bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution of Genetic Polymorphisms of Genes Implicated in Thiopurine Drugs Metabolism
Authors: Chadli Zohra , Kerkeni Emna , Hannachi Ibtissem , Chouchene Saoussen , Ben Fredj Nadia , Boughattas Naceur A. , Aouam Karim , Chaabane Amel 
Published: August 2018

Abstract:
Thiopurine-S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are crucial enzymes involved in the metabolism of thiopurine drugs. Significant interethnic variation in the expression of TPMT and ITPA is caused by single nucleotide polymorphisms of genes encoding these proteins. The aim of this study was to describe the distribution of TPMT and ITPA polymorphisms in healthy Tunisian subjects and to establish the metabolizer status of thiopurine drugs in this population. A total of 309 healthy Tunisian subjects were recruited among blood donors of Fattouma Bourguiba Hospital of Monastir. A written informed consent was obtained from all subjects. Whole blood samples were collected from every subject in ethylenediaminetetraacetic acid tubes. TPMT (c.238 G > C, c.460 G > A and c.719A > G) and ITPA (c.94C > A and IVS2+21A > C) mutations were genotyped using polymerase chain reaction-restriction fragment length polymorphism. The observed frequencies of TPMT*3A and TPMT*3C alleles were both 0.8%. The phenotype distribution of TPMT was bimodal: 96.8% of subjects were extensive metabolizers and 3.2% were intermediate metabolizers. Genotyping of ITPA revealed frequencies of 9% and 3% for IVS2+21A > C and c.94C > A mutations, respectively. Accordingly, a trimodal phenotype distribution was found: 75.4% of the subjects were extensive metabolizers, 23.4% were intermediate metabolizers, and 1.2% wereslow metabolizers. Combination of TPMT and ITPA genotyping has revealed that a quarter of the Tunisian Population carries polymorphisms that reduce the metabolic activities of these enzymes.
Patient vs. Community Engagement: Emerging Issues
Authors: Kimminau Kim S. , Jernigan Cheryl , LeMaster Joseph , Aaronson Lauren S. , Christopher Myra , Ahmed Syed , Boivin Antoine , DeFino Mia , Greenlee Robert , Salvalaggio Ginetta , Hendricks Deborah , Herbert Carol , Mabachi Natabhona M. , Macaulay Ann , Westfall John M. , Waitman Lemuel R. 
Published: August 2018

Background:
The value proposition of including patients at each step of the research process is that patient perspectives and preferences can have a positive impact on both the science and the outcomes of comparative effectiveness research. How to accomplish engagement and the extent to which approaches to community engagement inform strategies for effective patient engagement need to be examined to address conducting and accelerating comparative effectiveness research.

Objectives:
To examine how various perspectives and diverse training lead investigators and patients to conflicting positions on how best to advance patient engagement.

Research Design:
Qualitative methods were used to collect perspectives and models of engagement from a diverse group of patients, researchers and clinicians. The project culminated with a workshop involving these stakeholders. The workshop used a novel approach, combining World Café and Future Search techniques, to compare and contrast aspects of patient engagement and community engagement.

Subjects:
Participants included patients, researchers, and clinicians.

Measures:
Group and workshop discussions provided the consensus on topics related to patient and community engagement.

Results:
Participants developed and refined a framework that compares and contrasts features associated with patient and community engagement.

Conclusions:
Although patient and community engagement may share a similar approach to engagement based on trust and mutual benefit, there may be distinctive aspects that require a unique lexicon, strategies, tactics, and activities.
Assessing Risk of HIV-Associated Neurocognitive Disorder
Authors: Cummins Denise , Waters Donna , Aggar Christina , O’Connor Catherine C. 
Published: August 2018

Background
People with HIV (PLHIV) are aging, and 20% are at risk of developing a neurological complication known as HIV-associated neurocognitive disorder (HAND). Signs and symptoms of HAND may be subtle; however, treatment can improve clinical outcomes.

Objective
The aim of the study was to identify and agree on a risk assessment and monitoring process for the regular review of patients at risk of HAND.

Methods
Between March and September 2017, 25 experts from four community healthcare services participated in three rounds of a modified Delphi study to reach consensus on the items, monitoring period, and format of assessment tools to identify risk of HAND in PLHIV in the community.

Results
More than 80% consensus was reached at all three Delphi rounds. A flow chart, an initial assessment, and an annual monitoring tool were developed for an ongoing assessment of risk of developing HAND.

Conclusion
Twenty percent of PLHIV may develop HAND, a treatable condition. The use of a modified Delphi method led to the successful development of two risk assessment tools to identify those at risk of HAND. The initial assessment tool may be used as a precursor to formal assessment by medical and nursing staff, whereas the annual monitoring tool may assist community-based health professionals in their ongoing assessment of risk of HAND in PLHIV, facilitating early formal medical review for this condition.
Individual slow wave morphology is a marker of ageing
Authors: Ujma Péter P , Simor Péter , Steiger Axel , Dresler Martin , Bódizs Róbert 
Published: August 2018

AbstractSlow wave activity is a hallmark of deep NREM sleep. Scalp slow wave morphology is stereotypical, it is highly correlated with the synchronized onset and cessation of cortical neuronal firing measured from the surface or depth of the cortex, strongly affected by ageing, and these changes are causally associated with age-related cognitive decline. We investigated how normal ageing affects the individual morphology of the slow wave, and whether these changes are captured by the summary slow wave parameters generally used in the literature. We recorded full-night polysomnography in 159 subjects (age 17-69 years) and automatically detected slow waves using six different detection methods to ensure methodological robustness. We established individual slow morphologies at 501 data points for each subject and also calculated the individual average slow wave amplitude, average ascending and descending slope steepness and the total number of slow waves (gross parameters). Using LASSO penalized regression we found that fine-grained slow wave morphology is associated with age beyond gross parameters, with young subjects having faster slow wave polarity reversals, suggesting a more efficient initiation and termination of slow wave down- and upstates. Our results demonstrate the superiority of the high-resolution slow wave morphology as a biomarker of ageing, and highlights state transitions as promising targets of restorative stimulation-based interventions.
Epigenetic findings in periodontitis in UK twins: a cross sectional study
Authors: Kurushima Yuko , Tsai Pei-Chien , Fernandez Juan Castillo , Alves Alexessander Couto , El-Sayed Moustafa Julia Sarah , Roy Caroline Le , Ide Mark , Hughes Francis J , Small Kerrin , Steves Claire J , Bell Jordana T 
Published: August 2018

ABSTRACTBackgroundGenetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease.MethodsSelf-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples.ResultsEpigenome-wide analyses in blood identified one CpG-site (cg21245277 inZNF804A) associated with gingival bleeding (FDR=0.03, nominal p-value=7.17e-8), and 58 sites associated with tooth mobility (FDR<0.05) with the top signals inIQCEandXKR6. Epigenetic variation at 28 candidate regions (256 CpG-sites) for chronic periodontitis showed a strong enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, andCXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue.ConclusionsEpigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.
Magnitude of road traffic accident related injuries and fatalities in Ethiopia
Authors: Abagaz Teferi , Gebremedhin Samson 
Published: August 2018

AbstractBackgroundIn many developing countries there is paucity of evidence regarding the epidemiology of road traffic accidents (RTAs). The study determines the rates of injuries and fatalities associated with RTAs in Ethiopia based on the data of a recent national survey.MethodsThe study is based on the secondary data of the Ethiopian Demographic and Health Survey conducted in 2016. The survey collected information about occurrence injuries and accidents including RTAs in the past 12 months among 75,271 members of 16,650 households. Households were selected from nine regions and two city administrations of Ethiopia using stratified cluster sampling procedure.ResultsOf the 75,271 household members enumerated, 123 encountered RTAs in the reference period and rate of RTA-related injury was 163 (95% confidence interval (CI): 136-195) per 100,000 population. Of the 123 causalities, 28 were fatal, making the fatality rate 37 (95% CI: 25-54) per 100,000 population. The RTA-related injuries and fatalities per 100,000 motor vehicles were estimated as 21,681 (95% CI: 18,090-25,938) and 4,922 (95% CI: 3325-7183), respectively. Next to accidental falls, RTAs were the second most common form of accidents and injuries accounting for 22.8% of all such incidents. RTAs contributed to 43.8% of all fatalities secondary to accidents and injuries. Among RTA causalities, 21.9% were drivers, 35.0% were passenger vehicle occupants and 36.0% were vulnerable road users including: motorcyclists (21.0%), pedestrians (12.1%) and cyclists (2.9%). Approximately half (47.1%) of the causalities were between 15-29 years of age and 15.3% were either minors younger than 15 years or seniors older than 64 years of age. Nearly two-thirds (65.0%) of the victims were males.ConclusionRTA-related causalities are extremely high in Ethiopia. Male young adults and vulnerable road users are at increased risk of RTAs. There is a urgent need for bringing road safety to the country’s public health agenda.
Delivery of GalNAc-conjugated splice-switching ASOs to non-hepatic cells through ectopic expression of asialoglycoprotein receptor
Authors: Scharner Juergen , Qi Sabrina , Rigo Frank , Bennett C. Frank , Krainer Adrian R. 
Published: August 2018

AbstractSplice-switching antisense oligonucleotides (ASOs) are promising therapeutic tools to target various genetic diseases, including cancer. However,in vivodelivery of ASOs to orthotopic tumors in cancer mouse models or to certain target tissues remains challenging. A viable solution already in use is receptor-mediated uptake of ASOs via tissue-specific receptors. For example, the asialoglycoprotein receptor (ASGP-R) is exclusively expressed in hepatocytes. Triantennary GalNAc (GN3)-conjugated ASOs bind to the receptor and are efficiently internalized by endocytosis, enhancing ASO potency in the liver. Here we explore the use of GalNAc-mediated targeting to deliver therapeutic splice-switching ASOs to cancer cells that ectopically express ASGP-R, bothin vitroand in tumor mouse models. We found that ectopic expression of the major isoform ASGP-R1 H1a is sufficient to promote uptake and increase GN3-ASO potency to various degrees in all tested cancer cells. We show that cell-type specific glycosylation of the receptor does not affect its activity.In vivo, GN3-conjugated ASOs specifically target subcutaneous xenograft tumors that ectopically express ASGP-R1, and modulate splicing significantly more strongly than unconjugated ASOs. Our work shows that GN3-targeting is a useful tool for proof-of-principle studies in orthotopic cancer models, until endogenous receptors are identified and exploited for efficiently targeting cancer cells.
Diverse endogenous retroviruses generate structural variation between human genomes via LTR recombination
Authors: Thomas Jainy , Perron Hervé , Feschotte Cédric 
Published: August 2018

ABSTRACTHuman endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. The vast majority of HERV sequences descend from ancient retroviral families no longer capable of infection or genomic propagation. In fact, most are no longer represented by full-length proviruses but by solitary long terminal repeats (solo LTRs) that arose via non-allelic recombination events between the two LTRs of a proviral insertion. Because LTR-LTR recombination events may occur long after proviral insertion but are challenging to detect in resequencing data, we hypothesize that this mechanism produces an underappreciated amount of genomic variation in the human population. To test this idea, we develop a computational pipeline specifically designed to capture such dimorphic HERV alleles from short-read genome sequencing data. When applied to 279 individuals sequenced as part of the Simons Genome Diversity Project, the pipeline retrieves most of the dimorphic variants previously reported for the HERV-K(HML2) subfamily as well as dozens of additional candidates, including members of the HERV-H and HERV-W families. We experimentally validate several of these candidates, including the first reported instance of an unfixed HERV-W provirus. These data indicate that human proviral content exhibit more extensive interindividual variation than previously recognized. These findings have important implications for our understanding of the contribution of HERVs to human physiology and disease.
Interaction information along lifespan of the resting brain dynamics reveals a major redundant role of the default mode network
Authors: Camino-Pontes Borja , Diez Ibai , Jimenez-Marin Antonio , Rasero Javier , Xu Paolo , Bonifazi Charles C.Y. , Stramaglia Sebastiano , Swinnen Stephan , Cortes Jesus M 
Published: August 2018

AbstractInteraction Information generalizes the univariate Shannon Entropy to triplets of variables, allowing the detection of redundant or synergetic interactions in dynamical networks. Here, we calculated interaction information from functional magnetic resonance imaging and asked whether redundancy or synergy vary across brain regions and along lifespan. We found high overlapping between the pattern of high redundancy and the default mode network, and this occurred along lifespan. The pattern of high values of synergy, more heterogeneous and variable along lifespan, was overlapping with different cognitive domains, such as spatial and temporal memory, emotion processing and motor skills. Moreover, the amount of redundancy and synergy seem to be balanced along lifespan, suggesting informational compensatory mechanisms in brain networks.
Dopamine Depletion Alters Macroscopic Network Dynamics in Parkinson’s Disease
Authors: Shine James M. , Bell Peter T. , Matar Elie , Poldrack Russell A. , Lewis Simon J.G. , Halliday Glenda M. , O’Callaghan Claire 
Published: August 2018

AbstractParkinson’s disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson’s disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinson’s disease, both ‘On’ and ‘Off’ dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson’s disease ‘Off’ state was associated with greater network-level integration than in the ‘On’ state. The extent of integration in the ‘Off’ state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted ‘Off’ state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic ‘Off’ state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic ‘Off’ state. Our findings provide a mechanistic basis for understanding the PD ‘Off’ state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson’s disease.
The potential aroma and flavor compounds inVitissp. cv. Koshu andV. viniferaL. cv. Chardonnay under different environmental conditions
Authors: Bahena-Garrido Sharon Marie , Ohama Tomoko , Suehiro Yuka , Hata Yuko , Isogai Atsuko , Iwashita Kazuhiro , Goto-Yamamoto Nami , Koyama Kazuya 
Published: August 2018

ABSTRACTBACKGROUNDKoshu, a hybrid ofVitis viniferaL. andV. davidiiFoex, is the most popular indigenous cultivar for wine production in Japan. However, little is known about the potential aroma compounds it contains and how environmental factors affect these. In this study, we obtained comprehensive profiles of the volatile (both glycosidically bound and free) and phenolic compounds that occur in Koshu berries, and compared these with similar profiles forV. viniferacv. Chardonnay. We then compared the response of these two cultivars to bunch shading and the ripening-related phytohormone abscisic acid (ABA).RESULTSKoshu berries contained significantly higher concentrations of phenolic compounds, hydroxycinnamic acid derivatives, and some volatile phenols, such as 4-vinyl guaiacol and eugenol, than Chardonnay berries, which are thought to contribute to the characteristics of Koshu wine. In addition, Koshu berries had a distinctly different terpenoid composition from Chardonnay berries. Shading reduced the concentrations of norisoprenoid in both cultivars, as well as several phenolic compounds particularly their volatile derivatives in Koshu. The exogenous application of ABA induced ripening and increased the concentrations of lipid derivatives, such ashexanol, octanol, nonanol, and 1-octen-3-ol. Linear discriminant analysis showed that the aromatic potential could be discriminated clearly based on cultivar, bunch shading, and ABA application.CONCLUSIONThe unique secondary metabolite profiles of Koshu and their different responses to environmental factors could be valuable for developing various styles of Koshu wines and new cultivars with improved quality and cultural characteristics.
HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand
Authors: Owen Henry , Vaughan-Jackson Alun , Nussbaum Lea , Vowles Jane , James William , Moore M.D. 
Published: August 2018

AbstractRetroviral restriction factors are important regulators of viral infection, targeting vulnerable steps of the virus lifecycle; steps that are also targeted by antiviral drugs. It has become clear that the route of cellular infection can alter the sensitivity of HIV-1 to these agents. Using CRISPR-Cas9 edited pluripotent stem cell-derived macrophages, we have explored the potential of a modified restriction factor (human TRIMCyp) to inhibit HIV-1 replication in both cell free and cell-cell infection models. We show that the expression of TRIMCyp from the endogenous TRIM5α locus potently restricts infection by cell-free HIV-1. Our results also show the importance of the human cyclophilin A-HIV-1 capsid interaction for viral escape from restriction by native human TRIM5α, highlighting the evolutionary interplay between virus and this host restriction factor. However, when co-cultured with infected T cells, stem cell-derived macrophages are primarily infected by fusion between the cells. We have termed infected cells that result from these fusions heterocytia, and show that their formation overcomes multiple restriction factors and the reverse transcriptase inhibitor AZT.ImportanceAs sentinels of the immune system, macrophages are relatively resistant to infection by pathogens such as HIV-1. However, infected macrophages are found in infected patients and they play key roles in the pathogenesis of the disease as well as being a component of the viral reservoir that must be targeted before treatment can become cure. In this article, we show that some of the mechanisms by which macrophages restrict HIV-1 can be overcome through a recently described cell-cell interaction leading to cell-cell fusion. We also highlight an evolutionary battle between virus and host and show how the virus has co-opted a host protein to protect it from destruction by an antiviral mechanism. These two key findings suggest potential novel treatment strategies that may reduce the viral reservoir and help our natural defences take back control from the virus.
Deficiency of the Endocytic ProteinHip1Leads to DecreasedGdpd3expression, Low Phosphocholine, and Kypholordosis
Authors: Wijayatunge Ranjula , Holmstrom Sam R. , Foley Samantha B. , Mgbemena Victoria E. , Bhargava Varsha , Perez Gerardo Lopez , McCrum Kelly , Ross Theodora S. 
Published: August 2018

ABSTRACTDeficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated aHip1deficiency allele where a floxed transcriptional stop-cassette and a humanHIP1cDNA were knocked-in to intron 1 of mouseHip1locus.CMV-Cre-mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue of theHip1knockout phenotype.Mxl-Cre--mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast,GFAP-Cre-mediatedHIP1expression in brain did not rescue the phenotype. Metabolomics and microarrays of severalHip1knockout tissues identified low phosphocholine (PC) levels and lowGlycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3) expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC,Gdpd3downregulation could lead to the low PC levels. To test ifGdpd3contributes to the Hip1 deficiency phenotype, we generatedGdpd3knockout mice. Double knockout ofGdpd3andHip1worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.