scholarly journals Comparative analyses of parasites with a comprehensive database of genome-scale metabolic models

2019 ◽  
Author(s):  
Maureen A. Carey ◽  
Gregory L. Medlock ◽  
Michał Stolarczyk ◽  
William A. Petri ◽  
Jennifer L. Guler ◽  
...  
Keyword(s):  
Metabolic Network ◽  
Protozoan Parasite ◽  
Global Impacts ◽  
Metabolic Models ◽  
Species Specific ◽  
Experimental Findings ◽  
Eukaryotic Organisms ◽  
Genome Scale

AbstractProtozoan parasites cause diverse diseases with large global impacts. Research on the pathogenesis and biology of these organisms is limited by economic and experimental constraints. Accordingly, studies of one parasite are frequently extrapolated to infer knowledge about another parasite, across and within genera. Model in vitro or in vivo systems are frequently used to enhance experimental manipulability, but these systems generally use species related to, yet distinct from, the clinically relevant causal pathogen. Characterization of functional differences among parasite species is confined to post hoc or single target studies, limiting the utility of this extrapolation approach. To address this challenge and to accelerate parasitology research broadly, we present a functional comparative analysis of 192 genomes, representing every high-quality, publicly-available protozoan parasite genome including Plasmodium, Toxoplasma, Cryptosporidium, Entamoeba, Trypanosoma, Leishmania, Giardia, and other species. We generated an automated metabolic network reconstruction pipeline optimized for eukaryotic organisms. These metabolic network reconstructions serve as biochemical knowledgebases for each parasite, enabling qualitative and quantitative comparisons of metabolic behavior across parasites. We identified putative differences in gene essentiality and pathway utilization to facilitate the comparison of experimental findings. This knowledgebase represents the largest collection of genome-scale metabolic models for both pathogens and eukaryotes; with this resource, we can predict species-specific functions, contextualize experimental results, and optimize selection of experimental systems for fastidious species.

Genome scale metabolic models and analysis for evaluating probiotic potentials

2020 ◽  
Vol 48 (4) ◽  
pp. 1309-1321
Author(s):  
Yoon-Mi Choi ◽  
Yi Qing Lee ◽  
Hyun-Seob Song ◽  
Dong-Yup Lee
Keyword(s):  
In Silico ◽  
Metabolic Characteristics ◽  
Knowledge Based ◽  
Main Challenge ◽  
Metabolic States ◽  
Probiotic Strains ◽  
Metabolic Models ◽  
Genome Scale

Probiotics are live beneficial microorganisms that can be consumed in the form of dairy and food products as well as dietary supplements to promote a healthy balance of gut bacteria in humans. Practically, the main challenge is to identify and select promising strains and formulate multi-strain probiotic blends with consistent efficacy which is highly dependent on individual dietary regimes, gut environments, and health conditions. Limitations of current in vivo and in vitro methods for testing probiotic strains can be overcome by in silico model guided systems biology approaches where genome scale metabolic models (GEMs) can be used to describe their cellular behaviors and metabolic states of probiotic strains under various gut environments. Here, we summarize currently available GEMs of microbial strains with probiotic potentials and propose a knowledge-based framework to evaluate metabolic capabilities on the basis of six probiotic criteria. They include metabolic characteristics, stability, safety, colonization, postbiotics, and interaction with the gut microbiome which can be assessed by in silico approaches. As such, the most suitable strains can be identified to design personalized multi-strain probiotics in the future.

scholarly journals Pan-American Lancehead Pit-Vipers: Coagulotoxic Venom Effects and Antivenom Neutralisation of Bothrops asper and B. atrox Geographical Variants

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 78
Author(s):  
Lachlan A. Bourke ◽  
Christina N. Zdenek ◽  
Edgar Neri-Castro ◽  
Melisa Bénard-Valle ◽  
Alejandro Alagón ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
In Vivo Studies ◽  
Factor X ◽  
Clotting Factors ◽  
Bothrops Asper ◽  
Species Specific

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species’ geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.

scholarly journals Seminal Plasma: Relevant for Fertility?

2021 ◽  
Vol 22 (9) ◽  
pp. 4368
Author(s):  
Heriberto Rodriguez-Martinez ◽  
Emilio A. Martinez ◽  
Juan J. Calvete ◽  
Fernando J. Peña Vega ◽  
Jordi Roca
Keyword(s):  
Seminal Plasma ◽  
Current Knowledge ◽  
Inorganic Ions ◽  
Vitro Fertilization ◽  
Dna And Rna ◽  
Model Animal ◽  
Sexual Glands ◽  
Species Specific

Seminal plasma (SP), the non-cellular component of semen, is a heterogeneous composite fluid built by secretions of the testis, the epididymis and the accessory sexual glands. Its composition, despite species-specific anatomical peculiarities, consistently contains inorganic ions, specific hormones, proteins and peptides, including cytokines and enzymes, cholesterol, DNA and RNA—the latter often protected within epididymis- or prostate-derived extracellular vesicles. It is beyond question that the SP participates in diverse aspects of sperm function pre-fertilization events. The SP also interacts with the various compartments of the tubular genital tract, triggering changes in gene function that prepares for an eventual successful pregnancy; thus, it ultimately modulates fertility. Despite these concepts, it is imperative to remember that SP-free spermatozoa (epididymal or washed ejaculated) are still fertile, so this review shall focus on the differences between the in vivo roles of the SP following semen deposition in the female and those regarding additions of SP on spermatozoa handled for artificial reproduction, including cryopreservation, from artificial insemination to in vitro fertilization. This review attempts, including our own results on model animal species, to critically summarize the current knowledge of the reproductive roles played by SP components, particularly in our own species, which is increasingly affected by infertility. The ultimate goal is to reconcile the delicate balance between the SP molecular concentration and their concerted effects after temporal exposure in vivo. We aim to appraise the functions of the SP components, their relevance as diagnostic biomarkers and their value as eventual additives to refine reproductive strategies, including biotechnologies, in livestock models and humans.

scholarly journals Solvent Exposure and Ionic Condensation Drive Fuzzy Dimerization of Disordered Heterochromatin Protein Sequence

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 915
Author(s):  
Jazelli Mueterthies ◽  
Davit A. Potoyan
Keyword(s):  
Phase Separation ◽  
Low Complexity ◽  
Nuclear Bodies ◽  
Disordered Proteins ◽  
Solvent Exposure ◽  
Ion Release ◽  
Dimer Formation ◽  
Eukaryotic Organisms

Proteins with low complexity, disordered sequences are receiving increasing attention due to their central roles in the biogenesis and regulation of membraneless organelles. In eukaryotic organisms, a substantial fraction of disordered proteins reside in the nucleus, thereby facilitating the formation of nuclear bodies, nucleolus, and chromatin compartmentalization. The heterochromatin family of proteins (HP1) is an important player in driving the formation of gene silenced mesoscopic heterochromatin B compartments and pericentric regions. Recent experiments have shown that the HP1a sequence of Drosophila melanogaster can undergo liquid-liquid phase separation under both in vitro and in vivo conditions, induced by changes of the monovalent salt concentration. While the phase separation of HP1a is thought to be the mechanism underlying chromatin compartmentalization, the molecular level mechanistic picture of salt-driven phase separation of HP1a has remained poorly understood. The disordered hinge region of HP1a is seen as the driver of salt-induced condensation because of its charge enriched sequence and post-translational modifications. Here, we set out to decipher the mechanisms of salt-induced condensation of HP1a through a systematic study of salt-dependent conformations of single chains and fuzzy dimers of disordered HP1a hinge sequences. Using multiple independent all-atom simulations with and without enhanced sampling, we carry out detailed characterization of conformational ensembles of disordered HP1a chains under different ionic conditions using various polymeric and structural measures. We show that the mobile ion release, enhancement of local transient secondary structural elements, and side-chain exposure to solvent are robust trends that accompany fuzzy dimer formation. Furthermore, we find that salt-induced changes in the ensemble of conformations of HP1a disordered hinge sequence fine-tune the inter-chain vs. self-chain interactions in ways that favor fuzzy dimer formation under low salt conditions in the agreement with condensation trends seen in experiments.

scholarly journals STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii202-ii202
Author(s):  
Ana Nikolic ◽  
Anna Bobyn ◽  
Katrina Ellestad ◽  
Xueqing Lun ◽  
Michael Johnston ◽  
...  
Keyword(s):  
Chromatin Accessibility ◽  
Histone Variant ◽  
Clinical Settings ◽  
Glioblastoma Cells ◽  
Self Renewal ◽  
Viral Mimicry ◽  
Experimental Findings ◽  
Preclinical Work

Abstract Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

Host oyster tissue extracts modulate in vitro protease expression and cellular differentiation in the protozoan parasite, Perkinsus marinus

Parasitology ◽  
2003 ◽  
Vol 126 (4) ◽  
pp. 293-302 ◽  
Author(s):  
E. A. MACINTYRE ◽  
C. G. EARNHART ◽  
S. L. KAATTARI
Keyword(s):  
Serine Proteases ◽  
Protozoan Parasite ◽  
Eastern Oyster ◽  
Defined Medium ◽  
Tissue Homogenate ◽  
Oyster Tissue ◽  
Perkinsus Marinus ◽  
Tissue Extracts

Perkinsus marinus is responsible for a chronic disease (Dermo) of the Eastern oyster, Crassostrea virginica. In order to simulate the in vivo environment more closely, a chemically defined medium (JL-ODRP-3) was supplemented with tissue homogenate extracts or plasma from oysters possessing varying degrees of susceptibility to P. marinus infection. In media supplemented with extracts from highly susceptible oysters (C. virginica), P. marinus cells secreted elevated amounts of a set of low molecular weight serine proteases (LMP: 30–45 kDa) as assessed by enhanced digestion within gelatin-substrate SDS–PAGE gels. Oyster species of low susceptibility (C. gigas and C. ariakensis) did not exhibit this ability to upregulate P. marinus LMP expression. Oyster extract supplementation also led to pronounced changes in P. marinus cellular morphology, such that the cells were comparable to those observed within naturally infected oysters.

scholarly journals Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

ADMET & DMPK ◽  
2022 ◽  
Author(s):  
Marilyn N. Martinez ◽  
Mark G. Papich ◽  
Raafat Fahmy
Keyword(s):  
Species Differences ◽  
Oral Dosage ◽  
Oral Drug ◽  
Fluid Composition ◽  
In Vitro Test ◽  
Drug Solubility ◽  
Drug Solubilization ◽  
Species Specific

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a question-and-answer section that addresses some of the formulation issues that can arise in the development of veterinary medicinals.

scholarly journals Bioinformatic and experimental findings to indicate anti-cancer targets and mechanisms of calycosin against nasopharyngeal carcinoma

2020 ◽  
Author(s):  
Fangxian Liu ◽  
Qijin Pan ◽  
Liangliang Wang ◽  
Shijiang Yi ◽  
Peng Liu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Cell Number ◽  
Network Pharmacology ◽  
Tunel Staining ◽  
Pharmacological Targets ◽  
Experimental Findings

Abstract Background: Calycosin is a naturally-occurring phytoestrogen that reportedly exerts anti- nasopharyngeal carcinoma (NPC) effects. Nevertheless, the molecular mechanisms for anti-NPC using calycosin remain unrevealed. Methods: Thus, a network pharmacology was used to uncover anti-NPC pharmacological targets and mechanisms of calycosin. Additionally, validated experiments were conducted to validate the bioinformatic findings of calycosin for treating NPC. Results: As results, bioinformatic assays showed that the predictive pharmacological targets of calycosin against NPC were TP53, MAPK14, CASP8, MAPK3, CASP3, RIPK1, JUN, ESR1, respectively. And the top 20 biological processes and pharmacological mechanisms of calycosin against NPC were identified accordingly. In clinical data, NPC samples showed positive expression of MAPK14, reduced TP53, CASP8 expressions. In studies in vitro and in vivo, calycosin-dosed NPC cells resulted in reduced cell proliferation, promoted cell apoptosis. In TUNEL staining, calycosin exhibited elevated apoptotic cell number. And immunostaining assays resulted in increased TP53, CASP8 positive cells, and reduced MAPK14 expressions in calycosin-dosed NPC cells and tumor-bearing nude mice. Conclusion: Altogether, these bioinformatic findings reveal optimal pharmacological targets and mechanisms of calycosin against NPC, following with representative identification of human and preclinical experiments. Notably, some of original biotargets may be potentially used to treat NPC.

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