Digital Commons Network^™

Single-Cell Multi-Omics Reveals Dyssynchrony Of The Innate And Adaptive Immune System In Progressive Covid-19., Avraham Unterman, Tomokazu S Sumida, Nima Nouri, Xiting Yan, Amy Y Zhao, Victor Gasque, Jonas C Schupp, Hiromitsu Asashima, Yunqing Liu, Carlos Cosme, Wenxuan Deng, Ming Chen, Micha Sam Brickman Raredon, Kenneth B Hoehn, Guilin Wang, Zuoheng Wang, Giuseppe Deiuliis, Neal G Ravindra, Ningshan Li, Christopher Castaldi, Patrick Wong, John Fournier, Santos Bermejo, Lokesh Sharma, Arnau Casanovas-Massana, Chantal B F Vogels, Anne L Wyllie, Nathan D Grubaugh, Anthony Melillo, Hailong Meng, Yan Stein, Maksym Minasyan, Subhasis Mohanty, William E Ruff, Inessa Cohen, Khadir Raddassi, Laura E Niklason, Albert I Ko, Ruth R Montgomery, Shelli F Farhadian, Akiko Iwasaki, Albert C Shaw, David Van Dijk, Hongyu Zhao, Steven H Kleinstein, David A Hafler, Naftali Kaminski, Charles S Dela Cruz

Faculty Research 2022

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty Research 2022

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

The Human Disease Ontology 2022 Update., Lynn M Schriml, James B Munro, Mike Schor, Dustin Olley, Carrie Mccracken, Victor Felix, J Allen Baron, Rebecca Jackson, Susan M. Bello, Cynthia Bearer, Richard Lichenstein, Katharine Bisordi, Nicole Campion Dialo, Michelle Giglio, Carol Greene

Faculty Research 2022

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO's 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and …

Identification Of Quantitative Trait Loci For Survival In The Mutant Dynactin P150glued Mouse Model Of Motor Neuron Disease., Guillermo M Alexander, Terry D Heiman-Patterson, Frank Bearoff, Roger B Sher, Laura Hennessy, Shannon Terek, Nicole Caccavo, Gregory A Cox, Vivek M. Philip, Elizabeth A Blankenhorn

Faculty Research 2022

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5-10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. …

Editorial: Stromal And Immune Microenvironment In Breast Cancer Metastasis., Xin Lu, Xia Liu, Toni Celià-Terrassa, Guangwen Ren

Faculty Research 2022

No abstract provided.

Engineering A "Detect And Destroy" Skin Probiotic To Combat Methicillin-Resistant Staphylococcus Aureus., Changhui Guan, Peter J Larson, Elizabeth Fleming, Alexander P Tikhonov, Sara Mootien, Trudy H Grossman, Caroline Golino, Julia Oh

Faculty Research 2022

The prevalence and virulence of pathogens such as methicillin-resistant Staphylococcus (S.) aureus (MRSA), which can cause recurrent skin infections, are of significant clinical concern. Prolonged antibiotic exposure to treat or decolonize S. aureus contributes to development of antibiotic resistance, as well as depletion of the microbiome, and its numerous beneficial functions. We hypothesized an engineered skin probiotic with the ability to selectively deliver antimicrobials only in the presence of the target organism could provide local bioremediation of pathogen colonization. We constructed a biosensing S. epidermidis capable of detecting the presence of S. aureus quorum sensing autoinducer peptide and producing lysostaphin …

Genomic Heterogeneity Underlies Multidrug Resistance In Pseudomonas Aeruginosa: A Population-Level Analysis Beyond Susceptibility Testing., Laura J Rojas, Mohamad Yasmin, Jacquelynn Benjamino, Steven M Marshall, Kailynn J Deronde, Nikhil P Krishnan, Federico Perez, Andrew A Colin, Monica Cardenas, Octavio Martinez, Armando Pérez-Cardona, Daniel D Rhoads, Michael R Jacobs, John J Lipuma, Michael W Konstan, Alejandro J Vila, Andrea Smania, Andrew R Mack, Jacob G Scott, Mark D Adams, Lilian M Abbo, Robert A Bonomo

Faculty Research 2022

BACKGROUND: Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with Cystic Fibrosis (CF). Herein, we describe a longitudinal analysis of a series of multidrug resistant (MDR) P. aeruginosa isolates recovered in a 17-month period, from a young female CF patient who underwent double lung transplantation. Our goal was to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence evolution over time.

METHODS: Twenty-two sequential P. aeruginosa isolates were obtained within a 17-month period, before and after a double-lung transplant. At the end of the …

Genome-Wide Variant Calling In Reanalysis Of Exome Sequencing Data Uncovered A Pathogenic Tubb3 Variant., Elke De Boer, Burcu Yaldiz, Anne-Sophie Denommé-Pichon, Leslie Matalonga, Steve Laurie, Solve-Rd Snv-Indel Working Group, Daniel Danis, Peter N Robinson, Solve-Rd-Ditf Ithaca

Faculty Research 2022

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite …

Curation And Expansion Of Human Phenotype Ontology For Defined Groups Of Inborn Errors Of Immunity., Matthias Haimel, Julia Pazmandi, Raúl Jiménez Heredia, Jasmin Dmytrus, Sevgi Köstel Bal, Samaneh Zoghi, Paul Van Daele, Tracy A Briggs, Carine Wouters, Brigitte Bader-Meunier, Florence A Aeschlimann, Roberta Caorsi, Despina Eleftheriou, Esther Hoppenreijs, Elisabeth Salzer, Shahrzad Bakhtiar, Beata Derfalvi, Francesco Saettini, Maaike A A Kusters, Reem Elfeky, Johannes Trück, Jacques G Rivière, Mirjam Van Der Burg, Marco Gattorno, Markus G Seidel, Siobhan Burns, Klaus Warnatz, Fabian Hauck, Paul Brogan, Kimberly C Gilmour, Catharina Schuetz, Anna Simon, Christoph Bock, Sophie Hambleton, Esther De Vries, Peter N Robinson, Marielle Van Gijn, Kaan Boztug

Faculty Research 2022

BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms.

OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of …

The Th1/Tfh-Like Biased Responses Elicited By The Rasp-1 Innate Adjuvant Are Dependent On Trif And Type I Ifn Receptor Pathways., Parakkal Jovvian George, Radu Marches, Djamel Nehar-Belaid, Jacques Banchereau, Sara Lustigman

Faculty Research 2022

No abstract provided.

Epidermal Growth Factor Receptor Inhibition Is Protective In Hyperoxia-Induced Lung Injury., Zachary M Harris, Ying Sun, John Joerns, Brian Clark, Buqu Hu, Asawari Korde, Lokesh Sharma, Hyeon Jun Shin, Edward P Manning, Lindsey Placek, Derya Unutmaz, Gail Stanley, Hyung Chun, Maor Sauler, Govindarajan Rajagopalan, Xuchen Zhang, Min-Jong Kang, Jonathan L Koff

Faculty Research 2022

AIMS: Studies have linked severe hyperoxia, or prolonged exposure to very high oxygen levels, with worse clinical outcomes. This study investigated the role of epidermal growth factor receptor (EGFR) in hyperoxia-induced lung injury at very high oxygen levels (>95%).

RESULTS: Effects of severe hyperoxia (100% oxygen) were studied in mice with genetically inhibited EGFR and wild-type littermates. Despite the established role of EGFR in lung repair, EGFR inhibition led to improved survival and reduced acute lung injury, which prompted an investigation into this protective mechanism. Endothelial EGFR genetic knockout did not confer protection. EGFR inhibition led to decreased levels …

Causes Of Death And Conditional Survival Estimates Of Long-Term Lung Cancer Survivors., Qun Zhang, Yuan Dai, Hongda Liu, Wenkui Sun, Yuming Huang, Zheng Gong, Shanlin Dai, Hui Kong, Weiping Xie

Faculty Research 2022

INTRODUCTION: Lung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer.

METHODS: We collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients' survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy …

Editorial: Genetic Basis Of Tolerance Induction Defects Underlying The Development Of Autoimmune Pathologies., Jeremy Racine, Laurence Morel, Yi-Guang Chen, David V. Serreze

Faculty Research 2022

No abstract provided.

An Artifact In Intracellular Cytokine Staining For Studying T Cell Responses And Its Alleviation., Zheng Gong, Qing Li, Jiayuan Shi, Guangwen Ren

Faculty Research 2022

Intracellular cytokine staining (ICS) is a widely employed ex vivo method for quantitative determination of the activation status of immune cells, most often applied to T cells. ICS test samples are commonly prepared from animal or human tissues as unpurified cell mixtures, and cell-specific cytokine signals are subsequently discriminated by gating strategies using flow cytometry. Here, we show that when ICS samples contain Ly6G⁺ neutrophils, neutrophils are ex vivo activated by an ICS reagent - phorbol myristate acetate (PMA) - which leads to hydrogen peroxide (H₂O₂) release and death of cytokine-expressing T cells. This artifact …