bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment
Authors: Sliz Eeva , Kettunen Johannes , Holmes Michael V , Oliver-Williams Clare , Boachie Charles , Wang Qin , Männikkö Minna , Sebert Sylvain , Walters Robin , Lin Kuang , Millwood Iona Y , Clarke Robert , Li Liming , Rankin Naomi , Welsh Paul , Delles Christian , Jukema J. Wouter , Trompet Stella , Ford Ian , Perola Markus , Salomaa Veikko , Järvelin Marjo-Riitta , Chen Zhengming , Lawlor Debbie A , Ala-Korpela Mika , Danesh John , Smith George Davey , Sattar Naveed , Butterworth Adam , Würtz Peter 
Published: March 2018

ABSTRACTBackgroundBoth statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.Methods228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) usingPCSK9rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.ResultsScaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C;P=2 × 10−7for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.ConclusionsGenetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.
Protein-Protein Interaction Network Analysis and Identification of Key Players in nor-NOHA and NOHA Mediated Pathways for Treatment of Cancer through Arginase Inhibition: Insights from Systems Biology
Authors: Ahammad Ishtiaque 
Published: March 2018

AbstractL-arginine is involved in a number of biological processes in our bodies. Metabolism of L-arginine by the enzyme arginase has been found to be associated with cancer cell proliferation. Arginase inhibition has been proposed as a potential therapeutic means to inhibit this process. N-hydroxy-nor-L-Arg (nor-NOHA) and N (omega)-hydroxy-L-arginine (NOHA) has shown promise in inhibiting cancer progression through arginase inhibition. In this study, nor-NOHA and NOHA-associated genes and proteins were analyzed with several Bioinformatics and Systems Biology tools to identify the associated pathways and the key players involved so that a more comprehensive view of the molecular mechanisms including the regulatory mechanisms can be achieved and more potential targets for treatment of cancer can be discovered. Based on the analyses carried out, 3 significant modules have been identified from the PPI network. Five pathways/processes have been found to be significantly associated with nor-NOHA and NOHA associated genes. Out of the 1996 proteins in the PPI network, 4 have been identified as hub proteins-SOD, SOD1, AMD1, and NOS2. These 4 proteins have been implicated in cancer by other studies. Thus, this study provided further validation into the claim of these 4 proteins being potential targets for cancer treatment.
Time-dependent mnemonic vulnerability induced by new-learning
Authors: Shen Fengtao , Ku Yixuan , Wu Jue , Cui Yue , Li Jianqi , Wang Zhaoxin , Wang Huimin , Kwok Sze Chai 
Published: March 2018

AbstractReactivation renders consolidated memory labile again, and the ensuing temporary reconsolidation process is highly susceptible to mnemonic modification. Here, we show that memories in such an unstable state could be reprogrammed by sheer behavioral means, bypassing the need for pharmacological intervention. In two experiments using a “face-location associationc” paradigm in which participants experienced a “Learning – New-learning – Final-test” programme, we demonstrate that reactivated memory traces were robustly hampered when the new learning was strategically administered within a critical 20-minute time window. Using fMRI, we further advance our theoretical understanding that this lability can be mechanistically explained by the differential activation in the hippocampal-amygdala memory system implicated by the new-learning whereas the mnemonic intrusion caused by newly learned memories is efficaciously reconciled by the left inferior frontal gyrus. Our findings provide important implications for educational and clinical practices in devising effective strategies for memory integration.
Physiological Significance of R-fMRI Indices: Can Functional Metrics Differentiate Structural Lesions (Brain Tumors)?
Authors: Fan Zhen , Chen Xiao , Qi Zeng-Xin , Li Le , Lu Bin , Jiang Cong-Lin , Zhu Ren-Qing , Chen Liang , Yan Chao-Gan 
Published: March 2018

ABSTRACTResting-state functional MRI (R-fMRI) research has recently entered the era of “big data”, however, few studies have provided a rigorous validation of the physiological underpinnings of R-fMRI indices. Although studies have reported that various neuropsychiatric disorders exhibit abnormalities in R-fMRI measures, these “biomarkers” have not been validated in differentiating structural lesions (brain tumors) as a concept proof. We enrolled 60 patients with intracranial tumors located in the unilateral cranial cavity and 60 matched normal controls to test whether R-fMRI indices can differentiate tumors, which represents a prerequisite for adapting such indices as biomarkers for neuropsychiatric disorders. Common R-fMRI indices of tumors and their counterpart control regions, which were defined as the contralateral normal areas (for amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo) and degree centrality (DC)) and ipsilateral regions surrounding the tumors (for voxel-mirrored homotopic connectivity (VMHC)), were comprehensively assessed. According to paired t-tests with a Bonferroni correction, only ALFF (both with and without Z-standardization) and VMHC (Fisher’s r-to-z transformed) could successfully differentiate substantial tumors from their counterpart normal regions in patients. And DC was not able to differentiate tumor from normal unless employed Z-standardization. To validate the lower power in the between-subject design than in the within-subject design, each metric was calculated in a matched control group, and two-sample t-tests were used to compare the patient tumors and the normal controls at the same area. Only ALFF (and that with Z-standardization) along with VMHC succeeded in differentiating significant differences between tumors and the sham tumors areas of normal controls. This study tested the premise of R-fMRI biomarkers for differentiating lesions, and brings a new understanding to physical significance of the Z-standardization.
Novel role of Lin28 signaling in regulation of mammalian PNS and CNS axon regeneration
Authors: Wang Xue-Wei , Liu Chang-Mei , Hall Philip A. , Jiang Jing-Jing , Katchis Christopher D. , Kang Sehwa , Dong Bryan C. , Li Shuxin , Zhou Feng-Quan 
Published: March 2018

SummarySeveral signaling molecules involved in cellular reprogramming have been shown to regulate mammalian axon regeneration. We hypothesized that reprogramming factors are key regulators of axon regeneration. Here we investigated the role of Lin28, an important reprogramming factor, in the regulation of axon regeneration. We found that Lin28a and Lin28b and their regulatory partners, let-7 microRNAs (miRNAs), were both necessary and sufficient in regulating mature sensory axon regeneration in vivo. More importantly, overexpression of either Lin28a or Lin28b in mature retinal ganglion cells (RGCs) promoted robust and sustained optic nerve regeneration. Additionally, combined overexpression of Lin28a and downregulation of PTEN in RGCs acted additively to promote optic nerve regeneration by reducing the backward turning of regenerating RGC axons. Our findings not only identified a novel molecule promoting optic nerve regeneration but also suggested that reprogramming factors may play vital roles in regulating axon regeneration in mammals.
Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes
Authors: Altanerova Ursula , Jakubechova Jana , Benejova Katarina , Priscakova Petra , Pesta Martin , Pitule Pavel , Topolcan Ondrej , Kausitz Juraj , Zdurjencikova Martina , Repiska Vanda , Altaner Cestmir 
Published: March 2018

AbstractHuman tumor trophic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‒MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‒MSCs contained mRNA of the suicide gene in the exosome’s cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‒fluorocytosine (5‒FC) effectively triggered dose‒dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‒FC to 5‒fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. MSCs transduced with the Herpes simplex virus thymidine kinase gene released exosomes causing death of tumor cells in the presence of ganciclovir. The presence of microRNAs in exosomes produced from naive MSCs and corresponding transgene transduced MSCs did not differ significantly. microRNAs from yCD::UPRT‒MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
Testing an Optimally Weighted Combination of Common and/or Rare Variants with Multiple Traits
Authors: Wang Zhenchuan , Sha Qiuying , Zhang Kui , Zhang Shuanglin 
Published: March 2018

AbstractJoint analysis of multiple traits has recently become popular since it can increase statistical power to detect genetic variants and there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. Currently, most of existing methods test the association between multiple traits and a single common variant. However, the variant-by-variant methods for common variant association studies may not be optimal for rare variant association studies due to the allelic heterogeneity as well as the extreme rarity of individual variants. In this article, we developed a statistical method by testing an optimally weighted combination of variants with multiple traits (TOWmuT) to test the association between multiple traits and a weighted combination of variants (rare and/or common) in a genomic region. TOWmuT is robust to the directions of effects of causal variants and is applicable to different types of traits. Using extensive simulation studies, we compared the performance of TOWmuT with the following five existing methods: gene association with multiple traits (GAMuT), multiple sequence kernel association test (MSKAT), adaptive weighting reverse regression (AWRR), single-TOW, and MANOVA. Our results showed that, in all of the simulation scenarios, TOWmuT has correct type I error rates and is consistently more powerful than the other five tests. We also illustrated the usefulness of TOWmuT by analyzing a whole-genome genotyping data from a lung function study.
Population genetics ofParameciummitochondrial genomes: recombination, mutational spectrum, and efficacy of selection
Authors: Johri Parul , Marinov Georgi K. , Doak Thomas G. , Lynch Michael 
Published: March 2018

ABSTRACTThe evolution of mitochondrial genomes and their population-genetic environment among unicellular eukaryotes are understudied. Ciliate mitochondrial genomes exhibit a unique combination of characteristics, including a linear organization and the presence of multiple genes with no known function or detectable homologs in other eukaryotes. Here we study the variation of ciliate mitochondrial genomes both within and across thirteen highly divergedParameciumspecies, including multiple species from theP. aureliaspecies complex, with four outgroup species:P. caudatum,P. multimicronucleatum, and two strains that may represent novel related species. We observe extraordinary conservation of gene order and protein-coding content inParameciummitochondria across species. In contrast, significant differences are observed in tRNA content and copy number, which is highly conserved in species belonging to theP. aureliacomplex but variable among and even within the otherParameciumspecies. There is an increase in GC content from ~20% to ~40% on the branch leading to theP. aureliacomplex. Patterns of polymorphism in population-genomic data and mutation-accumulation experiments suggest that the increase in GC content is primarily due to changes in the mutation spectra in theP. aureliaspecies. Finally, we find no evidence of recombination inParameciummitochondria and find that the mitochondrial genome appears to experience either similar or stronger efficacy of purifying selection than the nucleus.
A network of MAP-Kinase pathways and transcription factors regulates cell-to-cell communication and cell wall integrity inNeurospora crassa
Authors: Fischer Monika S. , Wu Vincent W. , Lee Ji E. , O’Malley Ronan C. , Glass N. Louise 
Published: March 2018

ABSTRACTMaintenance of cell integrity and cell-to-cell communication are fundamental biological processes. Filamentous fungi, such asNeurospora crassa, depend on communication to locate compatible cells, coordinate cell fusion, and establish a robust hyphal network. Two MAP-Kinase pathways are essential for communication and cell fusion inN. crassa; the Cell Wall Integrity/MAK-1 pathway and the MAK-2 (signal response) pathway. Previous studies have demonstrated several points of cross talk between the MAK-1 and MAK-2 pathways, which is likely necessary for oordinating chemotropic growth toward an extracellular signal, and then mediating cell fusion. Canonical MAP-Kinase pathways begin with signal reception and end with a transcriptional response. Two transcription factors, ADV-1 and PP-1, are essential for communication and cell fusion. PP-1 is the conserved target of MAK-2, while it is unclear what targets ADV-1. We did RNAseq onΔadv-1, Δpp-1, and wild-type cells and found that ADV-1 and PP-1 have a shared regulon including many genes required for communication, cell fusion, growth, development, and stress response. We identified ADV-1 and PP-1 binding sites across the genome by adapting thein vitromethod of DNA-Affinity Purification sequencing (DAP-seq) forN. crassa. To elucidate the regulatory network, we misexpressed each transcription factor in each upstream MAPK deletion mutant. Misexpression ofadv-1was sufficient to fully suppress the phenotype of theΔpp-1mutant and partially suppress the phenotype of theΔmak-1mutant. Collectively, our data demonstrate that the MAK-1-ADV-1 and MAK-2- PP-1 pathways form a tight regulatory network that maintains cell integrity and mediates communication and cell fusion.
Prosody perception in children: studying individual differences with novel brain and behavioral approaches
Authors: Myers Brett , Vaughan Chloe , Soman Uma , Blain Scott , Korsnack Kylie , Camarata Stephen , Gordon Reyna L. 
Published: March 2018

AbstractA sizeable literature has shown that perception of prosodic elements bolsters speech comprehension across developmental stages; recent work also suggests that variance in musical aptitude predicts individual differences in prosody perception in adults. The current study investigates brain and behavioral methods of assessing prosody perception and tests the relationship with musical rhythm perception in 35 school-aged children (age range: 5;5 to 8;0 years, M = 6;7 years, SD = 10 months; 18 females). We applied stimulus reconstruction, a technique for analyzing EEG data by fitting a temporal response function that maps the neural response back to the sensory stimulus. In doing so, we obtain a measure of neural encoding of the speech envelope in passive listening to continuous narratives. We also present a behavioral prosody assessment that requires holistic judgments of filtered speech. The results from these typically developing children revealed that individual differences in stimulus reconstruction in the delta band, indexing neural synchrony to the speech envelope, are significantly related to individual differences in behavioral measurement of prosody perception. In addition, both of these measures are moderately to strongly correlated with musical rhythm perception skills. Results support a domain-general mechanism for cognitive processing of speech and music.Graphical Abstract
Host-derived population genomics data provides insights into bacterial and diatom composition of the killer whale skin
Authors: Hooper Rebecca , Brealey Jaelle C. , van der Valk Tom , Alberdi Antton , Durban John W. , Fearnbach Holly , Robertson Kelly M. , Baird Robin W. , Hanson M. Bradley , Wade Paul , Thomas M. , Gilbert P. , Morin Phillip A. , Wolf Jochen B.W. , Foote Andrew D. , Guschanski Katerina 
Published: March 2018

AbstractRecent exploration into the interactions and relationship between hosts and their microbiota has revealed a connection between many aspects of the host’s biology, health and associated microorganisms. Whereas amplicon sequencing has traditionally been used to characterise the microbiome, the increasing number of published population genomics datasets offer an underexploited opportunity to study microbial profiles from the host shotgun sequencing data. Here, we use sequence data originally generated from killer whale Orcinus orca skin biopsies for population genomics, to characterise the skin microbiome and investigate how host social and geographic factors influence the microbial community composition. Having identified 845 microbial taxa from 2.4 million reads that did not map to the killer whale reference genome, we found that both ecotypic and geographic factors influence community composition of killer whale skin microbiomes. Furthermore, we uncovered key taxa that drive the microbiome community composition and showed that they are embedded in unique networks, one of which is tentatively linked to diatom presence and poor skin condition. Community composition differed between Antarctic killer whales with and without diatom coverage, suggesting that the previously reported episodic migrations of Antarctic killer whales to warmer waters associated with skin turnover may control the effects of potentially pathogenic bacteria such as Tenacibaculum dicentrarchi. Our work demonstrates the feasibility of microbiome studies from host shotgun sequencing data and highlights the importance of metagenomics in understanding the relationship between host and microbial ecology.
Spatial and ontogenetic variation in susceptibility to polarotacticecological traps
Authors: Villalobos-Jiménez Giovanna , Meah Rochelle , Hassall Christopher 
Published: March 2018

AbstractEcological traps occur when environmental cues become unreliable, causing an evolutionary mismatch between features of the environment and expected outcome that leads to suboptimal behavioural responses and, ultimately, reduced fitness. Ecological traps arise due to anthropogenic disturbance in the environment introducing novel elements that mimic those environmental cues. Therefore, ecological traps represent a strong selective pressure in areas where anthropogenic changes are frequent, such as cities. However, given the exposure to these traps over generations, localised adaptations to ecological traps might be expected in urban populations. Dragonflies and damselflies (Odonata) are one of the many taxa vulnerable to ecological traps: odonates use horizontally polarised light as a cue of suitable water bodies, although some artificial surfaces also reflect horizontally polarised light strongly, thus misleading odonates to oviposit preferentially on these unsuitable surfaces rather than in water. Here, we compare the behavioural response to horizontally polarised light between urban and rural populations of the odonateIschnura elegansto test the potential for localised adaptations to ecological traps. Laboratory choice experiments were performed using field-caught adults from urban and rural areas, and individuals reared in controlled conditions to account for environmental variation and exposure to polarised light. We also studied the association between ontogeny and polarotaxis that has been suggested – but not empirically tested – by other studies. The results showed that field-caught rural individuals had a significantly stronger preference for horizontally polarised light compared to urban individuals, suggesting there is strong selection against polarotaxis in urban areas. However, individuals reared in controlled conditions showed no difference between urban and rural populations, suggesting that there has not yet been adaptation in urban odonates. Instead, adults developed a strong preference for horizontally polarised light with increasing age, showing that mature adults are more prone to ecological traps. Possible mechanisms driving this response are discussed.
Weighted trait-abundance early warning signals better predict population collapse
Authors: Clements Christopher F. , de Pol Martijn van , Ozgul Arpat 
Published: March 2018

AbstractPredicting population collapse in the face of unprecedented anthropogenic pressures is a key challenge in conservation. Abundance-based early warning signals have been suggested as a possible solution to this problem; however, they are known to be susceptible to the spatial and temporal subsampling ubiquitous to abundance estimates of wild population. Recent work has shown that composite early warning methods that take into account changes in fitness-related phenotypic traits - such as body size - alongside traditional abundance-based signals are better able to predict collapse, as trait dynamic estimates are less susceptible to sampling protocols. However, these previously developed composite early warning methods weighted the relative contribution of abundance and trait dynamics evenly. Here we present an extension to this work where the relative importance of different data types can be weighted in line with the quality of available data. Using data from a small-scale experimental system we demonstrate that weighted indicators can improve the accuracy of composite early warning signals by >60%. Our work shows that non-uniform weighting can increase the likelihood of correctly detecting a true positive early warning signal in wild populations, with direct relevance for conservation management.