Simeone Marino

Simeone Marino
University of Michigan | U-M · Department of Microbiology and Immunology

About

85
Publications
15,622
Reads
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4,484
Citations
Citations since 2016
22 Research Items
3061 Citations
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500

Publications

Publications (85)
Article
Full-text available
Petabytes of health data are collected annually across the globe in electronic health records (EHR), including significant information stored as unstructured free text. However, the lack of effective mechanisms to securely share clinical text has inhibited its full utilization. We propose a new method, DataSifterText, to generate partially syntheti...
Article
Full-text available
There is a significant public demand for rapid data-driven scientific investigations using aggregated sensitive information. However, many technical challenges and regulatory policies hinder efficient data sharing. In this study, we describe a partially synthetic data generation technique for creating anonymized data archives whose joint distributi...
Article
Full-text available
Health advances are contingent on continuous development of new methods and approaches to foster data-driven discovery in the biomedical and clinical sciences. Open-science and team-based scientific discovery offer hope for tackling some of the difficult challenges associated with managing, modeling, and interpreting of large, complex, and multisou...
Preprint
Full-text available
Health advances are contingent on continuous development of new methods and approaches to foster data driven discovery in the biomedical and clinical health sciences. Open-science offers hope for tackling some of the challenges associated with Big Data and team-based scientific discovery. Domain-independent reproducibility, area-specific replicabil...
Article
Full-text available
The UK Biobank is a rich national health resource that provides enormous opportunities for international researchers to examine, model, and analyze census-like multisource healthcare data. The archive presents several challenges related to aggregation and harmonization of complex data elements, feature heterogeneity and salience, and health analyti...
Article
Full-text available
Within the first 2–3 months of a Mycobacterium tuberculosis (Mtb) infection, 2–4 mm spherical structures called granulomas develop in the lungs of the infected hosts. These are the hallmark of tuberculosis (TB) infection in humans and non-human primates. A cascade of immunological events occurs in the first 3 months of granuloma formation that like...
Article
Full-text available
There are no practical and effective mechanisms to share high-dimensional data including sensitive information in various fields like health financial intelligence or socioeconomics without compromising either the utility of the data or exposing private personal or secure organizational information. Excessive scrambling or encoding of the informati...
Article
Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long‐term control of infection while also preventing an over‐zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro‐...
Article
Full-text available
The theoretical foundations of Big Data Science are not fully developed, yet. This study proposes a new scalable framework for Big Data representation, high-throughput analytics (variable selection and noise reduction), and model-free inference. Specifically, we explore the core principles of distribution-free and model-agnostic methods for scienti...
Data
Pseudocode of the CBDA protocol. Pseudocode of the CBDA-SL algorithm as implemented purely in R as well as via the LONI graphical pipeline workflow environment. (DOCX)
Data
Mathematical formulation of CBDA. (DOCX)
Data
ADNI results binary outcome. (DOCX)
Data
SuperLearner and the ensemble algorithms used. Details about data imputation, normalization, rebalancing, as well as model-based and model-free analytics, including Linear Models, Elastic Net, Random Forest, SVM, BartMachine, SuperLearner, and Knockoff controlled variable selection. (DOCX)
Data
CBDA complete set of results. Additional Results. (DOCX)
Article
A granuloma is a physical pathological structure that manifests when the host mounts an immune response to fend off pathogens/infections, immunological aberrations, irritants, inflammations and other foreign particles. It is an amalgamation of immune cells (lymphocytes, phagocytes (mostly macrophages and their derivatives) plasma cells, neutrophils...
Article
Tuberculosis (TB) is an ancient and deadly disease characterized by complex host-pathogen dynamics playing out over multiple time and length scales and physiological compartments. Computational modeling can be used to integrate various types of experimental data and suggest new hypotheses, mechanisms, and therapeutic approaches to TB. Here, we offe...
Article
Full-text available
Results: The model was calibrated using experimental data from the lungs and blood of NHPs. The addition of DCs allowed us to investigate in greater detail mechanisms of recruitment, trafficking and antigen presentation and their role in tuberculosis infection. Conclusion: The main conclusion of this study is that early events after Mtb infectio...
Article
Full-text available
Identifying biomarkers for tuberculosis (TB) is an ongoing challenge in developing immunological correlates of infection outcome and protection. Biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. To effectively predict biomarkers for infection progression in any disease, including TB, large amounts o...
Article
Full-text available
Neisseria gonorrhoeae (GC) remains a serious burden in many high-sexual-activity, undertreated populations. Using empirical data from a 2009 study of GC burden among pastoralists in Kaokoveld, Namibia, we expand the standard gonorrhoea transmission model by using locally derived sexual contact data to explore transmission dynamics in a population w...
Article
Full-text available
Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent...
Article
Full-text available
Although almost a third of the world's population is infected with the bacterial pathogen Mycobacterium tuberculosis, our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine IL-10 at the level of the granuloma has proven difficult because of lesional...
Article
Full-text available
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, induces formation of granulomas, structures in which immune cells and bacteria co-localize. Macrophages are one of the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for Mtb infection and proliferation througho...
Article
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The use of multi-scale mathematical and computational models to study complex biological processes is becoming increasingly productive. Multi-scale models span a range of spatial and/or temporal scales and can encompass multi-compartment (e.g., multi-organ) models. Modeling advances are enabling virtual experiments to explore and answer questions t...
Article
Nontypeable Haemophilus influenzae (NTHi) is a bacterium that resides within the human pharynx. Because NTHi is human-restricted, its long-term survival is dependent upon its ability to successfully colonize new hosts. Adherence to host epithelium, mediated by bacterial adhesins, is one of the first steps in NTHi colonization. NTHi express several...
Article
Significance The colonization of the intestinal track by the trillions of bacteria that live in the gut (i.e., the gut microbiome) is a dynamic process. Through the use of next-generation sequencing and mathematical models, we were able to quantify the interpopulation interactions that occurred after a germfree mouse was inoculated with a murine mi...
Article
Full-text available
The pathologic hallmark of tuberculosis is the granuloma. A granuloma is a multifaceted cellular structure that serves to focus the host immune response, contain infection and pathology, and provide a niche for the bacillus to persist within the host. Granulomas form in response to Mycobacterium tuberculosis infection, and if a granuloma is capable...
Article
Full-text available
Macrophages in granulomas are both antimycobacterial effector and host cell for Mycobacterium tuberculosis, yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaqu...
Article
The effect of Mycobacterium tuberculosis inocula size on T cell priming in the lymph node and effector T cells in the lung remains controversial. In this study, we used a naive mouse model, without the transfer of transgenic T cells, in conjunction with mathematical model to test whether infection with higher aerosolized inocula would lead to incre...
Data
Gating scheme for immunophenotyping lung leukocyte populations. (A) Gating steps to analyze lung cell populations include gating on singlets as having a similar height and area (FSC-A/FSC-H), on live and myeloid cells (FSC-A/SSC-A), and on CD45+ hematopoietic cells (SSC-A/CD45). Each cell population is defined based on CD11b/CD11c staining profile:...
Data
Full-text available
Morphology of neutrophil cell death in pulmonary TB. (A) Ziehl-Neelsen staining (left panel) identified amorphous extracellular material with associated AFB (magnification, ×400). Scanning EM (middle panel) demonstrated the presence of cell-associated extracellular fibers consistent with NETs (magnification, ×5,000). High resolution of SEM image (r...
Data
Full-text available
Change in the proportion of intracellular bacillary load in monocytic cells. AFB per cell was counted in cytospin samples of whole lung leukocytes harvested 1, 2, 3 and 8 weeks after aerosol challenge with Mtb Erdman. Mtb burden per monocytic cell (comprising AM, RM, mDC) was counted and stratified into the indicated bins of 1–5, 6–10, 11–15, 16–20...
Data
Full-text available
Cells heavily burdened with Mtb appear nonviable. (A) Lung leukocytes were isolated from WT mice 2 weeks after aerosol challenge with Mtb Erdman. Cytospin preparations were made and Ziehl-Neelsen stain was used to visualize and count intracellular AFB by light microscopy at 400× magnification. Photomicrographs show examples of heavily infected cell...
Data
Cells with low intracellular Mtb appear like uninfected cells. BAL cells were isolated from WT mice 2 weeks p.i. and cytospin slides were prepared for (A) Ziehl-Neelsen or (B) DAPI plus carbolfuchsin staining. AFB were identified with light microscopy or fluorescence microscopy (magnification, 400×). Images of AFB+ cells with low intracellular Mtb...
Data
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Chromatin extrusion from DAPI stained AFB+ cells. BAL cells from mice with aerogenic TB infected were harvested 3 weeks, p.i. Samples were prepared on cytospin slides and stained with DAPI. The image shows nuclear condensation and chromatin extruding through a damaged nuclear membrane into the cytoplasm (white arrow; magnification, ×400). (PDF)
Data
Full-text available
Higher burst size parameter values result in higher total bacterial counts in computational simulation of Mtb replication in the lung. A multiscale computational model described in Materials and Methods was used to generate values for total bacterial counts over time in a 2 mm×2 mm virtual section of lung starting with a single macrophage infected...
Data
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Percentage and total cell count of different cells from lung leukocytes. (PDF)
Data
Distribution of AFB+ cells for each cell type found in lung leukocytes. (PDF)
Data
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Percentage and total cell count of different GFP+ cells from lung leukocytes. (PDF)
Article
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We previously reported that Mycobacterium tuberculosis triggers macrophage necrosis in vitro at a threshold intracellular load of ∼25 bacilli. This suggests a model for tuberculosis where bacilli invading lung macrophages at low multiplicity of infection proliferate to burst size and spread to naïve phagocytes for repeated cycles of replication and...
Article
Full-text available
Cancer is a major cause of death worldwide, resulting from the uncontrolled growth of abnormal cells in the body. Cells are the body’s building blocks, and cancer starts from normal cells. Normal cells divide to grow in order to maintain cell population equilibrium, balancing cell death. Cancer occurs when unbounded growth of cells in the body happ...
Article
IntroductionTuberculosis, TNF, and Anti-TNF DrugsTheoretical Models To Study TB InfectionPresent and Future WorkReferences
Article
Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis (Mtb). No available vaccine is reliable and, although treatment exists, approximately 2 million people still die each year. The hallmark of TB infection is the granuloma, a self-organizing structure of immune cells forming in the lung and lymph nodes in response t...
Article
Lactococcus lactis metabolizes glucose homofermentatively to lactate. However, after disruption of the gene coding for lactate dehydrogenase, LDH, a key enzyme in NAD+ regeneration, the glycolytic flux shifts from homolactic to mixed-acid fermentation with the redirection of pyruvate towards production of formate, acetate, ethanol and CO2. A mathem...
Article
Full-text available
Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-α. TNF-α has been experimentally characterized to have the following activities in...
Conference Paper
Tuberculosis (TB) is a common and deadly infectious disease caused by a highly successful bacterium, Mycobacterium tuberculosis (Mtb). Multiple host immune factors control the formation of a self-organizing aggregate of immune cells termed a granuloma in the lungs after inhalation of Mtb. One such factor, tumor necrosis factor-α (TNF), is a protein...
Article
Tuberculosis (TB) is one of the earliest recorded human diseases and still one of the deadliest worldwide. Its causative agent is the bacteria Mycobacterium tuberculosis (Mtb). Cytokine-mediated macrophage activation is a necessary step in control of bacterial growth, and early immunologic events in lymph node and lung are crucial to the outcome of...
Article
Full-text available
Generating adaptive immunity postinfection or immunization requires physical interaction within a lymph node T zone between Ag-bearing dendritic cells (DCs) and rare cognate T cells. Many fundamental questions remain regarding the dynamics of DC-CD4+ T cell interactions leading to priming. For example, it is not known how the production of primed C...
Conference Paper
Full-text available
Agent-based modeling has been recognized as a method to bridge the translational gap in integrative systems biology. However, the computational complexity of agent-based models at biologically relevant scales makes simulation impractical on traditional CPU-based serial computing. In this paper we present a series of algorithms for simulating large...
Article
Full-text available
Accuracy of results from mathematical and computer models of biological systems is often complicated by the presence of uncertainties in experimental data that are used to estimate parameter values. Current mathematical modeling approaches typically use either single-parameter or local sensitivity analyses. However, these methods do not accurately...
Article
Full-text available
Tumor necrosis factor (TNF) is a prototypic proinflammatory cytokine that contributes significantly to the development of immunopathology in various disease states. A complication of TNF blockade therapy, which is used increasingly for the treatment of chronic inflammatory diseases, is the reactivation of latent tuberculosis. This study used a low-...
Article
Tuberculosis is the leading cause of death due to infectious diseases in the world today, and it is increasing due to co-infection with HIV-1, the causative agent of AIDS. Here, we examine the impact that HIV-1 infection has on persons with latent tuberculosis. Based on previous work, we develop a mathematical model of an adaptive immune response i...
Article
Full-text available
The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tubercu...
Data
Full-text available
Total Bacterial Loads during VCT3 for TNF Receptor Fusion (A) and Anti-TNF Antibody (B) Treatments (130 KB PDF)
Data
Summary of Effects of TNF and TNFR1 Blocking during Experimental M. tuberuclosis Infection in Mice (27 KB DOC)
Data
Anti-TNF Antibody and TNF Receptor Fusion, Pharmacokinetics, Pharmacodynamics, and Treatment Protocols (21 KB DOC)
Data
Sensitivity Analysis for Anti-TNF Antibody Treatment Simulations (21 KB DOC)