Featured
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| Open AccessA generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections
Diagnosing acute infections based on transcriptional host response shows promise, but generalizability is wanting. Here, the authors use a co-normalization framework to train a classifier to diagnose acute infections and apply it to independent data on a targeted diagnostic platform.
- Michael B. Mayhew
- , Ljubomir Buturovic
- & Timothy E. Sweeney
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Article
| Open AccessSex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.
- Matthias Arnold
- , Kwangsik Nho
- & Gabi Kastenmüller
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Article
| Open AccessA case report of multiple primary prostate tumors with differential drug sensitivity
Prostate cancer is often a multifocal disease but how best to manage this clinically remains unclear. Here, the authors report a single case study of a patient with two genetically diverse tumours which showed differential response to therapy.
- Scott Wilkinson
- , Stephanie A. Harmon
- & Adam G. Sowalsky
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Article
| Open AccessSerum neurofilament light levels in normal aging and their association with morphologic brain changes
Neurofilament (NfL) levels in CSF and blood have been established as a biomarker of neuronal damage in neurodegenerative diseases, and there is an age-dependent increase in NfL levels in CSF. Here the authors demonstrate that serum NfL levels increase in healthy aging people and predict and correlate with brain volume loss.
- Michael Khalil
- , Lukas Pirpamer
- & Jens Kuhle
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Article
| Open AccessIncreased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
A locus on chromosome 1 encompassing the CFHR genes is highly associated with AMD risk. Here, Cipriani and colleagues investigate the role of CFHR4, encoding FHR-4, and demonstrate a relationship between AMD risk, circulating FHR-4 levels and genetic variants at this locus.
- Valentina Cipriani
- , Laura Lorés-Motta
- & Simon J. Clark
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Article
| Open AccessCerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia
Diagnosis of vascular dementia is hampered by the lack of biochemical markers for this disease. Here, the authors show that vascular dementia is associated with increased lipocalin-2 in cerebrospinal fluid, compared to controls and patients with other forms of dementia.
- Franc Llorens
- , Peter Hermann
- & Inga Zerr
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Article
| Open AccessWhite blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer
Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.
- Alessandro Leal
- , Nicole C. T. van Grieken
- & Victor E. Velculescu
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Article
| Open AccessMachine learning can identify newly diagnosed patients with CLL at high risk of infection
Chronic lymphocytic leukemia is an indolent disease, and many patients succumb to infection rather than the direct effects of the disease. Here, the authors use medical records and machine learning to predict the patients that may be at risk of infection, which may enable a change in the course of their treatment.
- Rudi Agius
- , Christian Brieghel
- & Carsten U. Niemann
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Article
| Open AccessA robust and efficient method for Mendelian randomization with hundreds of genetic variants
Mendelian randomization (MR) is a method for inferring causal relationships between risk factors and outcomes via associated genetic variants. Here, Burgess et al. develop the contamination mixture method which yields robust MR results in the presence of invalid instrumental variables and groups variants by their effect estimates.
- Stephen Burgess
- , Christopher N Foley
- & Joanna M. M. Howson
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Article
| Open AccessIntegrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
Here the authors provide a single-cell characterization of cerebrospinal fluid and blood of newly diagnosed multiple sclerosis (MS) patients, revealing altered composition of lymphocyte and monocyte subsets, validated by other methods including the interrogation of the TFH subset in mouse models of MS.
- David Schafflick
- , Chenling A. Xu
- & Gerd Meyer zu Horste
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Article
| Open AccessPain-free resting-state functional brain connectivity predicts individual pain sensitivity
An fMRI-based brain signature to predict an individual’s pain sensitivity could be useful clinically. Here the authors identify a network in the resting brain which can be used to predict responses to noxious stimuli in healthy subjects.
- Tamas Spisak
- , Balint Kincses
- & Ulrike Bingel
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Article
| Open AccessSelecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization
Multivariable Mendelian randomization (MR) extends the standard MR framework to consider multiple risk factors in a single model. Here, Zuber et al. propose MR-BMA, a Bayesian variable selection approach to identify the likely causal determinants of a disease from many candidate risk factors as for example high-throughput data sets.
- Verena Zuber
- , Johanna Maria Colijn
- & Stephen Burgess
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Article
| Open AccessObesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients
Here, the authors characterize immunological and microbiome alterations in a cohort of obese asthmatics, finding that disease severity negatively correlates with fecal abundance of Akkermansia muciniphila, and show in a mouse model that administration of A. muciniphila reduces airway hyper-reactivity and airway inflammation.
- David Michalovich
- , Noelia Rodriguez-Perez
- & Liam O’Mahony
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Article
| Open AccessPredictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders
Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.
- L. D’Abate
- , S. Walker
- & S. W. Scherer
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Article
| Open AccessAn open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma
Histology data exists for many cancer samples and the ability to automatically image this data may provide prognostic information. Here, the authors generated an algorithm to measure tumour infiltrating lymphocytes in melanoma histology specimens and show that the ratio of these immune cells to tumour cells has prognostic value.
- Balazs Acs
- , Fahad Shabbir Ahmed
- & David L. Rimm
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Article
| Open AccessIdentification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.
- Dan Su
- , Dadong Zhang
- & Weimin Mao
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Article
| Open AccessMetabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty
Risk of age-related chronic disorders and decrease in resilience is associated with ageing. Here the authors analyse the human blood metabolome and identify metabolites associated with frailty.
- Nicholas J. W. Rattray
- , Drupad K. Trivedi
- & Royston Goodacre
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Article
| Open AccessEvaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis
Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.
- Richard H. Kimura
- , Ling Wang
- & Sanjiv S. Gambhir
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Article
| Open AccessMetabolomic adaptations and correlates of survival to immune checkpoint blockade
Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.
- Haoxin Li
- , Kevin Bullock
- & Marios Giannakis
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Article
| Open AccessHigh-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
- David P. Labbé
- , Giorgia Zadra
- & Myles Brown
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Article
| Open AccessNon-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease
The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.
- Xavier Hadoux
- , Flora Hui
- & Peter van Wijngaarden
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Article
| Open AccessA metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals
Biomarkers that predict mortality are of interest for clinical as well as research applications. Here, the authors analyze metabolomics data from 44,168 individuals and identify key metabolites independently associated with all-cause mortality risk.
- Joris Deelen
- , Johannes Kettunen
- & P. Eline Slagboom
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Article
| Open AccessSynthetic molecular recognition nanosensor paint for microalbuminuria
Microalbuminuria, a clinical marker associated with cancer and hypertension, defined by low albumin levels in the urine, is normally detected by immunoassay. Herein, a nanosensor paint was developed using a polymer to mimic fatty acid binding to albumin, transduced by carbon nanotube fluorescence.
- Januka Budhathoki-Uprety
- , Janki Shah
- & Daniel A. Heller
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Article
| Open AccessSelective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
In acute myeloid leukemia, hypomethylating agents decitabine and azacytidine are used interchangeably. Here, the authors show that the major metabolite of decitabine, but not azacytidine, is subject to SAMHD1 inactivation, highlighting SAMHD1 as a potential biomarker and therapeutic target
- Thomas Oellerich
- , Constanze Schneider
- & Jindrich Cinatl Jr.
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Perspective
| Open AccessA systems biology approach towards understanding and treating non-neovascular age-related macular degeneration
No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.
- James T. Handa
- , Cathy Bowes Rickman
- & Lindsay A. Farrer
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Article
| Open AccessAnalysis of polygenic risk score usage and performance in diverse human populations
Predominant participation of European-ancestry individuals in genetic studies has hindered the better understanding of genetic risk in non-European ancestry individuals. Here, Duncan et al. quantify polygenic risk score use and performance in worldwide populations.
- L. Duncan
- , H. Shen
- & B. Domingue
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Article
| Open AccessThe generation and use of recombinant extracellular vesicles as biological reference material
There is no universal reference material to develop extracellular vesicle (EV) separation methods and carry out calibration and normalization. Here the authors use HIV-derived gag proteins to assemble recombinant fluorescent EV as a trackable reference material resembling the physical and biochemical properties of sample EV.
- Edward Geeurickx
- , Joeri Tulkens
- & An Hendrix
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Article
| Open AccessDetection of cell-type-specific risk-CpG sites in epigenome-wide association studies
Cellular heterogeneity is one of the major confounding factors in EWAS studies. Here the authors present a statistical method, HIgh REsolution (HIRE), which enables the detection of risk-CpG sites for individual cell types.
- Xiangyu Luo
- , Can Yang
- & Yingying Wei
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Article
| Open AccessThe nasal methylome as a biomarker of asthma and airway inflammation in children
Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in TH2 response.
- Andres Cardenas
- , Joanne E. Sordillo
- & Diane R. Gold
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Article
| Open AccessTherapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Dimethyl fumarate (DMF) is an established treatment for relapsing multiple sclerosis with unclear mechanism of action. Here the authors distinguish DMF responders by monocyte counts and redox gene signature in a prospective longitudinal cohort at 3 month of therapy, and associate NOX3 genetic variants with outcome.
- Karl E. Carlström
- , Ewoud Ewing
- & Fredrik Piehl
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Article
| Open AccessZero-field nuclear magnetic resonance of chemically exchanging systems
Zero-field nuclear magnetic resonance can identify species and collective behaviors in mixtures without applied magnetic fields. Here the authors demonstrate its use for resolving proton exchange in ammonium and for the detection of hyperpolarized pyruvic acid, an important imaging biomarker.
- Danila A. Barskiy
- , Michael C. D. Tayler
- & Alexander Pines
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Article
| Open AccessDeath effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
The use of of CDK4/6 inhibitors to treat patients with TNBC is limited by loss of Rb. Here, the authors show that a combination of CDK4/6 inhibitor and EGFR inhibitor is effective against DEDD-overexpressing TNBC, independent of Rb status.
- Yingjia Ni
- , Keon R. Schmidt
- & Siyuan Zhang
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Article
| Open AccessLarge-scale brain modes reorganize between infant sleep states and carry prognostic information for preterms
Patterns of brain activity during sleep in early stages of life influence brain development and behavior. Here, the authors reveal cortical dynamics underpinning quiet and active sleep states in pre- and full-term infants, and their links to neurodevelopmental outcomes.
- Anton Tokariev
- , James A. Roberts
- & Luca Cocchi
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Article
| Open AccessIntegrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.
- Darina Czamara
- , Gökçen Eraslan
- & Elisabeth B. Binder
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Article
| Open AccessComparative analysis of mRNA and protein degradation in prostate tissues indicates high stability of proteins
Protein degradation in clinical samples is largely unexplored. Here, the authors analyze the transcriptome and proteome of clinical tissue samples and develop an algorithm to assess protein degradation, showing that protein degradation is negligible in most tissue samples and does not correlate with transcript degradation.
- Wenguang Shao
- , Tiannan Guo
- & Ruedi Aebersold
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Article
| Open AccessJNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression
LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.
- Jian Liu
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessWhole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer
Structural variations in gastric cancer impact progression. Here, the authors perform whole-genome sequencing on 168 gastric cancer patients and identified tandem-duplications of super-enhancer ZFP36L2 in 10% of gastric cancer, and mutational signatures in tumors with cadherin 1 mutations that associated with poor prognoses.
- Rui Xing
- , Yong Zhou
- & Youyong Lu
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Article
| Open AccessCharacterizing pre-transplant and post-transplant kidney rejection risk by B cell immune repertoire sequencing
Adaptive immunity from both B and T cells critically controls the rejection or survival of transplanted organs. Here the authors show, by analyzing human B cell receptor repertoire in longitudinal studies of patients receiving kidney transplants, that repertoire diversity is positively associated with the incidence of kidney rejection.
- Silvia Pineda
- , Tara K. Sigdel
- & Minnie M. Sarwal
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Article
| Open AccessComprehensive genomic and immunological characterization of Chinese non-small cell lung cancer patients
The relationship between genomic alteration and immune context in non-small cell lung cancer (NSCLC) is complex. Here, the authors analyse the molecular and immunological landscape of 245 Chinese patients with NSCLC and find low immune infiltration correlates with genomic alterations.
- Xu-Chao Zhang
- , Jun Wang
- & Yi-Long Wu
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Article
| Open AccessBreast cancer quantitative proteome and proteogenomic landscape
Gene expression profiles can classify breast cancer into five clinically relevant subtypes. Here, the authors perform an in-depth quantitative profiling of the proteome of 45 breast tumors, and show they can recapitulate the transcriptome-based classifications and identify many potentially antigenic tumour-specific peptides.
- Henrik J. Johansson
- , Fabio Socciarelli
- & Janne Lehtiö
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Article
| Open AccessA temporary indwelling intravascular aphaeretic system for in vivo enrichment of circulating tumor cells
Ex vivo methods of circulating tumor cell (CTC) isolation use small blood volumes, limiting sensitivity and introducing analytical inaccuracies. The authors describe a proof-of-concept study of an in vivo aphaeresis system that continuously collects CTCs from a peripheral vein over several hours.
- Tae Hyun Kim
- , Yang Wang
- & Daniel F. Hayes
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Article
| Open AccessA gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease
Development of cirrhosis in individuals with non-alcoholic fatty liver disease can predict mortality. Here the authors used a unique twin and family cohort to identify a gut microbiome-derived 16sRNA signature that can detect cirrhosis in individuals with non-alcoholic fatty liver disease.
- Cyrielle Caussy
- , Anupriya Tripathi
- & Rohit Loomba
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Article
| Open AccessCervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery
Here, Elovitz et al. investigate associations between cervicovaginal microbiota (CVM) and spontaneous preterm birth (sPTB) in a large cohort of African American and non-African American women, and find that CVM and local immune response early in pregnancy are associated with sPTB in an ethnicity-dependent manner.
- Michal A. Elovitz
- , Pawel Gajer
- & Jacques Ravel
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Article
| Open AccessIntegrated systems approach defines the antiviral pathways conferring protection by the RV144 HIV vaccine
The RV144 vaccine trial showed reduced risk of HIV-1 acquisition, but mechanisms underlying protection are poorly understood. Here, Fourati et al. assess the transcriptomic profile of blood collected from 223 vaccinees and 40 placebo recipients and identify IRF7 as a mediator of protection.
- Slim Fourati
- , Susan Pereira Ribeiro
- & Rafick-Pierre Sékaly
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Article
| Open AccessMulti-cohort study identifies social determinants of systemic inflammation over the life course
Here, the authors explore the relationship between socioeconomic position (SEP) across the life course and inflammation in a multi-cohort study and show that educational attainment is most strongly related to inflammation, suggesting that socioeconomic disadvantage in young adulthood is independently associated with later life inflammation.
- Eloïse Berger
- , Raphaële Castagné
- & Michelle Kelly-Irving
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Article
| Open AccessSympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A
Diverse interactions between the nervous and immune systems have been shown, but specific mechanistic insights are still lacking. Here the authors show, using both mouse inflammation models and clinical correlation, that adrenergic nerve may ameliorate inflammation by inducing repulsive guidance molecule A signalling.
- Andreas Körner
- , Martin Schlegel
- & Valbona Mirakaj
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Article
| Open AccessClinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms
FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.
- Haijiao Zhang
- , Samantha Savage
- & Jeffrey W. Tyner
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Article
| Open AccessTranscriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma
In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.
- Anton Ogorodnikov
- , Michal Levin
- & Sven Danckwardt
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Article
| Open AccessMetabolite changes in blood predict the onset of tuberculosis
The tuberculosis pandemic requires new methods for diagnosing and containing infections prior to active disease. Here, the authors performed a multi-site observational study within sub-Saharan Africa and present serum and plasma metabolic signatures that can predict the onset of active TB with a high degree of sensitivity and specificity.
- January Weiner 3rd
- , Jeroen Maertzdorf
- & Sarah Zalwango