capacities and file access capabilities.
TET2 regulates the neuroinflammatory response in microglia
Authors: Carrillo-Jimenez Alejandro , Deniz Özgen , Niklison-Chirou Maria Victoria , Ruiz Rocio , Bezerra-Salomão Karina , Stratoulias Vassilis , Amouroux Rachel , Yip Ping Kei , Vilalta Anna , Cheray Mathilde , Scott-Egerton Alexander Michael , Rivas Eloy , Tayara Khadija , García-Domínguez Irene , Garcia-Revilla Juan , Fernandez-Martin Juan Carlos , Espinosa-Oliva Ana Maria , Shen Xianli , StGeorge-Hyslop Peter , Brown Guy Charles , Hajkova Petra , Joseph Bertrand , Venero Jose L. , Branco Miguel Ramos , Burguillos Miguel Angel 
Published: March 2019

SummaryEpigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPSin vivo. We observed that microglia associated to amyloid β plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimer’s disease (AD) and in 5×FAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response, and suggest TET2 as a potential target to combat neurodegenerative brain disorders.
Construction and analysis of an interologous protein-protein interaction network ofCamellia sinensisleaf (TeaLIPIN) from RNA-Seq datasets
Authors: Singh Gagandeep , Singh Vikram , Singh Vikram 
Published: March 2019

AbstractWorldwide, tea (Camellia sinensis) is the most consumed beverage primarily due to the taste, flavour and aroma of its newly formed leaves; and has been used as an important ingredient in several traditional medicinal systems because of its antioxidant properties. For this medicinally and commercially important plant, design principles of gene-regulatory and protein-protein interaction networks at sub-cellular level are largely un-characterized mainly because neither its reference assembly nor annotated genome is available though plenty of its transcriptomes have been studied. In this work, we report a tea leaf interologous PPI network (TeaLIPIN) consisting of 11,208 nodes and 1,97,820 interactions. A reference transcriptome assembly was first developed from all the 44 samples of 6 publicly available leaf transcriptomes (1,567,288,290 raw reads). By inferring the high-confidence interactions among potential proteins coded by these transcripts using known experimental information about PPIs in 14 plants, an interologous PPI network was constructed and its modular architecture was explored. Comparing this PPI network with 10,000 realisations of corresponding random networks (Erdős-Rényi models) and examining over three network centrality metrics, we predict 2,931 bottleneck proteins (havingp-values<0.01). 270 of these are deduced to have transcription factor domains by developing the HMM models of known plant TFs. Final transcripts were also mapped to the draft tea genome in order to search the probable loci of their origin. We believe that the proposed novel methodology can easily be adopted to develop and explore the PPI interactomes in other plant species by making use of the available transcriptomic data.
The mRNA-bound proteome ofLeishmania mexicana: novel genetic insight into an ancient parasite
Authors: de Pablos Luis M. , Ferreira Tiago R. , Dowle Adam A. , Forrester Sarah , Parry Ewan , Newling Katherine , Walrad Pegine B. 
Published: March 2019

AbstractLeishmaniaparasite infections, termed the leishmaniases, cause significant global infectious disease burden. The lifecycle of the parasite embodies three main stages that require precise coordination of gene regulation to survive environmental shifts between sandfly and mammalian hosts. Constitutive transcription in kinetoplastid parasites means that gene regulation is overwhelmingly reliant on post-transcriptional mechanisms, yet strikingly fewLeishmania trans-regulators are known. Utilizing optimised crosslinking and deep, quantified mass spectrometry, we present a comprehensive analysis of 1,400 mRNA binding proteins (mRBPs) and whole cell proteomes from the three mainLeishmanialifecycle stages. Supporting the validity, while the crosslinked RBPome is magnitudes more enriched the protein identities of the crosslinked and non-crosslinked RBPomes were nearly identical. Moreover, multiple candidate RBPs were endogenously tagged and found to associate with discrete mRNA target pools in a stage-specific manner. Results indicate that inL.mexicanaparasites, mRNA levels are not a strong predictor of the whole cell expression or RNA binding potential of encoded proteins. Evidence includes a low correlation between transcript and corresponding protein expression and stage-specific variation in protein expression versus RNA binding potential. Unsurprisingly, RNA binding protein enrichment correlates strongly with relative replication efficiency of the specific lifecycle stage. Our study is the first to quantitatively define and compare the mRBPome of multiple stages in kinetoplastid parasites. It provides novel, in-depth insight into thetrans-regulatory mRNA:Protein (mRNP) complexes that driveLeishmaniaparasite lifecycle progression.
Precuneus stimulation alters the neural dynamics of autobiographical memory retrieval
Authors: Hebscher Melissa , Ibrahim Christine , Gilboa Asaf 
Published: March 2019

AbstractAutobiographical memory (AM) unfolds over time, but little is known about the dynamics of its retrieval. Space-based models of memory implicate the hippocampus, retrosplenial cortex, and precuneus in early memory computations. Here we used inhibitory continuous theta burst stimulation (cTBS) to determine the causal role of the precuneus in the temporal dynamics of AM retrieval. Compared to vertex, precuneus stimulation altered evoked neural activity during early memory construction, as early as 400 ms after cue presentation, as well as during later memory elaboration. We further identified a parietal late positive component during memory elaboration, the amplitude of which was associated with spatial perspective during recollection. Precuneus stimulation disrupted this association, suggesting that this region plays a crucial role in the neural representation of spatial perspective during AM. These findings help clarify the neural correlates of early memory retrieval and demonstrate a causal role for the precuneus in the temporal dynamics of AM retrieval.
Patterning of the vertebrate head in time and space by BMP signalling
Authors: Zhu Kongju , Spaink Herman P. , Durston Antony J. 
Published: March 2019

AbstractHow head patterning is regulated in vertebrates is yet to be understood. In this study, we show that frog embryos injected with Noggin at different blastula and gastrula stages had their head development sequentially arrested at different positions. When timed BMP inhibition was applied to BMP-overexpressing embryos, the expression of five genes:xcg-1(a marker of the cement gland, which is the front-most structure in the frog embryo),six3(a forebrain marker),otx2(a forebrain and mid-brain marker),gbx2(an anterior hindbrain marker) andhoxd1(a posterior hindbrain marker) were sequentially fixed. These results suggest that timed interactions between BMP and anti-BMP are involved in patterning the vertebrate head progressively in time and space. Since the above genes are not expressed sequentially, there may be a BMP dependent gene sequence during head patterning that can be arrested by BMP inhibition and regulate the specification of positional values in the head.
Rate-limiting transport of positive charges through the Sec-machinery is integral to the mechanism of protein transport
Authors: Allen William J. , Corey Robin A. , Watkins Daniel W. , Oliveira A. Sofia F. , Hards Kiel , Cook Gregory M. , Collinson Ian 
Published: March 2019

AbstractTransport of proteins across and into membranes is a fundamental biological process with the vast majority being conducted by the ubiquitous Sec machinery. In bacteria, this is usually achieved when the SecY-complex engages the cytosolic ATPase SecA (secretion) or translating ribosomes (insertion). Great strides have been made towards understanding the mechanism of protein translocation. Yet, important questions remain – notably, the nature of the individual steps that constitute transport, and how the proton-motive force (PMF) across the plasma membrane contributes. Here, we apply a recently developed high-resolution protein transport assay to explore these questions. We find that pre-protein transport is limited primarily by the diffusion of arginine residues across the membrane, particularly in the context of bulky hydrophobic sequences. This specific effect of arginine, caused by its positive charge, is mitigated for lysine which can be deprotonated and transported across the membrane in its neutral form. These observations have interesting implications for the mechanism of protein secretion, suggesting a simple mechanism by which PMF can aid transport, and enabling a ‘proton ratchet’, wherein re-protonation of exiting lysine residues prevents channel re-entry, biasing transport in the outward direction.
A gene based approach to test genetic association based on an Optimally Weighted Combination of Multiple Traits
Authors: Zhang Jianjun , Sha Qiuying , Liu Guanfu , Wang Xuexia 
Published: March 2019

AbstractThere is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases for which multiple correlated traits are often measured. Joint analysis of multiple traits could increase statistical power by aggregating multiple weak effects. Existing methods for multiple trait association tests usually study each of the multiple traits separately and then combine the univariate test statistics or combine p-values of the univariate tests for identifying disease associated genetic variants. However, ignoring correlation between phenotypes may cause power loss. Additionally, the genetic variants in one gene (including common and rare variants) are often viewed as a whole that affects the underlying disease since the basic functional unit of inheritance is a gene rather than a genetic variant. Thus, results from gene level association test can be more readily integrated with downstream functional and pathogenic investigation, whereas many existing methods for multiple trait association tests only focus on testing a single common variant rather than a gene. In this article, we propose a statistical method by Testing an Optimally Weighted Combination of Multiple traits (TOW-CM) to test the association between multiple traits and multiple variants in a genomic region (a gene or pathway). We investigate the performance of the proposed method through extensive simulation studies. Our simulation studies show that the proposed method has correct type I error rates and is either the most powerful test or comparable with the most powerful tests. In addition, we illustrate the usefulness of TOW-CM by analyzing a whole-genome genotyping data from a COPDGene study.
Class I and II aminoacyl-tRNA synthetase tRNA groove discrimination created the first synthetase•tRNA cognate pairs and was therefore essential to the origin of genetic coding
Authors: Carter Charles W. , Wills Peter R. 
Published: March 2019

ABSTRACTThe genetic code likely arose when a bidirectional gene began to produce ancestral aminoacyl-tRNA synthetases (aaRS) capable of distinguishing between two distinct sets of amino acids. The synthetase Class division therefore necessarily implies a mechanism by which the two ancestral synthetases could also discriminate between two different kinds of tRNA substrates. We used regression methods to uncover the possible patterns of base sequences capable of such discrimination and find that they appear to be related to thermodynamic differences in the relative stabilities of a hairpin necessary for recognition of tRNA substrates by Class I aaRS. The thermodynamic differences appear to be exploited by secondary structural differences between models for the ancestral aaRS called synthetase Urzymes and reinforced by packing of aromatic amino acid side chains against the nonpolar face of the ribose of A76 if and only if the tRNA CCA sequence forms a hairpin. The patterns of bases 1, 2 and 73 and stabilization of the hairpin by structural complementarity with Class I, but not Class II aaRS Urzymes appears to be necessary and sufficient to have enabled the generation of the first two aaRS•tRNA cognate pairs, and the launch of a rudimentary binary genetic coding related recognizably to contemporary cognate pairs. As a consequence, it seems likely that non-random aminoacylation of tRNAs preceded the advent of the tRNA anticodon stem-loop. Consistent with this suggestion, coding rules in the acceptor-stem bases also reveal a palimpsest of the codon•anticodon interaction, as previously proposed.