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  1. Article: Multifidelity Analysis for Predicting Rare Events in Stochastic Computational Models of Complex Biological Systems.

    Pienaar, Elsje

    Biomedical engineering and computational biology

    2018  Volume 9, Page(s) 1179597218790253

    Abstract: Rare events such as genetic mutations or cell-cell interactions are important contributors to dynamics in complex biological systems, eg, in drug-resistant infections. Computational approaches can help analyze rare events that are difficult to study ... ...

    Abstract Rare events such as genetic mutations or cell-cell interactions are important contributors to dynamics in complex biological systems, eg, in drug-resistant infections. Computational approaches can help analyze rare events that are difficult to study experimentally. However, analyzing the frequency and dynamics of rare events in computational models can also be challenging due to high computational resource demands, especially for high-fidelity stochastic computational models. To facilitate analysis of rare events in complex biological systems, we present a multifidelity analysis approach that uses medium-fidelity analysis (Monte Carlo simulations) and/or low-fidelity analysis (Markov chain models) to analyze high-fidelity stochastic model results. Medium-fidelity analysis can produce large numbers of possible rare event trajectories for a single high-fidelity model simulation. This allows prediction of both rare event dynamics and probability distributions at much lower frequencies than high-fidelity models. Low-fidelity analysis can calculate probability distributions for rare events over time for any frequency by updating the probabilities of the rare event state space after each discrete event of the high-fidelity model. To validate the approach, we apply multifidelity analysis to a high-fidelity model of tuberculosis disease. We validate the method against high-fidelity model results and illustrate the application of multifidelity analysis in predicting rare event trajectories, performing sensitivity analyses and extrapolating predictions to very low frequencies in complex systems. We believe that our approach will complement ongoing efforts to enable accurate prediction of rare event dynamics in high-fidelity computational models.
    Language English
    Publishing date 2018-08-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2592051-0
    ISSN 1179-5972
    ISSN 1179-5972
    DOI 10.1177/1179597218790253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Evaluation of fendiline treatment in VP40 system with nucleation-elongation process: a computational model of Ebola virus matrix protein assembly.

    Liu, Xiao / Husby, Monica / Stahelin, Robert V / Pienaar, Elsje

    Microbiology spectrum

    2024  Volume 12, Issue 4, Page(s) e0309823

    Abstract: Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 laboratories hinder experimental work to advance our understanding of EBOV and the ... ...

    Abstract Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 laboratories hinder experimental work to advance our understanding of EBOV and the evaluation of treatment. In this work, we use a computational model to study the assembly and budding process of EBOV and evaluate the effect of fendiline on these processes in the context of fluctuating host membrane lipid levels. Our results demonstrate for the first time that the assembly of VP40 filaments may follow the nucleation-elongation theory, as this mechanism is critical to maintaining a pool of VP40 dimers for the maturation and production of virus-like particles (VLPs). We further find that this nucleation-elongation process is likely influenced by fluctuating phosphatidylserine (PS), which can complicate the efficacy of lipid-targeted therapies like fendiline, a drug that lowers cellular PS levels. Our results indicate that fendiline-induced PS reduction may actually increase VLP production at earlier time points (24 h) and under low fendiline concentrations (≤2 µM). However, this effect is transient and does not change the conclusion that fendiline generally decreases VLP production. In the context of fluctuating PS levels, we also conclude that fendiline can be more efficient at the late stage of VLP budding relative to earlier phases. Combination therapy with a VLP budding step-targeted drug may therefore further increase the treatment efficiency of fendiline. Finally, we also show that fendiline-induced PS reduction more effectively lowers VLP production when VP40 expression is high. Taken together, our results provide critical quantitative information on how fluctuating lipid levels (PS) affect EBOV assembly and egress and how this mechanism can be disrupted by lipid-targeting molecules like fendiline.
    Importance: Ebola virus (EBOV) infection can cause deadly hemorrhagic fever, which has a mortality rate of ~50%-90% without treatment. The recent outbreaks in Uganda and the Democratic Republic of the Congo illustrate its threat to human health. Though two antibody-based treatments were approved, mortality rates in the last outbreak were still higher than 30%. This can partly be due to the requirement of advanced medical facilities for current treatments. As a result, it is very important to develop and evaluate new therapies for EBOV infection, especially those that can be easily applied in the developing world. The significance of our research is that we evaluate the potential of lipid-targeted treatments in reducing EBOV assembly and egress. We achieved this goal using the VP40 system combined with a computational approach, which both saves time and lowers cost compared to traditional experimental studies and provides innovative new tools to study viral protein dynamics.
    MeSH term(s) Humans ; Hemorrhagic Fever, Ebola/drug therapy ; Ebolavirus/genetics ; Fendiline/metabolism ; Lipids ; Africa, Western
    Chemical Substances Fendiline (S253D559A8) ; Lipids
    Language English
    Publishing date 2024-02-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2807133-5
    ISSN 2165-0497 ; 2165-0497
    ISSN (online) 2165-0497
    ISSN 2165-0497
    DOI 10.1128/spectrum.03098-23
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  3. Article ; Online: Reduced macrophage killing of M. avium drives infection risk in post-menopausal patients.

    Weathered, Catherine / Wei, Ning / Pienaar, Elsje

    Tuberculosis (Edinburgh, Scotland)

    2023  Volume 139, Page(s) 102304

    Abstract: Non-tuberculous mycobacterial (NTM) infections, and Mycobacterium avium Complex (MAC) in particular, affect women at nearly twice the rate of men, and post-menopausal patients are at higher risk than pre-menopausal patients. The reasons for the ... ...

    Abstract Non-tuberculous mycobacterial (NTM) infections, and Mycobacterium avium Complex (MAC) in particular, affect women at nearly twice the rate of men, and post-menopausal patients are at higher risk than pre-menopausal patients. The reasons for the disproportionate number of cases in women and post-menopausal patients remain unclear. One possibility is that menopause-associated immunological changes contribute to higher MAC prevalence post-menopause compared to pre-menopause. Menopause-associated immune disruption includes increased cytokine and chemokine production, and reduced cytotoxicity and phagocytosis in macrophages. Here we use an agent-based model of bacterial and host immune interactions in the airway to translate the combined impact of menopause-associated cellular immune disruptions to tissue scale outcomes. Our simulations indicate that menopause-associated immune disruptions can result in increased macrophage recruitment. However, this increase in macrophage number is unable to overcome functional deficits in macrophage phagocytosis and killing, since the post-menopausal simulations also show increased bacterial loads. Post-menopausal conditions are also associated with a lower number of cleared infections, and more simulations that have predominantly extracellular bacteria. Taken together, our work quantifies the potential impact of menopause-associated disruptions of innate immune functions on early MAC infection progression. Our findings will support the development of new therapies targeted to this high-risk group of patients.
    MeSH term(s) Male ; Humans ; Female ; Postmenopause ; Mycobacterium tuberculosis ; Macrophages/microbiology ; Mycobacterium avium Complex ; Mycobacterium avium-intracellulare Infection
    Language English
    Publishing date 2023-01-06
    Publishing country Scotland
    Document type Letter
    ZDB-ID 2046804-0
    ISSN 1873-281X ; 1472-9792
    ISSN (online) 1873-281X
    ISSN 1472-9792
    DOI 10.1016/j.tube.2023.102304
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  4. Article ; Online: In silico agent-based modeling approach to characterize multiple in vitro tuberculosis infection models.

    Petrucciani, Alexa / Hoerter, Alexis / Kotze, Leigh / Du Plessis, Nelita / Pienaar, Elsje

    PloS one

    2024  Volume 19, Issue 3, Page(s) e0299107

    Abstract: In vitro models of Mycobacterium tuberculosis (Mtb) infection are a valuable tool for examining host-pathogen interactions and screening drugs. With the development of more complex in vitro models, there is a need for tools to help analyze and integrate ... ...

    Abstract In vitro models of Mycobacterium tuberculosis (Mtb) infection are a valuable tool for examining host-pathogen interactions and screening drugs. With the development of more complex in vitro models, there is a need for tools to help analyze and integrate data from these models. To this end, we introduce an agent-based model (ABM) representation of the interactions between immune cells and bacteria in an in vitro setting. This in silico model was used to simulate both traditional and spheroid cell culture models by changing the movement rules and initial spatial layout of the cells in accordance with the respective in vitro models. The traditional and spheroid simulations were calibrated to published experimental data in a paired manner, by using the same parameters in both simulations. Within the calibrated simulations, heterogeneous outputs are seen for bacterial count and T cell infiltration into the macrophage core of the spheroid. The simulations also predict that equivalent numbers of activated macrophages do not necessarily result in similar bacterial reductions; that host immune responses can control bacterial growth in both spheroid structure dependent and independent manners; that STAT1 activation is the limiting step in macrophage activation in spheroids; and that drug screening and macrophage activation studies could have different outcomes depending on the in vitro culture used. Future model iterations will be guided by the limitations of the current model, specifically which parts of the output space were harder to reach. This ABM can be used to represent more in vitro Mtb infection models due to its flexible structure, thereby accelerating in vitro discoveries.
    MeSH term(s) Humans ; Tuberculosis/microbiology ; Mycobacterium tuberculosis ; Latent Tuberculosis ; Computer Simulation ; Systems Analysis ; Host-Pathogen Interactions
    Language English
    Publishing date 2024-03-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0299107
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  5. Article: Evaluation of Fendiline Treatment in VP40 System with Nucleation-Elongation Process: A Computational Model of Ebola Virus Matrix Protein Assembly.

    Liu, Xiao / Husby, Monica / Stahelin, Robert V / Pienaar, Elsje

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 (BSL-4) laboratories hinders experimental work to advance our understanding of EBOV and ... ...

    Abstract Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 (BSL-4) laboratories hinders experimental work to advance our understanding of EBOV and evaluation of treatment. In this work, we use a computational model to study the assembly and budding process of EBOV and evaluate the effect of fendiline on these processes. Our results indicate that the assembly of VP40 filaments may follow the nucleation-elongation theory, as it is critical to maintain a pool of VP40 dimer for the maturation and production of virus-like particles (VLPs). We further find that the nucleation-elongation process can also be influenced by phosphatidylserine (PS), which can complicate the efficacy of fendiline, a drug that lowers cellular PS levels. We observe that fendiline may increase VLP production at earlier time points (24 h) and under low concentrations (≤ 2 μM). But this effect is transient and does not change the conclusion that fendiline generally decreases VLP production. We also conclude that fendiline can be more efficient at the stage of VLP budding relative to earlier phases. Combination therapy with a VLP budding step-targeted drug may further increase the treatment efficiency of fendiline. Finally, we also show that fendiline has higher efficacy when VP40 expression is high. While these are single-cell level results based on the VP40 system, it points out a potential way of fendiline application affecting EBOV assembly, which can be further tested in experimental studies with multiple EBOV proteins or live virus.
    Language English
    Publishing date 2023-08-03
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.03.551833
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Agent-based model indicates chemoattractant signaling caused by Mycobacterium avium biofilms in the lung airway increases bacterial loads by spatially diverting macrophages.

    Weathered, Catherine / Pennington, Kelly / Escalante, Patricio / Pienaar, Elsje

    Tuberculosis (Edinburgh, Scotland)

    2022  Volume 138, Page(s) 102300

    Abstract: Incidence and prevalence of MAC infections are increasing globally, and reinfection is common. Thus, MAC infections present a significant public health challenge. We quantify the impact of MAC biofilms and repeated exposure on infection progression using ...

    Abstract Incidence and prevalence of MAC infections are increasing globally, and reinfection is common. Thus, MAC infections present a significant public health challenge. We quantify the impact of MAC biofilms and repeated exposure on infection progression using a computational model of MAC infection in lung airways. MAC biofilms aid epithelial cell invasion, cause premature macrophage apoptosis, and limit antibiotic efficacy. In this computational work we develop an agent-based model that incorporates the interactions between bacteria, biofilm, and immune cells. In this computational model, we perform virtual knockouts to quantify the effects of the biofilm sources (deposited with bacteria vs. formed in the airway), and their impacts on macrophages (inducing apoptosis and slowing phagocytosis). We also quantify the effects of repeated bacterial exposures to assess their impact on infection progression. Our simulations show that chemoattractants released by biofilm-induced apoptosis bias macrophage chemotaxis towards pockets of infected and apoptosed macrophages. This bias results in fewer macrophages finding extracellular bacteria, allowing the extracellular planktonic bacteria to replicate freely. These spatial macrophage trends are further exacerbated with repeated deposition of bacteria. Our model indicates that interventions to abrogate macrophages' apoptotic responses to bacterial biofilms and/or reduce frequency of patient exposure to bacteria will lower bacterial load, and likely overall risk of infection.
    MeSH term(s) Humans ; Mycobacterium avium ; Bacterial Load ; Mycobacterium tuberculosis ; Macrophages/microbiology ; Biofilms ; Lung ; Mycobacterium avium Complex
    Language English
    Publishing date 2022-12-25
    Publishing country Scotland
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2046804-0
    ISSN 1873-281X ; 1472-9792
    ISSN (online) 1873-281X
    ISSN 1472-9792
    DOI 10.1016/j.tube.2022.102300
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  7. Article ; Online: Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection.

    Hoerter, Alexis / Arnett, Eusondia / Schlesinger, Larry S / Pienaar, Elsje

    Frontiers in immunology

    2022  Volume 13, Page(s) 1014515

    Abstract: The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy ... ...

    Abstract The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between
    MeSH term(s) Humans ; HIV-1 ; Coinfection ; Systems Biology ; Tuberculosis ; Granuloma ; HIV Infections/complications
    Language English
    Publishing date 2022-10-31
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.1014515
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  8. Article ; Online: The Role of Biofilms, Bacterial Phenotypes, and Innate Immune Response in Mycobacterium avium Colonization to Infection.

    Weathered, Catherine / Pennington, Kelly / Escalante, Patricio / Pienaar, Elsje

    Journal of theoretical biology

    2021  Volume 534, Page(s) 110949

    Abstract: Mycobacterium avium complex (MAC), is known for colonizing and infecting humans following inhalation of the bacteria. MAC pulmonary disease is notoriously difficult to treat and prone to recurrence. Both the incidence and prevalence MAC pulmonary disease ...

    Abstract Mycobacterium avium complex (MAC), is known for colonizing and infecting humans following inhalation of the bacteria. MAC pulmonary disease is notoriously difficult to treat and prone to recurrence. Both the incidence and prevalence MAC pulmonary disease have been increasing globally. MAC is well known to form biofilms in the environment. In vitro, these biofilms have been shown to aid MAC in epithelial cell invasion, protect MAC from phagocytosis, and cause premature apoptosis in macrophages. In vivo, the system of interactions between MAC, biofilms and host macrophages is complex, difficult to replicate in vitro and in animal models, has not been fully characterized. Here we present a three-dimensional agent-based model of a lung airway to help understand how these interactions evolve in the first 14 days post-bacterial inhalation. We parameterized the model using published data and performed uncertainty analysis to characterize outcomes and parameters' effects on those outcomes. Model results show diverse outcomes, including wide ranges of macrophage recruitment levels, and bacterial loads and phenotype distribution. Though most bacteria are phagocytosed by macrophages and remain intracellular, there are also many simulations in which extracellular bacteria continue to drive the colonization and infection. Initial parameters dictating host immune levels, bacterial loads introduced to the airway, and biofilm conditions have significant and lasting impacts on the course of these results. Additionally, though macrophage recruitment is key for suppressing bacterial loads, there is evidence of significant excess recruitment that fail to impact bacterial numbers. These results highlight a need and identify a path for further exploration into the inhalation events in MAC infection. Early infection dynamics could have lasting impacts on the development of nodular bronchiectatic or fibrocavitary disease as well as inform possible preventative and treatment intervention targeting biofilm-macrophage interactions.
    MeSH term(s) Animals ; Biofilms ; Immunity, Innate ; Mycobacterium avium ; Mycobacterium avium Complex/genetics ; Phenotype
    Language English
    Publishing date 2021-10-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2972-5
    ISSN 1095-8541 ; 0022-5193
    ISSN (online) 1095-8541
    ISSN 0022-5193
    DOI 10.1016/j.jtbi.2021.110949
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  9. Article ; Online: Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.

    Cody, Jonathan W / Ellis-Connell, Amy L / O'Connor, Shelby L / Pienaar, Elsje

    PLoS computational biology

    2023  Volume 19, Issue 8, Page(s) e1011425

    Abstract: Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non- ... ...

    Abstract Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes.
    MeSH term(s) Animals ; Simian Immunodeficiency Virus ; Interleukin-15 ; Viral Load ; Immunotherapy ; CD8-Positive T-Lymphocytes
    Chemical Substances Interleukin-15
    Language English
    Publishing date 2023-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1011425
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  10. Article ; Online: Microglial roles in Alzheimer's disease: An agent-based model to elucidate microglial spatiotemporal response to beta-amyloid.

    Weathered, Catherine / Bardehle, Sophia / Yoon, Choya / Kumar, Niyanta / Leyns, Cheryl E G / Kennedy, Matthew E / Bloomingdale, Peter / Pienaar, Elsje

    CPT: pharmacometrics & systems pharmacology

    2024  Volume 13, Issue 3, Page(s) 449–463

    Abstract: Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In ... ...

    Abstract Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Because of the high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells that transition into a neuroprotective state and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed an agent-based model to characterize the spatiotemporal interactions between microglia and Aβ. Our model qualitatively reproduces mouse data trends where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p < 0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. In addition, in silico behavioral knockout simulations show that phagocytosis knockouts have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knockouts had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activation. These simulations suggest that phagocytosis, chemotaxis, and replication of activated microglia have complex impacts on plaque volume and coverage, whereas microglial activation remains fairly robust to perturbations of these functions. Thus, our work provides insights into the potential and limitations of targeting microglial activation as a pharmacological strategy for the treatment of AD.
    MeSH term(s) Mice ; Animals ; Alzheimer Disease/drug therapy ; Microglia/metabolism ; Microglia/pathology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Plaque, Amyloid
    Chemical Substances Amyloid beta-Peptides
    Language English
    Publishing date 2024-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.13095
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