A physiologically based pharmacokinetic model of diethyl phthalates in humans.

Phthalates are a family of industrial and consumer product chemicals, among which diethyl phthalate (DEP) has been widely used. DEP is metabolized into the active metabolite monoethyl phthalate (MEP) and exposure to DEP may induce male reproductive toxicity, developmental toxicity and hepatotoxicity. To better assess the toxicity of DEP and MEP, it is important to understand and predict their internal concentrations, especially in reproductive organs. Here we present a human physiologically based pharmacokinetic (PBPK) model of DEP. Implemented in R, the PBPK model consists of seven tissue compartments, including blood, gut, liver, fat, skin, gonad, and rest of body (RB). In the blood both DEP and MEP partition into free and bound forms, and tissue distribution is considered as blood flow-limited. DEP is metabolized in the gut and liver into MEP which is further glucuronidated and cleared through the urine. The chemical-specific parameters of the model were predicted in silico or estimated based on published human urinary MEP data after exposure to DEP in the air at 250 or 300 µg/m3 for 3 or 6 h through inhalation and dermal absorption. Sensitivity analysis identified important parameters including partition coefficients of DEP for fat, RB, and skin compartments, and the rate constants for glucuronidation of MEP and urinary excretion, with regard to Cmax, area under the curve (AUC), and clearance half-lives of DEP and MEP. A subset of the sensitive parameters was then included in hierarchical population Bayesian Markov chain Monte Carlo (MCMC) simulations to characterize the uncertainty and variability of these parameters. The model is consistent with the notion that dermal absorption represents a significant route of exposure to DEP in ambient air and clothing can be an effective barrier. The developed human PBPK model can be utilized upon further refinement as a quantitative tool for DEP risk assessment.

Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves.

In the process of the production of recombinant proteins by using an Agrobacterium-mediated transient gene expression system, the effectiveness of the control of light conditions pre- and post-agroinfiltration on efficiency of transient expression is worth being evaluated. In this study, Nicotiana benthamiana plants were used as a bioreactor to investigate the effects of different light conditions pre- and post-agroinfiltration on the transient expression of green fluorescent protein (GFP). The results showed that the plants grown under light condition for 5 weeks had the highest level of transient expression among those grown for 4-8 weeks. In the pre-agroinfiltration, the level of transient expression of GFP was obviously decreased by the increase in light intensity or by the shortening of the photoperiod. Although the shortening of the photoperiod post-agroinfiltration also decreased the level of transient expression, moderate light intensity post-agroinfiltration was needed for higher level of transient expression efficiency. However, there was no strong correlation between the transient expression efficiency and plant growth. The results suggested that light condition was an important factor affecting the level of transient expression in plants. Hence, light conditions should be optimized to obtain higher productivity of recombinant protein from transient expression systems.

A New Harziane Diterpene, Harziaketal A, and a New Sterol, Trichosterol A, from the Marine-Alga-Epiphytic Trichoderma sp. Z43.

One new diterpene, harziaketal A (1), and one new highly degraded sterol, trichosterol A (2), along with three known compounds, including one diterpene, harzianone (3), and two steroids, (22E,24R)-5α,6α-epoxy-ergosta-8(14),22-dien-3ß,7α-diol (4) and isoergokonin B (5), were isolated from the culture of the marine-alga-epiphytic fungus Trichoderma sp. Z43 by silica gel column chromatography (CC), Sephadex LH-20 CC, and preparative thin-layer chromatography (TLC). Their structures and relative configurations were assigned by nuclear magnetic resonance (NMR) and high resolution electrospray ionisation mass spectrometry (HR-ESI-MS) data, and the absolute configuration of 1 was established by X-ray diffraction. Compound 1 features a hemiketal unit situated at the four-membered ring of harziane-type diterpenes for the first time, while 2 represents the rare occurrence of sterols with rings A and B being degraded. Compounds 1 and 2 displayed weak inhibition against the tested phytoplankton (Amphidinium carterae, Heterocapsa circularisquama, Heterosigma akashiwo, and Prorocentrum donghaiense) with half maximal inhibitory concentration (IC50 ) ranging from 14 to 53 µg/mL.

Lipids and Terpenoids from the Deep-Sea Fungus Trichoderma lixii R22 and Their Antagonism against Two Wheat Pathogens.

Five new lipids, tricholixins A-E (1-5), and two known terpenoids, brasilane A (6) and harzianone A (7), were discovered from a deep-sea strain (R22) of the fungus Trichoderma lixii isolated from the cold seep sediments of the South China Sea. Their structures and relative configurations were identified by meticulous analysis of MS and IR as well as NMR data. The absolute configuration of 5 was ascertained by dimolybdenum-induced ECD data in particular. Compounds 1 and 2 represent the only two new butenolides from marine-derived Trichoderma, and they further add to the structural diversity of these molecules. Although 6 has been reported from a basidiomycete previously, it is the first brasilane aminoglycoside of Trichoderma origin. During the assay against wheat-pathogenic fungi, both 1 and 2 inhibited Fusarium graminearum with an MIC value of 25.0 µg/mL, and 6 suppressed Gaeumannomyces graminis with an MIC value of 12.5 µg/mL. Moreover, the three isolates also showed low toxicity to the brine shrimp Artemia salina.

Trichoderols B-G, Six New Lipids from the Marine Algicolous Fungus Trichoderma sp. Z43.

Six new lipids, trichoderols B-G (1-6), along with a known one, triharzianin B (7), were isolated from the culture of Trichoderma sp. Z43 obtained from the surface of the marine brown alga Dictyopteris divaricata. Their structures and relative configurations were identified by interpretation of 1D/2D NMR and MS data. Compounds 1-7 were assayed for inhibiting the growth of three phytopathogenic fungi (Fusarium graminearum, Gaeumannomyces graminis, and Glomerella cingulata), four marine phytoplankton species (Amphidinium carterae, Heterocapsa circularisquama, Heterosigma akashiwo, and Prorocentrum donghaiense), and one marine zooplankton (Artemia salina). Compounds 1, 4, and 7 exhibited weak antifungal activities against three phytopathogenic fungi tested with MIC ≥ 64 µg/mL. All compounds displayed moderate antimicroalgal activity with IC50 ≥ 15 µg/mL and low toxicity to the brine shrimp Artemia salina.

Application of mNGS in the study of pulmonary microbiome in pneumoconiosis complicated with pulmonary infection patients and exploration of potential biomarkers.

Background: Pneumoconiosis patients have a high prevalence of pulmonary infections, which can complicate diagnosis and treatment. And there is no comprehensive study of the microbiome of patients with pneumoconiosis. The application of metagenomic next-generation sequencing (mNGS) fills the gap to some extent by analyzing the lung microbiota of pneumoconiosis population while achieving accurate diagnosis. Methods: We retrospectively analyzed 44 patients with suspected pneumoconiosis complicated with pulmonary infection between Jan 2020 and Nov 2022. Bronchoalveolar lavage fluid (BALF) specimens from 44 patients were collected and tested using the mNGS technology. Results: Among the lung microbiome of pneumoconiosis patients with complicated pulmonary infection (P group), the most frequently detected bacteria and fungi at the genus level were Streptococcus and Aspergillus, at the species level were Streptococcus pneumoniae and Aspergillus flavus, respectively, and the most frequently detected DNA virus was Human gammaherpesvirus 4. There was no significant difference in α diversity between the P group and the non-pneumoconiosis patients complicated with pulmonary infection group (Non-P group) in pulmonary flora, while P< 0.01 for ß diversity analysis, and the differential species between the two groups were Mycobacterium colombiense and Fusobacterium nucleatum. In addition, we monitored a high distribution of Malassezia and Pneumocystis in the P group, while herpes virus was detected in the majority of samples. Conclusions: Overall, we not only revealed a comprehensive lung microbiome profile of pneumoconiosis patients, but also compared the differences between their microbiome and that of non-pneumoconiosis complicated with pulmonary infection patients. This provides a good basis for a better understanding of the relationship between pneumoconiosis and microorganisms, and for the search of potential biomarkers.

New ophiobolin sesterterpenoid and drimane sesquiterpenoids from a marine-alga-derived fungus Aspergillus sp.

Further investigation of secondary metabolites of a marine-alga-derived fungus Aspergillus sp. RR-YLW-12 led to isolate one new ophiobolin-type sesterterpenoid (1), four new drimane-type sesquiterpenoids (2-5) and one natural occurring compound (6), together with seven known compounds (7-13). Their structures and stereochemistry were elucidated by extensive spectroscopic analysis of NMR and HRMS experiments, and by comparison with the literature data. All isolates were evaluated for growth inhibition of five marine harmful microalgae. The new compounds exhibited significant to moderate inhibitory effects towards all tested microalgae species with IC50 values ranging from 5.8 to 54.5 µg/mL.

Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.

Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.

Validation of two automated ASPECTS software on non-contrast computed tomography scans of patients with acute ischemic stroke.

Purpose: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was designed for semi-quantitative assessment of early ischemic changes on non-contrast computed tomography (NCCT) for acute ischemic stroke (AIS). We evaluated two automated ASPECTS software in comparison with reference standard. Methods: NCCT of 276 AIS patients were retrospectively reviewed (March 2018-June 2020). A three-radiologist consensus for ASPECTS was used as reference standard. Imaging data from both baseline and follow-up were evaluated for reference standard. Automated ASPECTS were calculated from baseline NCCT with 1-mm and 5-mm slice thickness, respectively. Agreement between automated ASPECTS and reference standard was assessed using intra-class correlation coefficient (ICC). Correlation of automated ASPECTS with baseline stroke severity (NIHSS) and follow-up ASPECTS were evaluated using Spearman correlation analysis. Results: In score-based analysis, automated ASPECTS calculated from 5-mm slice thickness images agreed well with reference standard (software A: ICC = 0.77; software B: ICC = 0.65). Bland-Altman analysis revealed that the mean differences between automated ASPECTS and reference standard were ≤ 0.6. In region-based analysis, automated ASPECTS derived from 5-mm slice thickness images by software A showed higher sensitivity (0.60 vs. 0.54), lower specificity (0.91 vs. 0.94), and higher AUC (0.76 vs. 0.74) than those using 1-mm slice thickness images (p < 0.05). Automated ASPECTS derived from 5-mm slice thickness images by software B showed higher sensitivity (0.56 vs. 0.51), higher specificity (0.87 vs. 0.81), higher accuracy (0.80 vs. 0.73), and higher AUC (0.71 vs. 0.66) than those using 1-mm slice thickness images (p < 0.05). Automated ASPECTS were significantly associated with baseline NIHSS and follow-up ASPECTS. Conclusion: Automated ASPECTS showed good reliability and 5 mm was the optimal slice thickness.

Sorbicillinoids from the alga-epiphytic fungus Trichoderma reesei Z56-8.

A new highly transformed sorbicillinoid derivative, trichoreesin A (1), and four known monomeric sorbicillinoids, sorbicillin (2), 2',3'-dihydrosorbicillin (3), 3-demethylsorbicillin (4), and sohirnone A (5), were discovered from Trichoderma reesei Z56-8, an epiphyte from the marine brown alga Sargassum sp. The structure and relative configuration of 1 were determined by interpretation of UV, IR, NMR, and MS signals, and its absolute configuration was assigned by analysis of ECD data aided by quantum chemical calculations. This is the first survey of metabolites from marine algicolous T. reesei. Compound 1 represents the first bicyclic vertinolide derivative, and it possesses inhibition of several marine phytoplankton species.

Hepatitis B and Hepatitis D Viruses: A Comprehensive Update with an Immunological Focus.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) are highly prevalent viruses estimated to infect approximately 300 million people and 12-72 million people worldwide, respectively. HDV requires the HBV envelope to establish a successful infection. Concurrent infection with HBV and HDV can result in more severe disease outcomes than infection with HBV alone. These viruses can cause significant hepatic disease, including cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, and represent a significant cause of global mortality. Therefore, a thorough understanding of these viruses and the immune response they generate is essential to enhance disease management. This review includes an overview of the HBV and HDV viruses, including life cycle, structure, natural course of infection, and histopathology. A discussion of the interplay between HDV RNA and HBV DNA during chronic infection is also included. It then discusses characteristics of the immune response with a focus on reactions to the antigenic hepatitis B surface antigen, including small, middle, and large surface antigens. This paper also reviews characteristics of the immune response to the hepatitis D antigen (including small and large antigens), the only protein expressed by hepatitis D. Lastly, we conclude with a discussion of recent therapeutic advances pertaining to these viruses.

Genome-wide DNA methylation differences between conservation and breeding populations of Shaoxing ducks.

The genome-wide DNA methylation assay was used to analyze the difference in methylation between the breeding and conservation populations of Shaoxing ducks. The methylation level of the breeding population was higher than that of the two conservation populations, and the proportion of CG methylation sites was the largest in the three populations, most of the methylation sites were located in the exon region. There were 1247 different methylation regions in the two populations (group A and B), and 927 different methylation regions in the two groups (group A and group C). The differential methylation regions of the three groups were evenly distributed in the gene and intergene regions. GO and KEGG enrichment analysis showed that the differentially expressed genes in the A and B groups were mainly involved in synaptic and cell connections and the signaling pathways were significantly enriched in cAMP and oxytocin signaling pathways. The results showed that the group C was significantly enriched in eight signaling pathways, including the cAMP signaling pathway and long-term enhancement, compared to the group A. There were thirty-five differentially methylated genes, including CACNA1C, GRIA1, GRIA2, GABBR2, PDE10A, BRAF, GRM5, CPEB3, FMn2, GABRB2, PTK2, and CNTN1. These genes were involved in the development and ovulation of ovaries and follicles and were closely related to the excellent production performance of the breeding population. In addition, ATP2B1, ATP2B2, and other genes related to eggshell quality were identified, which can be used as molecular markers to improve eggshell quality in the future.

One-pot construction of highly efficient TaON/Bi2O3/S-BiOCl ternary photocatalysts: Simultaneously integrating type-â with Z-scheme junctions for improved visible light-driven removal of organic pollutants.

Bismuth oxychloride (BiOCl) has appeared as a popular candidate in photocatalysis field but is plagued by its poor visible light harvesting and low carriers-flow steering inherited from wide band gap. Integration of doping and heterojunction engineering into the bulk has proven to be an optimal and generally applied method for enabling excellent photocatalytic activity. Nevertheless, the previous reported BiOCl-based photocatalysts fabricated by the above strategies are still suffered from harsh synthesis process, poor interface stability and narrow application area. Here, we introduce a facile one-pot hydrothermal strategy to achieve in-situ growth of TaON as a medium on the surface of Bi2O3 and S-doped BiOCl (denoted as S-BiOCl) for constructing ternary TaON/Bi2O3/S-BiOCl heterostructures, which were obtained by the simultaneous coprecipitation and ripening process. Current investigation suggests that such a unique TaON/Bi2O3/S-BiOCl exhibits a relatively much higher photocatalytic activity for visible light-driven removal of rhodamine B (RhB), tetracycline (TC) and tetracycline hydrochloride (TC-HCl) than those of hybrid Bi2O3/S-BiOCl and pristine S-BiOCl. It is ascribed to the synergetic effect on the introduction of S dopant level in BiOCl lattice as well as the construction of intimate double heterointerfaces among Bi2O3, TaON and S-BiOCl, which endows the TaON/Bi2O3/S-BiOCl photocatalysts with considerable advantages for highly elevating photocatalytic performances, such as the intensive optical absorption, high redox potential as well as high-efficient photocharge separation originated from type-I and Z-scheme pathways. This work delivers novel insights for design and one-pot preparation of high-active BiOX (X = Cl, Br and I)-based photocatalysts towards organic dye and antibiotic removal in the future research.

Identification of nonmonotonic concentration-responses in Tox21 high-throughput screening estrogen receptor assays.

Environmental endocrine-disrupting chemicals (EDCs) interfere with the metabolism and actions of endogenous hormones. It has been well documented in numerous in vivo and in vitro studies that EDCs can exhibit nonmonotonic dose response (NMDR) behaviors. Not conforming to the conventional linear or linear-no-threshold response paradigm, these NMDR relationships pose practical challenges to the risk assessment of EDCs. In the meantime, the endocrine signaling pathways and biological mechanisms underpinning NMDR remain incompletely understood. The US Tox21 program has conducted in vitro cell-based high-throughput screening assays for estrogen receptors (ER), androgen receptors, and other nuclear receptors, and screened the 10 K-compound library for potential endocrine activities. Using 15 concentrations across several orders of magnitude of concentration range and run in both agonist and antagonist modes, these Tox21 assay datasets contain valuable quantitative information that can be explored to evaluate the nonlinear effects of EDCs and may infer potential mechanisms. In this study we analyzed the concentration-response curves (CRCs) in all 8 Tox21 ERα and ERß assays by developing clustering and classification algorithms customized to the datasets to identify various shapes of CRCs. After excluding NMDR curves likely caused by cytotoxicity, luciferase inhibition, or autofluorescence, hundreds of compounds were identified to exhibit Bell or U-shaped CRCs. Bell-shaped CRCs are about 7 times more frequent than U-shaped ones in the Tox21 ER assays. Many compounds exhibit NMDR in at least one assay, and some EDCs well-known for their NMDRs in the literature were also identified, suggesting their nonmonotonic effects may originate at cellular levels involving transcriptional ER signaling. The developed computational methods for NMDR identification in ER assays can be adapted and applied to other high-throughput bioassays.

Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings.

In the present study, we explored whether magnetic iron oxide nanoparticles (MNPs-Fe3O4) can be used to alleviate the toxicity of 3-nitrophenol (3-NP) to rice (Oryza sativa L.) seedlings grown under hydroponic conditions. The results showed that 3-NP from 7 to 560 µM decreased the growth, photochemical activity of the photosystem II (PS II), and chlorophyll content of the seedlings in a concentration-dependent manner. In the presence of 3-NP, 2,000 mg L-1 MNPs-Fe3O4 were added to the growth medium as the absorbents of 3-NP and then were separated with a magnet. The emergence of MNPs-Fe3O4 effectively alleviated the negative effects of 3-NP on rice seedlings. In addition, the long-term presence of MNPs-Fe3O4 (from 100 to 2,000 mg L-1) in the growth medium enhanced the growth, production of reactive oxygen species (ROS), activities of antioxidant enzymes, photochemical activity of PS II, and chlorophyll content of the rice seedlings. These results suggest that MNPs-Fe3O4 could be used as potential additives to relieve the physiological toxicity of 3-NP to rice seedlings.

The involvement of extracellular ATP in regulating the stunted growth of Arabidopsis plants by repeated wounding.

BACKGROUND: Extracellular ATP (exATP) has been shown to act as a signal molecule for regulating growth, development, and responses of plants to the external environment. RESULTS: In this study, we investigated the possible involvement of exATP in regulating the stunted growth caused by repeated wounding. The present work showed that the repeated wounding caused the decreases in leaf area, fresh weight, dry weight, and root length of Arabidopsis seedlings, while the exATP level was enhanced by the repeated wounding. Repeated application of exogenous ATP had similar effects on the plant growth, as the repeated wounding. Through the comparison of p2k1-3 mutant (in which T-DNA disrupted the gene coding P2K1, as exATP receptor) and wide type (WT) plants, it was found that the mutation in P2K1 decreased the sensitivity of plant growth to the repeated wounding and exogenous ATP application. Further works showed that the ibuprofen (IBU, an inhibitor of jasmonate biosynthesis) partially rescued the wound-induced growth degradation. In comparison, the P2K1 mutation partly rescued the wound-induced growth degradation, whereas this mutation failed to do so in the wounded seedlings treated with IBU, indicating that the role of exATP in regulating the growth degradation by repeated wounding could be linked to the JA signaling pathway. CONCLUSIONS: In conclusion, these results indicate that exATP could be a regulator for the stunted growth of plants by repeated wounding.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Extracellular ATP is involved in regulating Arabidopsis seed germination.

MAIN CONCLUSION: Extracellular ATP level induced a transient increase during germination of Arabidopsis seeds, and extracellular ATP could negatively regulate the seed germination by its receptor, DORN1. Extracellular ATP (exATP) acts as a signal molecule for regulating growth, development, and responses of plants to external environments. In this study, we investigated the possible involvement of exATP in regulating the seed germination of Arabidopsis thaliana. Treatments of Arabidopsis seeds with exogenous ATP delayed seed germination, suggesting that exATP could be a repressor for seed germination. During the germination of Arabidopsis seeds, the exATP level of the seeds presented a transient increase. When exogenous application of the glucose-hexokinase system effectively decreased the exATP level of the Arabidopsis seeds during germination, the percentage of germination was significantly enhanced, while the products of ATP hydrolysis had no effects on the germination. Further studies showed that the seeds of dorn 1-3 mutant plants (mutation in exATP receptor) showed a higher germination percentage, compared to the seeds of wide type (WT) plants. In addition, the dorn 1-3 mutant seeds were less sensitive to the delay-effect of exogenous ATP on seed germination than the WT seeds. The dorn 1-3 mutant seeds presented a higher GA (gibberellin) content, lower ABA (abscisic acid) content, and lower ratio of ABA/GA contents before the imbibition, compared to the WT seeds. The regulation of seed germination by exATP was dependent on the external temperature. These data suggest that exATP is involved in regulating Arabidopsis seed germination.

Hybrid computational modeling demonstrates the utility of simulating complex cellular networks in type 1 diabetes.

Persistent destruction of pancreatic ß-cells in type 1 diabetes (T1D) results from multifaceted pancreatic cellular interactions in various phase progressions. Owing to the inherent heterogeneity of coupled nonlinear systems, computational modeling based on T1D etiology help achieve a systematic understanding of biological processes and T1D health outcomes. The main challenge is to design such a reliable framework to analyze the highly orchestrated biology of T1D based on the knowledge of cellular networks and biological parameters. We constructed a novel hybrid in-silico computational model to unravel T1D onset, progression, and prevention in a non-obese-diabetic mouse model. The computational approach that integrates mathematical modeling, agent-based modeling, and advanced statistical methods allows for modeling key biological parameters and time-dependent spatial networks of cell behaviors. By integrating interactions between multiple cell types, model results captured the individual-specific dynamics of T1D progression and were validated against experimental data for the number of infiltrating CD8+T-cells. Our simulation results uncovered the correlation between five auto-destructive mechanisms identifying a combination of potential therapeutic strategies: the average lifespan of cytotoxic CD8+T-cells in islets; the initial number of apoptotic ß-cells; recruitment rate of dendritic-cells (DCs); binding sites on DCs for naïve CD8+T-cells; and time required for DCs movement. Results from therapy-directed simulations further suggest the efficacy of proposed therapeutic strategies depends upon the type and time of administering therapy interventions and the administered amount of therapeutic dose. Our findings show modeling immunogenicity that underlies autoimmune T1D and identifying autoantigens that serve as potential biomarkers are two pressing parameters to predict disease onset and progression.