bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuous Aerosol Medication Therapy in an in vitro High-Flow System Using Wire Mesh Technology
Authors: Cappiello Jhaymie , Bremenour Carla , Boyle Jason , Lumbard Jessica , Ghadimi Kamrouz 
Published: February 2020

AbstractBACKGROUNDJet nebulizers are commonly used to provide continuous aerosolized medication therapy (CAMT). We observed the function of our CAMT system that utilizes the Aeroneb Solo nebulizer system (Aerogen Ltd, Galway, Ireland). METHODS: An observational study was performed on 2 CAMT systems with 15 Aeroneb nebulizers for each system. CAMT was simulated for 1, 2 and 3 hours. Continuous nebulization was monitored and residual volumes were recorded at the end of each simulation. Our primary endpoint was established as intermittent nebulization observed by nebulizer filling of > 1 ml during CAMT simulation. Secondary endpoint was a residual volume of < 0.1 ml.RESULTSOut of 30 simulations in two arms, a fluid level was observed to accumulate intermittently in three nebulizers with a residual volume of 0.7 mls in one of these three. This produced a total success rate of 90%, Arm-A 80%, Arm B-100%, for our primary endpoint. Our secondary endpoint was achieved in 29 of the 30 nebulizers for an overall 97% success rate, Arm A-93%, Arm B-100%. CONCLUSION: Our Aerogen Solo CAMT system successfully emitted the set dose with 90% accuracy.
Predicting and elucidating the etiology of fatty liver disease using a machine learning-based approach: an IMI DIRECT study
Authors: Atabaki-Pasdar Naeimeh , Ohlsson Mattias , Viñuela Ana , Frau Francesca , Pomares-Millan Hugo , Haid Mark , Jones Angus G , Thomas E Louise , Koivula Robert W , Kurbasic Azra , Mutie Pascal M , Fitipaldi Hugo , Fernandez Juan , Dawed Adem Y , Giordano Giuseppe N , Forgie Ian M , McDonald Timothy J , Rutters Femke , Cederberg Henna , Chabanova Elizaveta , Dale Matilda , De Masi Federico , Thomas Cecilia Engel , Allin Kristine H , Hansen Tue H , Heggie Alison , Hong Mun-Gwan , Elders Petra JM , Kennedy Gwen , Kokkola Tarja , Pedersen Helle Krogh , Mahajan Anubha , McEvoy Donna , Pattou Francois , Raverdy Violeta , Häussler Ragna S , Sharma Sapna , Thomsen Henrik S , Vangipurapu Jagadish , Vestergaard Henrik , ‘t Hart Leen M , Adamski Jerzy , Musholt Petra B , Brage Soren , Brunak Søren , Dermitzakis Emmanouil , Frost Gary , Hansen Torben , Laakso Markku , Pedersen Oluf , Ridderstråle Martin , Ruetten Hartmut , Hattersley Andrew T , Walker Mark , Beulens Joline WJ , Mari Andrea , Schwenk Jochen M , Gupta Ramneek , McCarthy Mark I , Pearson Ewan R , Bell Jimmy D , Pavo Imre , Franks Paul W 
Published: February 2020

ABSTRACTBackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in type 2 diabetes (T2D) and beyond. Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and ultimately hepatocellular carcinomas.Methods and FindingsUtilizing the baseline data from the IMI DIRECT participants (n=1514) we sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI image-derived liver fat content (<5% or ≥5%). We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and Random Forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operator characteristic area under the curve (ROCAUC) of 0.84 (95% confidence interval (CI)=0.82, 0.86), which compared with a ROCAUC of 0.82 (95% CI=0.81, 0.83) for a model including nine clinically-accessible variables. The IMI DIRECT prediction models out-performed existing non-invasive NAFLD prediction tools.ConclusionsWe have developed clinically useful liver fat prediction models (see:www.predictliverfat.org) and identified biological features that appear to affect liver fat accumulation.
A non-APOE Polygenic score for Alzheimer’s disease and APOE-ε4 have independent associations with dementia in the Health and Retirement Study
Authors: Bakulski Kelly M. , Vadari Harita S. , Faul Jessica D. , Heeringa Steven G. , Kardia Sharon LR , Langa Kenneth M , Smith Jennifer A. , Manly Jennifer J. , Mitchell Colter M. , Benke Kelly S. , Ware Erin B. 
Published: February 2020

AbstractINTRODUCTIONAlzheimer’s disease (AD) is a common and costly neurodegenerative disorder. A large proportion of risk is heritable and many genetic risk factors for AD have been identified. The cumulative genetic risk of known markers has not been benchmarked for dementia in a population-based sample.METHODSIn the United States population-based Health and Retirement Study (HRS) (waves 1995-2014), we evaluated the role of cumulative genetic risk for AD, with and without the APOE-ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.RESULTSIn the European ancestry sample (n=8399), both AD polygenic score excluding the APOE genetic region (odds ratio (OR)=1.10; 95% confidence interval (CI): 1.00, 1.20) and the presence of any APOE-ε4 alleles (OR=2.42; 95% CI: 1.99, 2.95) were associated with the odds of dementia relative to normal cognition in a mutually-adjusted model. In the African ancestry sample (n=1605), the presence of any APOE-ε4 alleles was associated with 1.77 (95% CI: 1.20, 2.61) times higher odds of dementia, while the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97, 1.30).DISCUSSIONCumulative genetic risk for AD and APOE-ε4 are both independent predictors of dementia. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.
Normative modelling using deep autoencoders: a multi-cohort study on mild cognitive impairment and Alzheimer’s disease
Authors: Pinaya Walter H. L. , Scarpazza Cristina , Garcia-Dias Rafael , Vieira Sandra , Baecker Lea , da Costa Pedro F. , Redolfi Alberto , Frisoni Giovanni B. , Pievani Michela , Calhoun Vince D. , Sato João R. , Mechelli Andrea ,   the Alzheimer’s Disease Neuroimaging Initiative,   the Australian Imaging Biomarkers and Lifestyle flagship study of ageing
Published: February 2020

AbstractNormative modelling is an emerging method for quantifying how individuals deviate from the healthy populational pattern. Several machine learning models have been implemented to develop normative models to investigate brain disorders, including regression, support vector machines and Gaussian process models. With the advance of deep learning technology, the use of deep neural networks has also been proposed. In this study, we assessed normative models based on deep autoencoders using structural neuroimaging data from patients with Alzheimer’s disease (n=206) and mild cognitive impairment (n=354). We first trained the autoencoder on an independent dataset (UK Biobank dataset) with 11,034 healthy controls. Then, we estimated how each patient deviated from this norm and established which brain regions were associated to this deviation. Finally, we compared the performance of our normative model against traditional classifiers. As expected, we found that patients exhibited deviations according to the severity of their clinical condition. The model identified medial temporal regions, including the hippocampus, and the ventricular system as critical regions for the calculation of the deviation score. Overall, the normative model had comparable cross-cohort generalizability to traditional classifiers. In order to promote open science, we are making all scripts and the trained models available to the wider research community.
Plasticity in gene expression facilitates invasion of the desert environment in house mice
Authors: Bittner Noëlle K. J. , Mack Katya L. , Nachman Michael W. 
Published: February 2020

AbstractUnderstanding how organisms adapt to new environments is a key problem in evolution, yet it remains unclear whether phenotypic plasticity generally facilitates or hinders this process. Here we studied the evolved and plastic responses to water stress in lab-born descendants of wild house mice (Mus musculus domesticus) collected from desert and non-desert environments. Using a full sib design, we measured organismal phenotypes and gene expression under normal (hydrated) and water stressed (dehydrated) conditions. After many generations in the lab, mice from the desert consumed significantly less water than mice from other localities, indicating that this difference has a genetic basis. Under water stress, desert mice lost less weight than non-desert mice, and desert mice exhibited differences in blood chemistry related to osmoregulatory function. Gene expression in the kidney revealed evolved differences between mice from different environments as well as plastic responses between hydrated and dehydrated mice. Desert mice showed reduced gene expression plasticity under water stress compared to non-desert mice. Importantly, the non-desert mice generally showed shifts towards desert-like expression under water stress, consistent with adaptive plasticity. Finally, patterns of gene expression identified several candidate genes for adaptation to the desert, includingAqp1andApoe. These findings provide evidence for local adaptation in a recently introduced species and suggest that adaptive plasticity may have facilitated the colonization of the desert environment.
Insulin-Like Growth Factor I Modulates Vulnerability to Stress Through Orexin Neurons
Authors: Fernandez de Sevilla ME , Pignatelli J , Mendez P. , Zegarra-Valdivia J , Torres Alemán I 
Published: February 2020

AbstractKnowledge of mechanisms involved in vulnerability/resilience to stress disorders is crucial for prevention and treatment schemes. We previously documented that insulin-like growth factor I (IGF-I) is associated to vulnerability to stress both in mice and humans. Since hypothalamic orexin neurons express IGF-I receptors and are involved in responses to stress, we analyzed their role in the modulatory actions of IGF-I on stress. Anxiolytic actions of IGF-I after exposure to a predator were absent in mice lacking IGF-I receptors in orexin neurons (Firoc mice). Based on these observations we speculated that Firoc mice may be prone to develop fear-related disturbances, including post-traumatic stress disorder (PTSD)-like symptoms when confronted to fear learning, a process that is postulated to be altered in PTSD. Firoc mice submitted to fear conditioning showed increased freezing responses, suggesting aberrant fear learning. Exaggerated freezing was accompanied by increased levels of orexin, together with enhanced c-fos staining of these neurons –an indicator of increased cell activity, and of noradrenergic neurons of the locus coeruleus nucleus, a region downstream of orexinergic activation. After fear conditioning, Firoc mice developed PTSD-like behavioral traits such as prolonged context-dependent fear and post-stress anhedonia. Since abnormal fear learning was ameliorated by chemogenetic (DREADD) inhibition of orexin neurons, reduced IGF-I input to orexin neurons in Firoc mice seems to enhance their excitability to fear-related inputs. Collectively, these results suggest that IGF-I input to orexin neurons is an important determinant of vulnerability to stress disorders, which provides additional targets for therapy of these high social impact conditions.
A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation
Authors: van der Weyden Louise , Swiatkowska Agnieszka , Iyer Vivek , Speak Anneliese O. , Adams David J. 
Published: February 2020

ABSTRACTMetastatic colonisation, whereby a disseminated tumour cell is able to survive and proliferate at a secondary site, involves both tumour cell-intrinsic and -extrinsic factors. To identify tumour cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumour cells to effectively colonise a tissue, we performed a genome-wide screen utilising the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonisation (15 increased and 19 decreased;P<0.005 and genotype effect <-60 or >+60). Whilst several of these genes have known roles in immune system regulation (Bach2, Cyba, Cybb, Cybc1, Id2, Igh-6, Irf1, Irf7, Ncf1, Ncf2, Ncf4andPik3cg) most are involved in a disparate range of biological processes, ranging from ubiquitination (Herc1) to diphthamide synthesis (Dph6) to Rho GTPase-activation (Arhgap30andFgd4), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonisation, which may represent potential therapeutic targets.
Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis
Authors: Jamalpoor Amer , van Gelder Charlotte AGH , Yousef Yengej Fjodor A , Zaal Esther A , Berlingerio Sante Princiero , Veys Koenraad R , Casellas Carla Pou , Voskuil Koen , Essa Khaled , Ammerlaan Carola ME , Rega Laura Rita , van der Welle Reini , Lilien Marc R , Rookmaaker Maarten B , Clevers Hans , Klumperman Judith , Levtchenko Elena , Berkers Celia R , Verhaar Marianne C , Altelaar Maarten , Masereeuw Rosalinde , Janssen Manoe J 
Published: February 2020

AbstractNephropathic cystinosis is a severe monogenetic kidney disorder caused by mutations inCTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established proximal tubulopathy. Here, we developed a new therapeutic strategy by applying an omics-based strategy to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a key metabolite linking cystinosin loss, lysosomal autophagy defect and proximal tubular impairment in cystinosis. This insight offered a bicalutamide-cysteamine combination treatment as a novel dual target pharmacological approach for the phenotypical correction of cystinotic proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.
Activation of Rab11a and endocytosis by Phosphatidylinositol 4-kinase III beta promotes oncogenic signaling in breast cancer
Authors: MacDonald Spencer A , Harding Katherine , Bilodeau Patricia , de Souza Christiano T , Campa Carlo Cosimo , Hirsch Emilio , Auer Rebecca C , Lee Jonathan M 
Published: February 2020

ABSTRACTEndosomes are now recognized as important sites for regulating signal transduction. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates both endocytic kinetics and receptor signaling in breast cancer cells. PI4KIIIβ generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of breast cancers. However, the molecular mechanism by which PI4KIIIβ promotes breast cancer is unclear. We demonstrate that ectopic PI4KIIIβ expression increases the rates of both endocytic internalization and recycling. PI4KIIIβ deletion reduces endocytic kinetics accompanied by a concomitant decrease in activity of the Rab11a GTPase, a protein required for endocytic function. Finally, we find that PI4KIIIβ activates IGF-IRβ signaling dependent on endosome function. Regulation of endocytic function by PI4KIIIβ is independent of its kinase activity but requires interaction with the Rab11a. This suggests that PI4KIIIβ controls endosomal kinetics and signaling by directly modulating Rab11a function. Our work suggests a novel regulatory role for PI4KIIIβ in endosome function and plasma membrane receptor signaling.
Importin-9 regulates chromosome segregation and packaging inDrosophilagerm cells
Authors: Palacios Victor , Kimble Garrett C , Tootle Tina L. , Buszczak Michael 
Published: February 2020

SummaryGerm cells undergo distinct nuclear processes as they differentiate into gametes. While these events must be coordinated to ensure proper maturation, the stage-specific transport of proteins in and out of germ cell nuclei remains incompletely understood.Our efforts to genetically characterizeDrosophilagenes that exhibit enriched expression in germ cells led to the finding that loss of the highly-conserved Importin β/karyopherin family member Importin-9 (Ipo9) results in female and male sterility.Immunofluorescence and fluorescent in situ hybridization (FISH) revealed thatIpo9KOmutants display chromosome condensation and segregation defects during meiosis. In addition,Ipo9KOmutant males form abnormally structured sperm and fail to properly exchange histones for protamines. Ipo9 physically interacts with proteasome proteins andIpo9mutant males exhibit loss of nuclear ubiquitination and disruption of the nuclear localization of several proteasome components. Thus, Ipo9 coordinates the nuclear import of functionally related factors necessary for the completion of gametogenesis.HighlightsDrosophilaImportin-9 functions in female and male meiosisLoss of Importin-9 disrupts the histone to protamine transition during spermiogenesis Importin-9 physically interacts with components of the proteasomeImportin-9 is required for the efficient nuclear transport of proteasome proteins during spermiogenesis
A pedigree-based prediction model identifies carriers of deleteriousde novomutations in families with Li-Fraumeni syndrome
Authors: Gao Fan , Pan Xuedong , Dodd-Eaton Elissa B. , Recio Carlos Vera , Montierth Matthew D. , Bojadzieva Jasmina , Mai Phuong L. , Zelley Kristin , Johnson Valen E. , Braun Danielle , Nichols Kim E. , Garber Judy E. , Savage Sharon A. , Strong Louise C. , Wang Wenyi 
Published: February 2020

ABSTRACTDe novomutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation (FM)) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: 1) cancer and mutation spectra along with parental ages were similarly distributed; 2) ascertainment criteria like early-onset breast cancer (age 20 to 35 years) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs versus 25 FMs); 3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome, and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those inTP53.
Imaging and tracking mRNA in live mammalian cells via fluorogenic photoaffinity labeling
Authors: Ayele Tewoderos M. , Loya Travis , Valdez-Sinon Arielle N. , Bassell Gary J. , Heemstra Jennifer M. 
Published: February 2020

ABSTRACTCellular RNA labeling using light-up aptamers that bind to and activate fluorogenic molecules has gained interest in recent years as an alternative to protein-based RNA labeling approaches. Aptamer-based systems are genetically encodable and cover the entire visible spectrum. However, the relatively weak nature of the non-covalent aptamer-fluorogen interaction limits the utility of these systems in that multiple copies of the aptamer are often required, and in most cases the aptamer must be expressed on a second scaffold such as a transfer RNA. We propose that these limitations can be averted through covalent RNA labeling, and here we describe a photoaffinity approach in which the aptamer ligand is functionalized with a photoactivatable reactive group such that irradiation with UV light results in covalent attachment to the RNA of interest. In addition to the robustness of the covalent linkage, this approach benefits from the ability to temporally control RNA labeling. To demonstrate this method, we incorporated a photoaffinity linker onto malachite green and fused the malachite green aptamer to a specific mRNA reporter of interest. We observed markedly improved sensitivity for fixed cell imaging of mRNA using this approach compared toin situhybridization. Additionally, we demonstrate visualization of RNA dynamics in live cells using an mRNA having only a single copy of the aptamer, minimizing perturbation of the structure and localization. Our initial biological application utilizes the photoaffinity labeling approach to monitor RNA stress granule dynamics and we envision future application of this method for a wide range of investigations into the cellular localization, dynamics, and protein binding properties of cellular RNAs.
Mobile Element Insertions and Associated Structural Variants in Longitudinal Breast Cancer Samples
Authors: Steely Cody J. , Russell Kristi L. , Feusier Julie E. , Qiao Yi , Tavtigian Sean V. , Marth Gabor , Jorde Lynn B. 
Published: February 2020

AbstractWhile mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and structural variants involving existing mobile elements in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. With whole-genome sequencing data from multiple timepoints through tumor progression, we used mobile element detection software followed by visual confirmation of the insertions. We identified 11 mobile element insertions or structural variants involving existing elements and found that the majority of these occurred early in tumor progression. Two of the identified insertions were SVA elements, which have rarely been found in previous cancer studies. Most of the variants appear to impact intergenic regions; however, we identified a translocation interruptingMAP2K4involvingAluelements and a deletion inYTHDF2involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of theMAP2K4translocation, the loss of the other copy ofMAP2K4, the recurrent loss-of-function mutations found in this gene in other human cancers, and the important function ofMAP2K4indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.