bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associatedSCN1Amutation
Authors: Xie Yunyao , Ng Nathan N. , Safrina Olga S. , Ramos Carmen M. , Ess Kevin C. , Schwartz Philip H. , Smith Martin A. , O’Dowd Diane K. 
Published: January 2019

AbstractOver 1250 mutations inSCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270TSCN1Amutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.
Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr−/− mice
Authors: Tao Huan , Huang Jiansheng , Yancey Patricia G. , Yermalitsky Valery , Blakemore John L. , Zhang Youmin , Ding Lei , Zagol-Ikapitte Irene , Amarnath Venkataraman , Boutaud Olivier , Oates John A. , Roberts L. Jackson , Davies Sean S. , Linton MacRae F. 
Published: January 2019

AbstractThe pathogenesis of atherosclerosis may be accelerated by oxidative stress, which produces lipid peroxidation. Among the products of lipid peroxidation are highly reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. We investigated the impact of treatment with the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in hyperlipidemic Ldlr−/− mice, a model of familial hypercholesterolemia (FH). Compared to mice treated with vehicle, 2-HOBA significantly decreased atherosclerosis in hypercholesterolemic Ldlr−/− mice by 31% in the proximal aortas and 60% in en face aortas, in the absence of changes in blood lipid levels. 2-HOBA reduced MDA content in HDL and LDL. Consuming a western diet increased plasma MDA-apoAI adduct levels in Ldlr−/− mice. 2-HOBA inhibited MDA-apoAI formation and increased the capacity of the mouse HDL to reduce macrophage cholesterol stores. Importantly, 2-HOBA reduced the MDA- and IsoLG-lysyl content in atherosclerotic aortas in Ldlr−/− mice. Furthermore, 2-HOBA diminished oxidative stress-induced inflammatory responses in macrophages, reduced the number of TUNEL-positive cells in atherosclerotic lesions by 72%, and decreased serum proinflammatory cytokines. Furthermore, 2-HOBA enhanced efferocytosis and promoted characteristics of stable plaque formation in mice as evidenced by a 69% (p<0.01) reduction in necrotic core and by increased collagen content (2.7-fold) and fibrous cap thickness (2.1-fold). HDL from patients with FH had increased MDA content resulting in a reduced ability of FH-HDL to decrease macrophage cholesterol content versus controls. Our results demonstrate that dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects on lipoproteins and reduces atherosclerosis in a murine model of FH, supporting its potential as a novel therapeutic approach for the prevention and treatment of human atherosclerotic cardiovascular disease.Abbreviations2-HOBA, 2-hydroxybenzylamine; 4-HOBA, 4-hydroxybenzylamine; MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal; IsoLGs, isolevuglandins; HDL, high-density lipoproteins; LDL, lowdensity lipoprotein; LDLR, low-density lipoprotein receptor; ApoAI, apolipoprotein AI; ApoB, apolipoprotein B; ROS, reactive oxygen species; IL, interleukin.
Domain-specific working memory, but not dopamine-related genetic variability, shapes reward-based motor learning
Authors: Holland Peter , Codol Olivier , Oxley Elizabeth , Taylor Madison , Hamshere Elizabeth , Joseph Shadiq , Huffer Laura , Galea Joseph M. 
Published: January 2019

AbstractThe addition of rewarding feedback to motor learning tasks has been shown to increase the retention of learning, spurring interest in the possible utility for rehabilitation. However, laboratory-based motor tasks employing rewarding feedback have repeatedly been shown to lead to great inter-individual variability in performance. Understanding the causes of such variability is vital for maximising the potential benefits of reward-based motor learning. Thus, using a large cohort (n=241) we examined whether spatial (SWM), verbal (VWM) and mental rotation (RWM) working memory capacity and dopamine-related genetic profiles were associated with performance in two reward-based motor tasks. The first task assessed participant’s ability to follow a hidden and slowly shifting reward region based on hit/miss (binary) feedback. The second task investigated participant’s capacity to preserve performance with binary feedback after adapting to the rotation with full visual feedback. Our results demonstrate that higher SWM is associated with greater success and a greater capacity to reproduce a successful motor action, measured as change in reach angle following reward. Whereas higher RWM was predictive of an increased propensity to express an explicit strategy when required to make large adjustments in reach angle. Therefore, both SWM and RWM were reliable predictors of success during reward-based motor learning. Change in reach direction following failure was also a strong predictor of success rate, although we observed no consistent relationship with any type of working memory. Surprisingly, no dopamine-related genotypes predicted performance. Therefore, working memory capacity plays a pivotal role in determining individual ability in reward-based motor learning.Significance statementReward-based motor learning tasks have repeatedly been shown to lead to idiosyncratic behaviours that cause varying degrees of task success. Yet, the factors determining an individual’s capacity to use reward-based feedback are unclear. Here, we assessed a wide range of possible candidate predictors, and demonstrate that domain-specific working memory plays an essential role in determining individual capacity to use reward-based feedback. Surprisingly, genetic variations in dopamine availability were not found to play a role. This is in stark contrast with seminal work in the reinforcement and decision-making literature, which show strong and replicated effects of the same dopaminergic genes in decision-making. Therefore, our results provide novel insights into reward-based motor learning, highlighting a key role for domain-specific working memory capacity.
Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression
Authors: Sasse Sarah K. , Gruca Margaret , Allen Mary A. , Kadiyala Vineela , Song Tengyao , Gally Fabienne , Gupta Arnav , Pufall Miles A. , Dowell Robin D. , Gerber Anthony N. 
Published: January 2019

AbstractThe glucocorticoid receptor (GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements remains controversial. Here, using Global Run-on Sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 minutes. Many repressed regulatory regions reside within ‘hyper-ChIPable’ genomic regions that are subject to non-specific interactions with some antibodies. When this was accounted for, we determined that transcriptional repression occurs without local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and enhancer-reporter assays. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions. Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.
Brain Abnormalities Associated with Self-Injurious Thoughts and Behaviors: A Meta-Analysis of Neuroimaging Studies
Authors: Huang Xieyining , Rootes-Murdy Kelly , Bastidas Diana M. , Nee Derek E. , Franklin Joseph C. 
Published: January 2019

AbstractSelf-injurious thoughts and behaviors (SITBs) have long been believed to result in part from brain abnormalities. This meta-analysis aims to evaluate whether the extant literature justifies any definitive conclusions about whether and how SITBs may be associated with aberrant findings. Sixty studies published through June 1st, 2017 that compared individuals with and without SITBs were included, resulting in 734 coordinates. A pooled meta-analysis assessing for general risk for SITBs indicated a lack of convergence on structural abnormalities. Functional abnormalities in the precuneus/posterior cingulate cortex (PCC), temporal-parietal junction, and rostral-lateral prefrontal cortex were significant using multi-level kernel density analysis but nonsignificant using activation-likelihood estimation. Separate analyses for types of SITBs suggested that deliberate self-harm might be associated with abnormalities in the precuneus/PCC. Some moderator effects were detected. Overall, the meta-analytic evidence was not robust. More studies are needed to reach definitive conclusions about whether SITBs are associated with brain abnormalities.
Identification of the best index case significantly improves mutation detection rates in families with hereditary breast and ovarian cancer
Authors: Wyrwoll Margot J. , Fuchs Lea , Waschk Daniel E.J. 
Published: January 2019

AbstractTo date, a disease-causing mutation can be found in 15-30% of families with hereditary breast and ovarian cancer (HBOC) and it is believed that more than half of the cases still remain unsolved. Usually it is intended to perform genetic analyses in the family member with the most severe phenotype, which, however, may not always be possible. Moreover, no standard criteria have been established to define the person who is most suitable for genetic testing within a family: ‘the best index case’. We therefore established clinical criteria to identify the best index case in HBOC and analyzed the impact on genetic testing. 130 patients who presented at our department from 2016 to 2018 were divided into two groups. In group A (N = 98) genetic analyses were performed in the best index case based on our criteria. In group B (N = 32) at least one other family member was considered a better index case. The detection rate of expected mutations was significantly higher for group A (64.3% vs. 32.0%, p = 0.034) while there was no significant difference of calculated mutation carrier risks between these groups. We conclude that the mutation detection rate in families with HBOC is notably higher after identifying the best index case for genetic testing according to the clinical selection criteria reported here.
The visual system of the genetically tractable crustaceanParhyale hawaiensis: diversification of eyes and visual circuits associated with low-resolution vision
Authors: Ramos Ana Patricia , Gustafsson Ola , Labert Nicolas , Salecker Iris , Nilsson Dan-Eric , Averof Michalis 
Published: January 2019

AbstractBackgroundArthropod eyes have diversified during evolution to serve multiple needs, such as finding mates, hunting prey, and navigating in complex surroundings under varying light conditions. This diversity is reflected in the optical apparatus, photoreceptors and neural circuits that underpin vision. While this diversity has been extensively documented, our ability to genetically manipulate the visual system to investigate its function is largely limited to a single species, the fruitflyDrosophila melanogaster. Here, we describe the visual system ofParhyale hawaiensis, an amphipod crustacean for which we have established tailored genetic tools.ResultsAdultParhyalehave apposition-type compound eyes made up of ∼50 ommatidia. Each ommatidium contains four photoreceptor cells with large rhabdomeres (R1-4), expected to be sensitive to the polarisation of light, and one photoreceptor cell with a smaller rhabdomere (R5). The two types of photoreceptors express different opsins, belonging to families with distinct wavelength sensitivities. Using thecis.-regulatory regions of opsin genes, we established transgenic reporters expressed in each photoreceptor cell type. Based on these reporters, we show that R1-4 and R5 photoreceptors extend axons to the first optic lobe neuropil, revealing striking differences compared with the photoreceptor projections found in related crustaceans and insects. Investigating visual function, we show thatParhyalehas a positive phototactic response and is capable of adapting its eyes to different levels of light intensity.ConclusionsWe propose that the visual system ofParhyaleserves low-resolution visual tasks, such as orientation and navigation, based on broad gradients of light intensity and polarisation. Optic lobe structure and photoreceptor projections point to significant divergence from the conserved visual circuits found in other malacostracan crustaceans and insects, which could be associated with a shift to low-resolution vision. Our study provides the foundation for research in the visual system of this genetically tractable species.
A novel thermostable aspartic protease fromTalaromyces leycettanusand its specific autocatalytic activation through an intermediate transition state
Authors: Guo Yujie , Tu Tao , Ren Yaxin , Wang Yaru , Bai Yingguo , Su Xiaoyun , Wang Yuan , Yao Bin , Huang Huoqing , Luo Huiying 
Published: January 2019

ABSTRACTAspartic proteases exhibit optimum enzyme activity under acidic condition and have been extensively used in food, fermentation and leather industries. In this study, a novel aspartic protease precursor (proTlAPA1) fromTalaromyces leycettanuswas identified and successfully expressed inPichia pastoris. Subsequently, the auto-activation processing of the zymogen proTlAPA1 was studied by SDS-PAGE and N-terminal sequencing, under different processing conditions.TlAPA1 shared the highest identity of 70.3 % with the aspartic endopeptidase fromByssochlamys spectabilis(GAD91729) and was classified into a new subgroup of the aspartic protease A1 family, based on evolutionary analysis. MatureTlAPA1 protein displayed an optimal activity at 60 °C and remained stable at temperatures of 55 °C and below, indicating the thermostable nature ofTlAPA1 aspartic protease. During the auto-activation processing of proTlAPA1, a 45 kDa intermediate was identified that divided the processing mechanism into two steps: formation of intermediates, and activation of the mature protein (TlAPA1). The former step was completely induced by pH of the buffer, while the latter process depended on protease activity. The discovery of the novel aspartic proteaseTlAPA1 and study of its activation process will contribute to a better understanding of the mechanism of aspartic proteases auto-activation.IMPORTANCEThe novel aspartic proteaseTlAPA1 was identified fromT. leycettanusand expressed as a zymogen (proTlAPA1) inP. pastoris. Enzymatic characteristics of the mature protein were studied and the specific pattern of zymogen conversion was described. The auto-activation processing of proTlAPA1 proceeded in two stages and an intermediate was identified in this process. These results describe a new subgroup of aspartic protease A1 family and provide insights into a novel mode of activation processing in aspartic proteases.
Modelling the role of dual specificity phosphatases in Herceptin resistant breast cancer cell lines
Authors: Buiga Petronela , Elson Ari , Tabernero Lydia , Schwartz Jean-Marc 
Published: January 2019

AbstractBackgroundBreast cancer remains the most lethal type of cancer for women. A significant proportion of breast cancer cases are characterised by overexpression of the human epidermal growth factor receptor 2 protein (HER2). These cancers are commonly treated by Herceptin (Trastuzumab), but resistance to drug treatment frequently develops in tumour cells. Dual-specificity phosphatases (DUSPs) are thought to play a role in the mechanism of resistance, since some of them were reported to be overexpressed in tumours resistant to Herceptin.ResultsWe used a systems biology approach to investigate how DUSP overexpression could favour cell proliferation and to predict how this mechanism could be reversed by targeted inhibition of selected DUSPs. We measured the expression of 20 DUSP genes in two breast cancer cell lines following long-term (6 months) exposure to Herceptin, after confirming that these cells had become resistant to the drug. We constructed several Boolean models including specific substrates of each DUSP, and showed that our models correctly account for resistance when overexpressed DUSPs were kept activated. We then simulated inhibition of both individual and combinations of DUSPs, and determined conditions under which the resistance could be reversed.ConclusionsThese results show how a combination of experimental analysis and modelling help to understand cell survival mechanisms in breast cancer tumours, and crucially enable us to generate testable predictions potentially leading to new treatments of resistant tumours.
Individuals’ expected genetic contributions to future generations, reproductive value, and short-term metrics of fitness in free-living song sparrows (Melospiza melodia)
Authors: Reid Jane M. , Nietlisbach Pirmin , Wolak Matthew E. , Keller Lukas F. , Arcese Peter 
Published: January 2019

AbstractAppropriately defining and enumerating ‘fitness’ is fundamental to explaining and predicting evolutionary dynamics. Yet theoretical concepts of fitness are often hard to translate into quantities that can be quantified in wild populations experiencing complex environmental, demographic, genetic and selective variation. While the ‘fittest’ entities might be widely understood to be those that ultimately leave most descendants at some future time, such long-term legacies are hard to measure, impeding evaluation of how well more tractable short-term metrics of individual fitness directly predict longer-term outcomes. One opportunity for conceptual and empirical convergence stems from the principle of individual reproductive value (Vi), defined as the number of copies of each of an individual’s alleles that is expected to be present in future generations given the individual’s realised pedigree of descendants. Since Vi tightly predicts an individual’s longer-term genetic contribution, quantifying Vi provides a tractable route to quantifying what, to date, has been an abstract fitness concept. We used complete pedigree data from free-living song sparrows (Melospiza melodia) to demonstrate that individuals’ expected genetic contributions stabilise within an observed 20-year time period, allowing individual Vi to be evaluated. Considerable among-individual variation in Vi was evident in both sexes. However, standard short-term metrics of individual fitness, comprising lifespan, lifetime reproductive success and projected growth rate, typically explained less than half the variation. Given these results, we discuss what evolutionary inferences can and cannot be directly drawn from short-term versus longer-term fitness metrics observed on individuals, and highlight that analyses of pedigree structure may provide useful complementary insights into evolutionary processes and outcomes.
Dosage-sensitivity of human transcription factor genes
Authors: Ni Zhihua , Zhou Xiao-Yu , Aslam Sidra , Niu Deng-Ke 
Published: January 2019

AbstractChanges in the copy number of protein-coding genes would lead to detrimental effects if the consequent changes in protein concentration disrupt essential cellular functions. Large-scale genomic studies have identified thousands of dosage-sensitive genes in human genome. We are interested in the dosage-sensitivity of transcription factor (TF) genes whose products are essential for the growth, division and differentiation of cells by regulating the expression of the genetic information encoded in the genome. We first surveyed the enrichment of human TF genes in four recently curated datasets of dosage-sensitive genes, including the haploinsufficient genes identified by a large-scale genomic study, the haploinsufficient genes predicted by a machine learning approach, the genes with conserved copy number across mammals, and the ohnologs. Then we selected the dosage-sensitive genes that are present in all the four dataset and regarded them as the most reliable dosage-sensitive genes, and the genes that are absent from any one of the four datasets as the most reliable dosage-insensitive genes, and surveyed the enrichments of TFs genes in these two datasets. A large number of TF genes were found to be dosage-insensitive, which is beyond the expectation based on the role of TFs. In spite of this, the likeness of TF genes to be dosage-sensitive were supported by five datasets, with the conserved-copy-number genes as the exception. The nuclear receptors are the only one family of TFs whose dosage-sensitivity was consistently supported by all the six datasets. In addition, we found that TF families with very few members are also more likely to be dosage-sensitive while the largest TF family, C2H2-ZF, are most likely dosage-insensitive. The most extensively studied TFs, p53, are not special in dosage-sensitivity. They are significantly enriched in only three datasets. We also confirmed that dosage-sensitive genes generally have long coding sequences, high expression levels and experienced stronger selective pressure. Our results indicate some TFs function in a dose-dependent manner while some other not. Gene dosage changes in some TF families like nuclear receptor would result in disease phenotypes while the effects of such changes in some TFs like C2H2-ZF would be mild.