scholarly journals Metabolic and immune markers for precise monitoring of COVID-19 severity and treatment

2021 ◽  
Author(s):  
André F. Rendeiro ◽  
Charles Kyriakos Vorkas ◽  
Jan Krumsiek ◽  
Harjot Singh ◽  
Shashi Kapatia ◽  
...  
Keyword(s):  
Temporal Dynamics ◽  
Severe Disease ◽  
Deep Understanding ◽  
Response To Therapy ◽  
High Dimensional ◽  
Time Resolved ◽  
Novel Approach ◽  
Metabolomic Data ◽  
Clinical Action ◽  
Rich Information

AbstractDeep understanding of the SARS-CoV-2 effects on host molecular pathways is paramount for the discovery of early biomarkers of outcome of coronavirus disease 2019 (COVID-19) and the identification of novel therapeutic targets. In that light, we generated metabolomic data from COVID-19 patient blood using high-throughput targeted nuclear magnetic resonance (NMR) spectroscopy and high-dimensional flow cytometry. We find considerable changes in serum metabolome composition of COVID-19 patients associated with disease severity, and response to tocilizumab treatment. We built a clinically annotated, biologically-interpretable space for precise time-resolved disease monitoring and characterize the temporal dynamics of metabolomic change along the clinical course of COVID-19 patients and in response to therapy. Finally, we leverage joint immuno-metabolic measurements to provide a novel approach for patient stratification and early prediction of severe disease. Our results show that high-dimensional metabolomic and joint immune-metabolic readouts provide rich information content for elucidation of the host’s response to infection and empower discovery of novel metabolic-driven therapies, as well as precise and efficient clinical action.

scholarly journals Longitudinal high-dimensional analysis identifies biomarkers of response to anti-PD-1 immunotherapy

2021 ◽  
Author(s):  
Run-Ze Li ◽  
Xing-Xing Fan ◽  
Ze-Bo Jiang ◽  
Jumin Huang ◽  
Hu-Dan Pan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Response To Therapy ◽  
High Dimensional ◽  
Meso Scale Discovery ◽  
Peripheral Blood Mononuclear ◽  
Poor Outcomes ◽  
Nsclc Patients

Abstract The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with efficacy have yet to be validated. In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8+ and CD8+CD101hiTIM3+ (CCT T) subsets were significantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

scholarly journals Activation mechanism of ATP-sensitive K+ channels explored with real-time nucleotide binding

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Michael Puljung ◽  
Natascia Vedovato ◽  
Samuel Usher ◽  
Frances Ashcroft
Keyword(s):  
Conformational Change ◽  
Ionic Currents ◽  
Nucleotide Binding ◽  
Activation Mechanism ◽  
Time Resolved ◽  
K Channels ◽  
Novel Approach ◽  
Binding Event ◽  
Fluorescent Nucleotides

The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg2+ was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50 for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATP activation by the same amount.

scholarly journals Massively parallel, time-resolved single-cell RNA sequencing with scNT-Seq

2019 ◽  
Author(s):  
Qi Qiu ◽  
Peng Hu ◽  
Kiya W. Govek ◽  
Pablo G. Camara ◽  
Hao Wu
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Temporal Dynamics ◽  
Embryonic Stem ◽  
Droplet Microfluidics ◽  
Massively Parallel ◽  
Specific Gene ◽  
Time Resolved ◽  
Single Cell Rna Sequencing ◽  
Rna Biogenesis

ABSTRACTSingle-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal dynamics of RNA biogenesis and decay. Here we present single-cell new transcript tagging sequencing (scNT-Seq), a method for massively parallel analysis of newly-transcribed and pre-existing RNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking metabolically labeled newly-transcribed RNAs with T-to-C substitutions. By simultaneously measuring new and old transcriptomes, scNT-Seq reveals neuronal subtype-specific gene regulatory networks and time-resolved RNA trajectories in response to brief (minutes) versus sustained (hours) neuronal activation. Integrating scNT-Seq with genetic perturbation reveals that DNA methylcytosine dioxygenases may inhibit stepwise transition from pluripotent embryonic stem cell state to intermediate and totipotent two-cell-embryo-like (2C-like) states by promoting global RNA biogenesis. Furthermore, pulse-chase scNT-Seq enables transcriptome-wide measurements of RNA stability in rare 2C-like cells. Time-resolved single-cell transcriptomic analysis thus opens new lines of inquiry regarding cell-type-specific RNA regulatory mechanisms.

Effect of Rotor-Stator Configuration in the Generation of Vortical Scales and Wake Mixing in Single Stage Axial Fans: Part II — Assessment of Vortex Sound Sources

2013 ◽  
Author(s):  
Mónica Galdo Vega ◽  
Jesus Manuel Fernandez Oro ◽  
Katia María Argüelles Díaz ◽  
Carlos Santolaria Morros
Keyword(s):  
Deep Understanding ◽  
Operating Conditions ◽  
Axial Fan ◽  
Noise Sources ◽  
Sound Sources ◽  
Time Resolved ◽  
Vortex Sound ◽  
Starting Point ◽  
Axial Fans ◽  
The Impact

This second part is devoted to the identification of vortex sound sources in low-speed turbomachinery. As a starting point, the time-resolved evolution of the vortical motions associated to the wake shear layers (reported in the first part of the present study) is employed to obtain vorticity distributions in both blade-to-blade and traverse locations throughout the axial fan stage. Following, the Powell analogy for generation of vortex sound is revisited to obtain the noise sources in the nearfield region of the fan. Both numerical and experimental databases presented previously are now post-processed to achieve a deep understanding of the aeroacoustic behavior of the vortical scales present in the flow. A LES simulation at midspan, using a 2.5D scheme, allows an accurate description of the turn-out time of the shedding vortices, within high-density meshes in the blades and vanes passages, and a correct modeling of the dynamics of turbulence. Besides, thermal anemometry has been employed with a two-wire probe to measure the planar flow in the midspan sections of the fan. Statistical procedures and signal conditioning of velocity traces have confirmed experimentally the unsteady flow patterns devised in the numerical model. The comparison of the rotor-stator and the stator-rotor configurations provides the influence of the wake mixing and the nucleation of turbulent spots in the distribution of the Powell source terms. Moreover, the relation between the turbomachine configuration and the generation of vortex sound can be established, including the impact of the operating conditions and the contributions of the interaction mechanisms.

A Novel Approach to Visualization of High-Dimensional Data by Pairwise Fusion Matrices Using t-SNE

2021 ◽  
pp. 89-108
Author(s):  
Mujtaba Husnain ◽  
Malik Muhammad Saad Missen ◽  
Shahzad Mumtaz ◽  
Muhammad Muzzamil Luqman ◽  
Mickael Coustaty ◽  
...  
Keyword(s):  
High Dimensional Data ◽  
High Dimensional ◽  
Novel Approach

scholarly journals Deep-learning approach to identifying cancer subtypes using high-dimensional genomic data

2019 ◽  
Author(s):  
Runpu Chen ◽  
Le Yang ◽  
Steve Goodison ◽  
Yijun Sun
Keyword(s):  
Deep Learning ◽  
Cluster Structure ◽  
Data Representation ◽  
Supplementary Information ◽  
High Dimensional ◽  
Breast Cancer Dataset ◽  
Cancer Dataset ◽  
Cancer Subtypes ◽  
Novel Approach ◽  
Open Source Software Package

Abstract Motivation Cancer subtype classification has the potential to significantly improve disease prognosis and develop individualized patient management. Existing methods are limited by their ability to handle extremely high-dimensional data and by the influence of misleading, irrelevant factors, resulting in ambiguous and overlapping subtypes. Results To address the above issues, we proposed a novel approach to disentangling and eliminating irrelevant factors by leveraging the power of deep learning. Specifically, we designed a deep-learning framework, referred to as DeepType, that performs joint supervised classification, unsupervised clustering and dimensionality reduction to learn cancer-relevant data representation with cluster structure. We applied DeepType to the METABRIC breast cancer dataset and compared its performance to state-of-the-art methods. DeepType significantly outperformed the existing methods, identifying more robust subtypes while using fewer genes. The new approach provides a framework for the derivation of more accurate and robust molecular cancer subtypes by using increasingly complex, multi-source data. Availability and implementation An open-source software package for the proposed method is freely available at http://www.acsu.buffalo.edu/~yijunsun/lab/DeepType.html. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Genesis and spread of multiple reassortants during the 2016/2017 H5 avian influenza epidemic in Eurasia

2020 ◽  
Vol 117 (34) ◽  
pp. 20814-20825 ◽  
Author(s):  
Samantha J. Lycett ◽  
Anne Pohlmann ◽  
Christoph Staubach ◽  
Valentina Caliendo ◽  
Mark Woolhouse ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Severe Disease ◽  
Wild Birds ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
Highly Pathogenic ◽  
Time Resolved ◽  
Bird Populations ◽  
Pathogenic Avian Influenza ◽  
Reassortant Viruses

Highly pathogenic avian influenza (HPAI) viruses of the H5 A/goose/Guangdong/1/96 lineage can cause severe disease in poultry and wild birds, and occasionally in humans. In recent years, H5 HPAI viruses of this lineage infecting poultry in Asia have spilled over into wild birds and spread via bird migration to countries in Europe, Africa, and North America. In 2016/2017, this spillover resulted in the largest HPAI epidemic on record in Europe and was associated with an unusually high frequency of reassortments between H5 HPAI viruses and cocirculating low-pathogenic avian influenza viruses. Here, we show that the seven main H5 reassortant viruses had various combinations of gene segments 1, 2, 3, 5, and 6. Using detailed time-resolved phylogenetic analysis, most of these gene segments likely originated from wild birds and at dates and locations that corresponded to their hosts’ migratory cycles. However, some gene segments in two reassortant viruses likely originated from domestic anseriforms, either in spring 2016 in east China or in autumn 2016 in central Europe. Our results demonstrate that, in addition to domestic anseriforms in Asia, both migratory wild birds and domestic anseriforms in Europe are relevant sources of gene segments for recent reassortant H5 HPAI viruses. The ease with which these H5 HPAI viruses reassort, in combination with repeated spillovers of H5 HPAI viruses into wild birds, increases the risk of emergence of a reassortant virus that persists in wild bird populations yet remains highly pathogenic for poultry.

scholarly journals Metatranscriptomic reconstruction reveals RNA viruses with the potential to shape carbon cycling in soil

2019 ◽  
Vol 116 (51) ◽  
pp. 25900-25908 ◽  
Author(s):  
Evan P. Starr ◽  
Erin E. Nuccio ◽  
Jennifer Pett-Ridge ◽  
Jillian F. Banfield ◽  
Mary K. Firestone
Keyword(s):  
Carbon Cycling ◽  
Temporal Dynamics ◽  
Rna Viruses ◽  
Marker Genes ◽  
Experimental Conditions ◽  
Time Resolved ◽  
Host Cell Death ◽  
Root Litter ◽  
Viral Communities ◽  
Microbial Systems

Viruses impact nearly all organisms on Earth, with ripples of influence in agriculture, health, and biogeochemical processes. However, very little is known about RNA viruses in an environmental context, and even less is known about their diversity and ecology in soil, 1 of the most complex microbial systems. Here, we assembled 48 individual metatranscriptomes from 4 habitats within a planted soil sampled over a 22-d time series: Rhizosphere alone, detritosphere alone, rhizosphere with added root detritus, and unamended soil (4 time points and 3 biological replicates). We resolved the RNA viral community, uncovering a high diversity of viral sequences. We also investigated possible host organisms by analyzing metatranscriptome marker genes. Based on viral phylogeny, much of the diversity wasNarnaviridaethat may parasitize fungi orLeviviridae, which may infect Proteobacteria. Both host and viral communities appear to be highly dynamic, and rapidly diverged depending on experimental conditions. The viral and host communities were structured based on the presence of root litter. Clear temporal dynamics byLeviviridaeand their hosts indicated that viruses were replicating. With this time-resolved analysis, we show that RNA viruses are diverse, abundant, and active in soil. When viral infection causes host cell death, it may mobilize cell carbon in a process that may represent an overlooked component of soil carbon cycling.

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