bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genetic makeup of the electrocardiogram
Authors: Verweij Niek , Benjamins Jan-Walter , Morley Michael P. , van de Vegte Yordi , Teumer Alexander , Trenkwalder Teresa , Reinhard Wibke , Cappola Thomas P. , van der Harst Pim 
Published: May 2019

AbstractSince its original description in 1893 by Willem van Einthoven, the electrocardiogram (ECG) has been instrumental in the recognition of a wide array of cardiac disorders1,2. Although many electrocardiographic patterns have been well described, the underlying biology is incompletely understood. Genetic associations of particular features of the ECG have been identified by genome wide studies. This snapshot approach only provides fragmented information of the underlying genetic makeup of the ECG. Here, we follow the effecs of individual genetic variants through the complete cardiac cycle the ECG represents. We found that genetic variants have unique morphological signatures not identfied by previous analyses. By exploiting identified abberations of these morphological signatures, we show that novel genetic loci can be identified for cardiac disorders. Our results demonstrate how an integrated approach to analyse high-dimensional data can further our understanding of the ECG, adding to the earlier undertaken snapshot analyses of individual ECG components. We anticipate that our comprehensive resource will fuelin silicoexplorations of the biological mechanisms underlying cardiac traits and disorders represented on the ECG. For example, known disease causing variants can be used to identify novel morphological ECG signatures, which in turn can be utilized to prioritize genetic variants or genes for functional validation. Furthermore, the ECG plays a major role in the development of drugs, a genetic assessment of the entire ECG can drive such developments.
EGR1 transcriptional control of human cytomegalovirus latency
Authors: Buehler Jason , Carpenter Ethan , Zeltzer Sebastian , Igarashi Suzu , Rak Michael , Mikell Iliyana , Nelson Jay A. , Goodrum Felicia 
Published: May 2019

ABSTRACTSustained phosphotinositide3-kinase (PI3K) signaling is critical to the maintenance of herpesvirus latency. We have previously shown that the beta-herpesvirus, human cytomegalovirus (CMV), regulates epidermal growth factor receptor (EGFR), upstream of PI3K, to control states of latency and reactivation. Inhibition of EGFR signaling enhances CMV reactivation from latency and increases viral replication, but the mechanisms by which EGFR impacts replication and latency is not known. We demonstrate that HCMV downregulates MEK/ERK and AKT phosphorylation, but not STAT3 or PLCγ for productive replication. Similarly, inhibition of either MEK/ERK or PI3K/AKT, but not STAT or PLCγ, pathways increases viral reactivation from latently infected CD34+hematopoietic progenitor cells (HPCs), defining a role for these pathways in latency. We hypothesized that CMV modulation of EGFR signaling might impact viral transcription. Indeed, EGF-stimulation increased expression of theUL138latency gene, but not immediate early or early viral genes, suggesting that EGFR signaling promotes latent gene expression. The early growth response-1 (EGR1) transcription factor is induced downstream of EGFR signaling through both PI3K/AKT and MEK/ERK pathways. EGR1 expression is important for the maintenance of HPC stemness and its downregulation drives HPC differentiation and mobilization. We demonstrate that EGR1 binds upstream ofUL138and is sufficient to promoteUL138expression. Further, disruption of EGR1 binding upstream ofUL138prevented CMV from establishing a latent infection in CD34+HPCs. Our results indicate a model whereby UL138 modulation of EGFR signaling feeds back to promote UL138 expression and suppression of replication to establish or maintain viral quiescence.AUTHOR SUMMARYCMV regulates EGFR signaling to balance states of viral latency and replication. CMV blocks downstream PI3K/AKT and MEK/ERK signaling pathways through down-regulation of EGFR at the plasma membrane. PI3K/AKT and MEK/ERK signaling increases expression of the EGR1 transcription factor that is necessary for the maintenance of stem cell stemness. A decrease in EGR1 expression promotes HPC mobilization to the periphery and differentiation, a known stimulus for CMV reactivation. We identified functional EGR1 binding sites upstream of theUL138gene and EGR-1 binding stimulatesUL138expression. Additionally, down-regulation of EGR1 by CMV miR-US22 decreasesUL138expression emphasizing the importance of this transcription factor in expression of this latency gene. Lastly, we demonstrate that a CMV mutant virus lacking an upstream EGR1 binding site is unable to establish latency in CD34+HPCs. This study defines one mechanism by which EGFR signaling impacts viral gene expression to promote CMV latency.
A cell-free DNA metagenomic sequencing assay that integrates the damage response to infection
Authors: Cheng Alexandre Pellan , Burnham Philip , Lee John Richard , Cheng Matthew Pellan , Suthanthiran Manikkam , Dadhania Darshana , De Vlaminck Iwijn 
Published: May 2019

ABSTRACTHigh-throughput metagenomic sequencing offers an unbiased approach to identify pathogens in clinical samples. Conventional metagenomic sequencing however does not integrate information about the host, which is often critical to distinguish infection from infectious disease, and to assess the severity of disease. Here, we explore the utility of high-throughput sequencing of cell-free DNA after bisulfite conversion to map the tissue and cell types of origin of host-derived cell-free DNA, and to profile the bacterial and viral metagenome. We applied this assay to 51 urinary cfDNA isolates collected from a cohort of kidney transplant recipients with and without bacterial and viral infection of the urinary tract. We find that the cell and tissue types of origin of urinary cell-free DNA can be derived from its genome-wide profile of methylation marks, and strongly depend on infection status. We find evidence of kidney and bladder tissue damage due to viral and bacterial infection, respectively, and of the recruitment of neutrophils to the urinary tract during infection. Through direct comparison to conventional metagenomic sequencing as well as clinical tests of infection, we find this assay accurately captures the bacterial and viral composition of the sample. The assay presented here is straightforward to implement, offers a systems view into bacterial and viral infections of the urinary tract, and can find future use as a tool for the differential diagnosis of infections.
The parallel auditory brainstem response
Authors: Polonenko Melissa J , Maddox Ross K 
Published: May 2019

ABSTRACTThe frequency-specific tone-evoked auditory brainstem response (ABR) is an indispensable tool in both the audiology clinic and research laboratory. Most frequently the toneburst ABR is used to estimate hearing thresholds in infants, toddlers and other patients for whom behavioral testing is not feasible. Therefore, results of the ABR exam form the basis for decisions regarding interventions and hearing habilitation with implications extending far into the child’s future. Currently, responses are elicited by periodic sequences of toneburst stimuli presented serially to one ear at a time, which take a long time to measure multiple frequencies and intensities, and provide incomplete information if the infant wakes up early. Here we describe a new method, the parallel ABR (pABR), which uses randomly timed toneburst stimuli to simultaneously acquire ABR waveforms to 5 frequencies in both ears. Here we describe the pABR and quantify its effectiveness in addressing the greatest drawback of current methods: test duration. We show that in adults with normal hearing the pABR yields high-quality waveforms over a range of intensities, with similar morphology to the standard ABR in a fraction of the recording time. Furthermore, longer latencies and smaller amplitudes for low frequencies at a high intensity evoked by the pABR versus serial ABR suggest that responses may have better place specificity due to the masking provided by the other simultaneous toneburst sequences. Thus, the pABR has substantial potential for facilitating faster accumulation of more diagnostic information that is important for timely identification and treatment of hearing loss.
Intentions of Canadian health professionals towards recommending exercise to people living with ALS
Authors: Jones Kelvin E , Berry Tanya R , Bello-Haas Vanina Dal 
Published: May 2019

AbstractBackgroundTo provide a nationwide overview of the attitudes, social pressure, perceived ability and intentions of health professionals toward exercise prescription for people living with ALS (pALS).MethodsAn online survey of physician and other health professionals (HPs) working in academic ALS clinics across Canada.ResultsThe response rate was 48% (84/176) with 30% of respondents identifying as physicians, 63% as other HPs and the remainder as administrative or research personnel. Respondents were sharply divided in their intentions to provide exercise counsel: 24% unlikely and 45% likely. Respondents with low intentions were HPs that considered this activity outside their scope of practice. Measures of intention and attitude were more positive for flexibility compared to strength and aerobic exercise. Perceptions of social pressure and ability to provide exercise counsel were significantly correlated with intention across the three exercise modes in all respondents. Qualitative themes identified as barriers to exercise prescription were lack of confidence or competence (31% physicians, 32% HP), patient tolerance (30% HP), lack of evidence (22% physicians) and lack of infrastructure (22% physicians).ConclusionsWhile “lack of evidence” for the benefit of exercise was a deterrent for physicians, the larger issue for all respondents was building competence and confidence in exercise prescription for pALS.
Toward Broad Spectrum DHFR inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin-Resistant Staphylococcus aureus
Authors: Reeve Stephanie M. , Si Debjani , Krucinska Jolanta , Yan Yongzhao , Viswanathan Kishore , Wang Siyu , Holt Graham T. , Frenkel Marcel S. , Ojewole Adegoke A. , Estrada Alexavier , Agabiti Sherry S. , Alverson Jeremy B. , Gibson Nathan D. , Priestly Nigel D. , Wiemer Andrew J. , Donald Bruce R. , Wright Dennis L. 
Published: May 2019

AbstractThe spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-confering isoforms. Using a structure-based approach, we have developed a novel class of ionized non-classical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMPR MRSA isolates.
Type 2 Diabetes: One Disease, Many Pathways
Authors: Ha Joon , Sherman Arthur 
Published: May 2019

AbstractDiabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first, and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT, and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.
Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas
Authors: Xiao Yi , Clima Rosanna , Busch Jonas Felix , Rabien Anja , Kilic Ergin , Villegas Sonia , Türkmen Seval , Timmermann Bernd , Attimonelli Marcella , Jung Klaus , Meierhofer David 
Published: May 2019

SummaryChromophobe renal cell carcinomas (chRCC) are derived from intercalated cells of the collecting duct system, and are thought to be the malignant counterpart of benign renal oncocytomas. Here, we report the characterization of nine chRCC with adjacent healthy kidney tissues by applying proteome-, transcriptome (TCGA)-, and metabolome profiling. Most strikingly, the reactive oxygen species scavenger glutathione was significantly elevated in chRCC, caused by down-regulated enzymes involved in glutathione degradation. Metabolic reprogramming including stalled gluconeogenesis, down-regulated fatty acid- and amino acid metabolism was identified, even though, the abundance of amino acids and “energy carrier” molecules were unchanged. A striking anti-correlation of the mitochondrial respiratory chain between the transcriptome and the proteome was discovered, the transcripts coding for the respiratory chain were up-, while corresponding proteins and enzymatic activities were down-regulated. Similar to renal oncocytomas, chRCC exhibited a significant increase in glutathione, but are distinguishable by distinct regulation of the respiratory chain.
Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT
Authors: Aldiss Peter , Lewis Jo E , Lupini Irene , Boocock David J , Miles Amanda K , Ebling Francis J P , Budge Helen , Symonds Michael E 
Published: May 2019

AbstractBackground and aimExercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents. However, these animals are typically housed below their thermoneutral zone (i.e. 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e. thermoneutrality) on BAT and WAT in its basal (i.e. inactive) state.MethodsSprague-Dawley rats (n=12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet (HFD). At 12 weeks of age half these animals were randomised to 4-weeks of exercise exercise training, i.e. swim-training (1 hour/day, 5 days per week). Metabolic assessment was undertaken during the final 48h and was followed by interscapular and perivascular BAT and inguinal (I)WAT sampling for the analysis of thermogenic genes and the proteome.ResultsExercise attenuated weight gain but did not affect fat mass or general metabolic parameters (i.e. fasting insulin and glucose). Interestingly, although BAT mass was increased, there was no change in thermogenic gene expression. Differentially regulated proteins in BAT enriched gene ontology (GO) terms including 2-oxoglutarate metabolic process, cytochrome-c activity and mitochondrial respiratory chain complex IV. This was accompanied by an upregulation of multiple proteins and GO terms involved in skeletal muscle physiology suggesting an adipocyte to myocyte switch in BAT. UCP1 mRNA was undetectable in IWAT despite an increase in classical ‘browning’ markers (i.e. PGC1a and ADRB3) with exercise. Enriched GO terms in IWAT included DNA binding and positive regulation of apoptosis. Impact analysis highlighted carbon metabolism and OXPHOS pathways were regulated by exercise in BAT whilst HIF-1 signalling and cytokine-cytokine receptor interaction were among those modified in IWAT.ConclusionExercise training reduces weight gain in obese animals at thermoneutrality and is accompanied by an oxidative, myogenic signature in BAT, rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT regulates body weight at thermoneutrality.
Identifying gene function and module connections by the integration of multi-species expression compendia
Authors: Li Hao , Rukina Daria , David Fabrice P. A. , Li Terytty Yang , Oh Chang-Myung , Gao Arwen W. , Katsyuba Elena , Sleiman Maroun Bou , Komljenovic Andrea , Huang Qingyao , Williams Robert W. , Robinson-Rechavi Marc , Schoonjans Kristina , Morgenthaler Stephan , Auwerx Johan 
Published: May 2019

AbstractThe functions of many eukaryotic genes are still poorly understood. We developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First,Gene-ModuleAssociationDetermination (G-MAD) allows the annotation of gene function. Second,Module-ModuleAssociationDetermination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multi-species expression compendia—1,700 datasets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast—collected in this study. Unlike most existing bioinformatics tools, GeneBridge exploits both positive and negative gene/module-module associations. We constructed association networks, such as those bridging mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available atsystems-genetics.org, to facilitate the identification of connections linking genes, modules, phenotypes, and diseases.
A Human Liver Cell Atlas: Revealing Cell Type Heterogeneity and Adult Liver Progenitors by Single-Cell RNA-sequencing
Authors: Aizarani Nadim , Saviano Antonio , Sagar  , Mailly Laurent , Durand Sarah , Pessaux Patrick , Baumert Thomas F. , Grün Dominic 
Published: May 2019

ABSTRACTThe human liver is an essential multifunctional organ, and liver diseases are rising with limited treatment options. However, the cellular complexity and heterogeneity of the liver remain poorly understood. Here, we performed single-cell RNA-sequencing of ~5,000 cells from normal liver tissue of 6 human donors to construct the first human liver cell atlas. Our analysis revealed previously unknown sub-types among endothelial cells, Kupffer cells, and hepatocytes with transcriptome-wide zonation of these populations. We show that the EPCAM+ population is highly heterogeneous and consists of hepatocyte progenitors, cholangiocytes and a MUC6+ stem cell population with a specific potential to form liver organoids. As proof-of-principle, we applied our atlas to unravel phenotypic changes in cells from hepatocellular carcinoma tissue and to investigate cellular phenotypes of human hepatocytes and liver endothelial cells engrafted into a humanized FAH-/- mouse liver. Our human liver cell atlas provides a powerful and innovative resource enabling the discovery of previously unknown cell types in the normal and diseased liver.
Distinct properties of layer 3 pyramidal neurons from prefrontal and parietal areas of the monkey neocortex
Authors: Gonzalez-Burgos Guillermo , Miyamae Takeaki , Krimer Yosef , Gulchina Yelena , Pafundo Diego , Krimer Olga , Bazmi Holly , Arion Dominique , Enwright John F , Fish Kenneth , Lewis David A 
Published: May 2019

AbstractIn primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (RS-L3PNs) and bursting (B-L3PNs) physiological subtypes. Whereas regional differences in single-cell excitability were modest, B-L3PNs were rare in PPC (RS-L3PN:B-L3PN, 94:6), but were abundant in DLPFC (50:50), showing greater physiological diversity. Moreover, DLPFC L3PNs display larger and more complex basal dendrites with higher dendritic spine density. Additionally, we found differential expression of hundreds of genes, suggesting a transcriptional basis for the differences in L3PN phenotype between DLPFC and PPC. These data show that the previously observed differences between DLPFC and PPC neuron activity during working memory tasks are associated with diversity in the cellular/molecular properties of L3PNs.Significance statementIn the human and non-human primate neocortex, layer 3 pyramidal neurons (L3PNs) differ significantly between dorsolateral prefrontal (DLPFC) and sensory areas. Hence, L3PN properties reflect, and may contribute to, a greater complexity of computations performed in DLPFC. However, across association cortical areas, L3PN properties are largely unexplored. We studied the physiology, dendrite morphology and transcriptome of L3PNs from macaque monkey DLPFC and posterior parietal cortex (PPC), two key nodes in the cortical working memory network. L3PNs from DLPFC had greater diversity of physiological properties and larger basal dendrites with higher spine density. Moreover, transcriptome analysis suggested a molecular basis for the differences in the physiological and morphological phenotypes of L3PNs from DLPFC and PPC.