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fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences
(Bioinformatics, 2017-05-01) Qian, Yong; Butler, Thomas J; Opsahl-Ong, Krista; Giroux, Nicholas S; Sidore, Carlo; Nagaraja, Ramaiah; Cucca, Francesco; Ferrucci, Luigi; Abecasis, Gonçalo R; Schlessinger, David; Ding, Jun
Abstract
Mitochondrial DNA (mtDNA) copy number is tightly regulated in tissues, and is both a critical determinant of mitochondrial function and a potential biomarker for disease. We and other groups have shown that the mtDNA copy number per cell can be directly estimated from whole-genome sequencing. The computation is based on the rationale that sequencing coverage should be proportional to the underlying DNA copy number for autosomal and mitochondrial DNA, and most computing time is spent calculating the average autosomal DNA coverage across ∼3 billion bases. That makes analyzing tens of thousands of available samples very slow. Here we present fastMitoCalc, which takes advantage of the indexing of sequencing alignment files and uses a randomly selected small subset (0.1%) of the nuclear genome to estimate autosomal DNA coverage accurately. It is more than 100 times faster than current programs. fastMitoCalc also provides an option to estimate copy number using a single autosomal chromosome, which could also achieve high accuracy but is slower. Using fastMitoCalc, it becomes much more feasible now to conduct analyses on large-scale consortium data to test for association of mtDNA copy number with quantitative traits or nuclear variants.
Availability and Implementation
fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html
Supplementary information
Supplementary data are available at Bioinformatics online.
Patient-derived micro-organospheres enable clinical precision oncology.
(Cell stem cell, 2022-06) Ding, Shengli; Hsu, Carolyn; Wang, Zhaohui; Natesh, Naveen R; Millen, Rosemary; Negrete, Marcos; Giroux, Nicholas; Rivera, Grecia O; Dohlman, Anders; Bose, Shree; Rotstein, Tomer; Spiller, Kassandra; Yeung, Athena; Sun, Zhiguo; Jiang, Chongming; Xi, Rui; Wilkin, Benjamin; Randon, Peggy M; Williamson, Ian; Nelson, Daniel A; Delubac, Daniel; Oh, Sehwa; Rupprecht, Gabrielle; Isaacs, James; Jia, Jingquan; Chen, Chao; Shen, John Paul; Kopetz, Scott; McCall, Shannon; Smith, Amber; Gjorevski, Nikolche; Walz, Antje-Christine; Antonia, Scott; Marrer-Berger, Estelle; Clevers, Hans; Hsu, David; Shen, Xiling
Patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here, we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of micro-organospheres (MOSs) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of recently diagnosed metastatic colorectal cancer (CRC) patients using an MOS-based precision oncology pipeline reliably assessed tumor drug response within 14 days, a timeline suitable for guiding treatment decisions in the clinic. Furthermore, MOSs capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.
DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.
(Biomaterials, 2022-04) Naqvi, Ibtehaj; Giroux, Nicholas; Olson, Lyra; Morrison, Sarah Ahn; Llanga, Telmo; Akinade, Tolu O; Zhu, Yuefei; Zhong, Yiling; Bose, Shree; Arvai, Stephanie; Abramson, Karen; Chen, Lingye; Que, Loretta; Kraft, Bryan; Shen, Xiling; Lee, Jaewoo; Leong, Kam W; Nair, Smita K; Sullenger, Bruce
Millions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in the Intensive Care Unit (ICU) display hallmarks of such hyper-stimulation with abundant agonists of nucleic acid-sensing TLRs present in their blood and lungs. These nucleic acid-containing Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs) can be depleted using nucleic acid-binding microfibers to limit the patient samples' ability to hyperactivate such innate immune receptors. Single-cell RNA-sequencing revealed that CD16+ monocytes from deceased but not recovered ICU patients exhibit a TLR-tolerant phenotype and a deficient anti-viral response after ex vivo TLR stimulation. Plasma proteomics confirmed such myeloid hyperactivation and revealed DAMP/PAMP carrier consumption in deceased patients. Treatment of these COVID-19 patient samples with MnO nanoparticles effectively neutralizes TLR activation by the abundant nucleic acid-containing DAMPs/PAMPs present in their lungs and blood. Finally, MnO nanoscavenger treatment limits the ability of DAMPs/PAMPs to induce TLR tolerance in monocytes. Thus, treatment with microfiber- or nanoparticle-based DAMP/PAMP scavengers may prove useful for limiting SARS-CoV-2 induced hyperinflammation, preventing monocytic TLR tolerance, and improving outcomes in severely ill COVID-19 patients.
Epigenetic and transcriptional responses in circulating leukocytes are associated with future decompensation during SARS-CoV-2 infection.
(iScience, 2024-01) McClain, Micah T; Zhbannikov, Ilya; Satterwhite, Lisa L; Henao, Ricardo; Giroux, Nicholas S; Ding, Shengli; Burke, Thomas W; Tsalik, Ephraim L; Nix, Christina; Balcazar, Jorge Prado; Petzold, Elizabeth A; Shen, Xiling; Woods, Christopher W
To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission. We performed combined single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) at admission and compared subjects who improved from their moderate disease with those who later clinically decompensated and required invasive mechanical ventilation or died. Chromatin accessibility and transcriptomic immune profiles were markedly altered between the two groups, with strong signals in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cells. Multiomic signature scores at admission were tightly associated with future clinical deterioration (auROC 1.0). Epigenetic and transcriptional changes in PBMCs reveal early, broad immune dysregulation before typical clinical signs of decompensation are apparent and thus may act as biomarkers to predict future severity in COVID-19.
Writing Hate / Performing Hate: Embodied Affect in Contemporary German Theater
(2024) Wilms, Leonie F.