bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial replacement therapy
Authors: Dougherty Michael P. , Dolitsky Shelley , Chattopadhyay Rhea , Sauer Mark V. 
Published: June 2018

Purpose of review
The present study briefly reviews the history of mitochondrial replacement therapy (MRT); however, the focus is on recent advancements and future directions of the field. Specifically addressing societal and legal concerns and advances in MRT.

Recent findings
There continue to be new ethical debates surrounding MRT. In addition, there have been advancements in MRT techniques which could improve potential outcomes. Furthermore, advances in genetics continue to provide alternative approaches to treatment of many diseases, including alternatives to MRT.

Summary
MRT may be beneficial to eradicate a severely debilitating and often fatal disease. Despite significant supporting safety and efficacy, there are still many social and legal barriers to instituting MRT to clinical practice.
Approach motivation in human cerebral cortex
Authors: Brookshire Geoffrey , Casasanto Daniel 
Published: June 2018

Different regions of the human cerebral cortex are specialized for different emotions, but the principles underlying this specialization have remained unknown. According to thesword and shield hypothesis, hemispheric specialization for affective motivation, a basic dimension of human emotion, varies across individuals according to the way they use their hands to perform approach- and avoidance-related actions. In a test of this hypothesis, here we measured approach motivation before and after five sessions of transcranial direct current stimulation to increase excitation in the left or right dorsolateral prefrontal cortex, in healthy adults whose handedness ranged from strongly left-handed to strongly right-handed. The strength and direction of participants' handedness predicted whether electrical stimulation to frontal cortex caused an increase or decrease in their experience of approach-related emotions. The organization of approach motivation in the human cerebral cortex varies across individuals as predicted by the organization of the individuals’ motor systems. These results show that the large-scale cortical organization of abstract concepts corresponds with the way people use their hands to interact with the world. Affective motivation may re-use neural circuits that evolved for performing approach- and avoidance-related motor actions.This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
Whole genome sequencing of Neisseria meningitidis W isolates from the Czech Republic recovered in 1984 – 2017
Authors: Honskus Michal , Okonji Zuzana , Musilek Martin , Kozakova Jana , Krizova Pavla 
Published: June 2018

AbstractIntroductionThe study presents the analysis of whole genome sequence (WGS) data for Neisseria meningitidis serogroup W isolates recovered in the Czech Republic in 1984 – 2017 and their comparison with WGS data from other countries.Material and MethodsThirty-one Czech N. meningitidis W isolates, 22 from invasive meningococcal disease (IMD) and nine from healthy carriers were analysed. The 33-year study period was divided into three periods: 1984-1999, 2000-2009, and 2010-2017.ResultsMost study isolates from IMD and healthy carriers were assigned to clonal complex cc22 (n = 10) in all study periods. The second leading clonal complex was cc865 (n = 8) presented by IMD (n = 7) and carriage (n = 1) isolates that emerged in the last study period, 2010 – 2017. The third clonal complex was cc11 (n = 4) including IMD isolates from the first (1984 – 1999) and third (2010 – 2017) study periods. The following clonal complex was cc174 (n = 3) presented by IMD isolates from the first two study periods, i.e. 1984 – 1999 and 2000 – 2009. One isolate of each cc41/44 and cc1136 originated from healthy carriers from the second study period, 2000 - 2009. The comparison of WGS data for N. meningitidis W isolates recovered in the Czech Republic in the study period 1984 – 2017 and for isolates from other countries recovered in the same period showed that clonal complex cc865, ST-3342 is unique to the Czech Republic since 2010. Moreover, the comparison shows that cc11 in the Czech Republic does not comprise novel hypervirulent lineages reported from both European and non-European countries. WGS data for Czech serogroup W meningococci point to the presence of MenB vaccine antigen genes and confirm the hypothesis about the MenB vaccine potential against N. meningitidis serogroup W. All 31 study isolates were assigned to Bexsero® Antigen Sequence Types (BAST), and seven of them were of newly described BASTs.ConclusionsWGS analysis contributed considerably to a more detailed molecular characterization of N. meningitidis W isolates recovered in the Czech Republic over a 33-year period and allowed for a spatial and temporal comparison of these characteristics between isolates from the Czech Republic and other countries. In addition, the WGS data precised the base for the update of the recommendation for vaccination in the Czech Republic.
Computational evidence of a new allosteric communication pathway between active sites and putative regulatory sites in the alanine racemase ofMycobacterium tuberculosis
Authors: Jyothikumar Jayanthy , Chandani Sushil , Ramakrishna Tangirala 
Published: June 2018

AbstractAlanine racemase, a popular drug target fromMycobacterium tuberculosis, catalyzes the biosynthesis of D-alanine, an essential component in bacterial cell walls. With the help of elastic network models of alanine racemase fromMycobacterium tuberculosis, we show that the mycobacterial enzyme fluctuates between two undiscovered states—a closed and an open state. A previous experimental screen identified several drug-like lead compounds against the mycobacterial alanine racemase, whose inhibitory mechanisms are not known. Docking simulations of the inhibitor leads onto the mycobacterial enzyme conformations obtained from the dynamics of the enzyme provide first clues to a putative regulatory role for two new pockets targeted by the leads. Further, our results implicate the movements of a short helix, behind the communication between the new pockets and the active site, indicating allosteric mechanisms for the inhibition. Based on our findings, we theorize that catalysis is feasible only in the open state. The putative regulatory pockets and the enzyme fluctuations are conserved across several alanine racemase homologs from diverse bacterial species, mostly pathogenic, pointing to a common regulatory mechanism important in drug discovery.Author summaryIn spite of the discovery of many inhibitors against the TB-causing pathogenMycobacterium tuberculosis, only a very few have reached the market as effective TB drugs. Most of the marketed TB drugs induce toxic side effects in patients, as they non-specifically target human cells in addition to pathogens. One such TB drug, D-cycloserine, targets pyridoxal phosphate moiety non-specifically regardless of whether it is present in the pathogen or the human host enzymes. D-cycloserine was developed to inactivate alanine racemase in TB causing pathogen. Alanine racemase is a bacterial enzyme essential in cell wall synthesis. Serious side effects caused by TB drugs like D-cycloserine, lead to patients’ non-compliance with treatment regimen, often causing fatal outcomes. Current drug discovery efforts focus on finding specific, non-toxic TB drugs. Through computational studies, we have identified new pockets on the mycobacterial alanine racemase and show that they can bind drug-like compounds. The location of these pockets away from the pyridoxal phosphate-containing active site, make them attractive target sites for novel, specific TB drugs. We demonstrate the presence of these pockets in alanine racemases from several pathogens and expect our findings to accelerate the discovery of non-toxic drugs against TB and other bacterial infections.
DrosophilaIMP regulates Kuzbanian to control the timing of Notch signalling in the follicle cells
Authors: Fic Weronika , Faria Celia , Johnston Daniel St 
Published: June 2018

AbstractThe timing ofDrosophilaegg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here we report that follicle cells lacking the RNA-binding protein IMP go through one extra division due to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression.impmutants are epistatic toDeltamutants and give an additive phenotype withbelleanddicermutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that theimpphenotype is rescued by over-expression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane inimpmutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.SummaryIMP regulates Notch signalling in follicle cells by controlling Kuzbanian localisation to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.
BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis
Authors: Yu Lei , Jearawiriyapaisarn Natee , Lee Mary P. , Hosoya Tomonori , Wu Qingqing , Myers Greggory , Lim Kim-Chew , Kurita Ryo , Nakamura Yukio , Vojtek Anne B. , Rual Jean-François , Engel James Douglas 
Published: June 2018

SummaryHuman globin gene production transcriptionally “switches” from fetal to adult synthesis shortly after birth, and is controlled by macromolecular complexes that enhance or suppress transcription by cis-elements scattered throughout the locus. The DRED repressor is recruited to the ε- and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA binding and epigenetic enzyme components (e.g. DNMT1 and LSD1) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: the deubiquitinase BAP1 is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.
Machine learning approach to identify resting-state functional connectivity pattern serving as an endophenotype of autism spectrum disorder
Authors: Yamagata Bun , Itahashi Takashi , Fujino Junya , Ohta Haruhisa , Nakamura Motoaki , Kato Nobumasa , Mimura Masaru , Hashimoto Ryu-ichiro , Aoki Yuta 
Published: June 2018

AbstractEndophenotype refers to a measurable and heritable component between genetics and diagnosis and exists in both individuals with a diagnosis and their unaffected siblings. We aimed to identify a pattern of endophenotype consisted of multiple connections. We enrolled adult male individuals with autism spectrum disorder (ASD) endophenotype (i.e., individuals with ASD and their unaffected siblings) and individuals without ASD endophenotype (i.e., pairs of typical development (TD) siblings) and utilized a machine learning approach to classify people with and without endophenotypes, based on resting-state functional connections (FCs). A sparse logistic regression successfully classified people as to the endophenotype (area under the curve=0.78, classification accuracy=75%), suggesting the existence of endophenotype pattern. A binomial test identified that nine FCs were consistently selected as inputs for the classifier. The least absolute shrinkage and selection operator with these nine FCs predicted severity of communication impairment among individuals with ASD (r=0.68,p=0.021). In addition, two of the nine FCs were statistically significantly correlated with the severity of communication impairment (r=0.81,p=0.0026 andr=-0.60,p=0.049). The current findings suggest that an ASD endophenotype pattern exists in FCs with a multivariate manner and is associated with clinical ASD phenotype.
Characterization ofDrosophila Nidogen/entactinreveals roles in basement membrane stability, barrier function and nervous system plasticity
Authors: Wolfstetter Georg , Dahlitz Ina , Pfeifer Kathrin , Alt Joscha Arne , Töpfer Uwe , Pfeifer Daniel Christoph , Lakes-Harlan Reinhard , Baumgartner Stefan , Palmer Ruth H. , Holz Anne 
Published: June 2018

AbstractBasement membranes (BMs) are specialized layers of extracellular matrix (ECM) mainly composed of Laminin, type IV Collagen, Perlecan and Nidogen/entactin (NDG). While the essential and evolutionary conserved functions of Laminin, Collagen and Perlecan are well documented inDrosophilaand other species, the proposed role of NDG as the major ECM linker molecule has been challenged by severalin vivostudies revealing that NDG is dispensable for viability and BM formation. Here, we report the characterization of the singleNdggene inDrosophila.EmbryonicNdgexpression differed from that of other BM components and was primarily observed in mesodermal tissues and the chordotonal organs, whereas NDG protein localized to all BMs. While loss of Laminin strongly affected BM-localization of NDG,Ndgnull mutants exhibited no overt changes in the distribution of BM core components. However, loss of NDG led to ultrastructural BM defects compromising barrier function and stabilityin vivo.AlthoughNdgmutants were viable, loss of NDG led to decreased fecundity in flies as well as impaired crawling behavior and reduced response to vibrational stimuli in larvae. Further morphological analysis revealed accompanying defects in the larval peripheral nervous system especially in the chordotonal organs and the neuromuscular junction (NMJ), whereNdggenetically interacted with theLeukocyte-antigen-related-like (Lar) receptorgene to regulate NMJ extension and synaptic differentiation. Taken together, our analysis suggests that NDG is not essential for BM assembly but mediates BM stability and ECM-dependent neural plasticity duringDrosophiladevelopment.Summary StatementIn this study we characterizeDrosophila Nidogen/Entactin (Ndg)mutants revealing that loss of Ndg impairs basement membrane (BM) stability and permeability as well as proper function of the nervous system.
Predicting peptide presentation by major histocompatibility complex class I using one million peptides
Authors: Boehm Kevin Michael , Bhinder Bhavneet , Raja Vijay Joseph , Dephoure Noah , Elemento Olivier 
Published: June 2018

AbstractImproved computational tools are needed to prioritize putative neoantigens within immunotherapy pipelines for cancer treatment. Herein, we assemble a database of over one million human peptides presented by major histocompatibility complex class I (MHC-I), the largest known database of its type. We use these data to train a random forest classifier (ForestMHC) to predict likelihood of MHC-I presentation. The information content of features mirrors the canonical importance of positions two and nine in determining likelihood of binding. Our random forest-based method outperforms NetMHC and NetMHCpan on test sets, and it outperforms both these methods and MixMHCpred on new mass spectrometry data from an ovarian carcinoma sample. Furthermore, the random forest scores correlate monotonically with peptide binding affinities, when known. Finally, we examine the effect size of gene expression on peptide presentation and find a moderately strong relationship. The ForestMHC method is a promising modality to prioritize neoantigens for experimental testing in immunotherapy.
Spatiotemporal Dynamics of Reward and Punishment Effects Induced by Associative Learning
Authors: Wang Huan , Kleffner Killian , Carolan Patrick L. , Liotti Mario 
Published: June 2018

AbstractWhile reward associative learning has been studied extensively across different species, punishment avoidance learning has received far less attention. Of particular interest is how the two types of learning change perceptual processing of the learned stimuli. We designed a task that required participants to learn the association of emotionally neutral images with reward, punishment, and no incentive value outcomes through trial-and-error. During learning, participants received monetary reward, neutral outcomes or avoided punishment by correctly identifying corresponding images. Results showed an early bias in favor of learning reward associations, in the form of higher accuracy and fewer trials needed to reach learning criterion. We subsequently assessed electrophysiological learning effects with a task in which participants viewed the stimuli with no feedback or reinforcement. Critically, we found modulation of two early event-related potential components for reward images: the frontocentral P2 (170 – 230 ms) and the anterior N2/Early Anterior Positivity (N2/EAP; 210 – 310 ms). We suggest that reward associations may change stimuli detection and incentive salience as indexed by P2 and N2/EAP. We also reported, on an exploratory basis, a late negativity with frontopolar distribution enhanced by punishment images.
Feasibility of constructing multi-dimensional genomic maps of juvenile idiopathic arthritis
Authors: Zhu Lisha , Jiang Kaiyu , Wong Laiping , Buck Michael J. , Chen Yanmin , Moncrieffe Halima , McIntosh Laura A. , O’Neil Kathleen M. , Liu Tao , Xing Xiaoyun , Li Daofeng , Wang Ting , Jarvis James N. 
Published: June 2018

AbstractBackgroundJuvenile idiopathic arthritis (JIA) is one of the most common chronic conditions of childhood. Like many common chronic human illnesses, JIA likely involves complex interactions between genes and the environment, mediated by the epigenome. Such interactions are best understood through multi-dimensional genomic maps that identify critical genetic and epigenetic components of the disease. However, constructing such maps in a cost-effective way is challenging, and this challenge is further complicated by the challenge of obtaining biospecimens from pediatric patients at time of disease diagnosis, prior to therapy, as well as the limited quantity of biospecimen that can be obtained from children,particularly those who are unwell. In this paper, we demonstrate the feasibility and utility of creating multi-dimensional genomic maps for JIA from limited sample numbers.MethodsTo accomplish our aims, we used an approach similar to that used in the ENCODE and Roadmap Epigenomics projects, which used only 2 replicates for each component of the genomic maps. We used genome-wide DNA methylation sequencing, whole genome sequencing on the Illumina 10x platform, RNA sequencing, and chromatin immunoprecipitation-sequencing for informative histone marks (H3K4me1 and H3K27ac) to construct a multi-dimensional map of JIA neutrophils, a cell we have shown to be important in the pathobiology of JIA.ResultsThe epigenomes of JIA neutrophils display numerous differences from those from healthy children. DNA methylation changes, however, had only a weak effect on differential gene expression. In contrast, H3K4me1 and H3K27ac, commonly associated with enhancer functions, strongly correlated with gene expression. Furthermore, although unique/novel enhancer marks were associated with insertion-deletion events (indels) identified on whole genome sequencing, we saw no strong association between epigenetic changes and underlying genetic variation. The initiation of treatment in JIA is associated with a re-ordering of both DNA methylation and histone modifications, demonstrating the plasticity of the epigenome in this setting.ConclusionsThese findings, generated from a small number of patient samples, demonstrate how multidimensional genomic studies may yield new understandings of biology of JIA and provide insight into how therapy alters gene expression patterns.
High throughput proteomics identifies 484 high-accuracy plasma protein biomarker signatures for ovarian cancer
Authors: Enroth Stefan , Berggrund Malin , Lycke Maria , Broberg John , Lundberg Martin , Assarsson Erika , Olovsson Matts , Stålberg Karin , Sundfeldt Karin , Gyllensten Ulf 
Published: June 2018

AbstractOvarian cancer is usually detected at a late stage with the 5-year survival at only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 981 proteins in patients with ovarian cancer and benign tumours, using the proximity extension assay. A novel combinatorial strategy was developed for identification of multivariate biomarker signatures, resulting in 484 mutually exclusive models out of which 448 did not contain the present biomarker MUCIN-16. The top-ranking model consisted of 14 proteins and had a AUC=0.95, PPV=1.0, sensitivity=0.99 and specificity=1.0 for detection of stage III-IV ovarian cancer in the discovery data, and an AUC=0.89, PPV=0.93, sensitivity=0.89 and specificity=0.95 in the replication data. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
Eldecalcitol is more effective for promoting osteogenesis than alfacalcidol in Cyp27b1-knockout Mice
Authors: Hirota Yoshihisa , Nakagawa Kimie , Isomoto Keigo , Sakaki Toshiyuki , Kubodera Noboru , Kamao Maya , Osakabe Naomi , Suhara Yoshitomo , Okano Toshio 
Published: June 2018

AbstractCalcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1−/− mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1−/− mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1−/− mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1−/− mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1−/− mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly.