Life Sciences Commons^™

(R)-Β-Lysine Modified Elongation Factor P Functions In Translation Elongation, Tammy J. Bullwinkle, S. Betty Zou, Andrei Rajkovic, Steven J. Hersch, Sara Elgamal, Nathaniel Robinson, David Smil, Yuri Bolshan, William Wiley Navarre, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Post-translational modification of bacterial elongation factor P (EF-P) with (R)-β-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity of the ribosome in vitro. The additional hydroxylation of EF-P at the same lysine residue by the YfcM protein has also recently been described. The roles of modified and unmodified EF-P during different steps in translation, and how this correlates to its physiological role in the cell, have recently been linked to the synthesis of polyproline stretches in proteins. Polysome analysis indicated that EF-P functions in translation elongation, rather than initiation as proposed previously. This was …

A Comparison Of Boltzmann And Gibbs Definitions Of Microcanonical Entropy For Small Systems, Randall B. Shirts

Faculty Publications

Two different definitions of entropy, S= klnW, in the microcanonical ensemble have been competing for over 100 years. The Boltzmann/Planck definition is that W is the number of states accessible to the system at its energy E (also called the surface entropy). The Gibbs/Hertz definition is that W is the number of states of the system up to the energy E (also called the volume entropy). These two definitions agree for large systems but differ by terms of order N^-1 for small systems, where N is the number of particles in the system. For three analytical …

Crystal Structures And Kinetics Of Monofunctional Proline Dehydrogenase Provide Insight Into Substrate Recognition And Conformational Changes Associated With Flavin Reduction And Product Release, Min Luo, Benjamin W. Arentson, Dhiraj Srivastava, Donald F. Becker, John J. Tanner

Department of Biochemistry: Faculty Publications

Proline dehydrogenase catalyzes the FAD-dependent oxidation of proline to Δ1- pyrroline-5- carboxylate, which is the first step of proline catabolism. Here, we report the structures of proline dehydrogenase from Deinococcus radiodurans in the oxidized state complexed with the proline analog L-tetrahydrofuroic acid and in the reduced state with the proline site vacant. The analog binds against the si face of the FAD isoalloxazine and is protected from bulk solvent by the α8 helix and the β1-α1 loop. The FAD ribityl chain adopts two conformations in the E-S complex, which is unprecedented for flavoenzymes. One of the conformations is novel for …

Selection Of Trna Charging Quality Control Mechanisms That Increase Mistranslation Of The Genetic Code, Srujana S. Yadavalli, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mistranslation can follow two events during protein synthesis: production of non-cognate amino acid:transfer RNA (tRNA) pairs by aminoacyl-tRNA synthetases (aaRSs) and inaccurate selection of aminoacyl-tRNAs by the ribosome. Many aaRSs actively edit non-cognate amino acids, but editing mechanisms are not evolutionarily conserved, and their physiological significance remains unclear. To address the connection between aaRSs and mistranslation, the evolutionary divergence of tyrosine editing by phenylalanyl-tRNA synthetase (PheRS) was used as a model. Certain PheRSs are naturally error prone, most notably a Mycoplasma example that displayed a low level of specificity consistent with elevated mistranslation of the proteome. Mycoplasma PheRS was found …

Transcription-Coupled Dna Supercoiling In Escherichia Coli: Mechanisms And Biological Functions, Xiaoduo Zhi

FIU Electronic Theses and Dissertations

Transcription by RNA polymerase can induce the formation of hypernegatively supercoiled DNA both in vivo and in vitro. This phenomenon has been explained by a “twin-supercoiled-domain” model of transcription where a positively supercoiled domain is generated ahead of the RNA polymerase and a negatively supercoiled domain behind it. In E. coli cells, transcription-induced topological change of chromosomal DNA is expected to actively remodel chromosomal structure and greatly influence DNA transactions such as transcription, DNA replication, and recombination.

In this study, an IPTG-inducible, two-plasmid system was established to study transcription-coupled DNA supercoiling (TCDS) in E. coli topA strains. By performing topology …

Tumour Inflammasome-Derived Il-1b Recruits Neutrophils And Improves Local Recurrence-Free Survival In Ebv-Induced Nasopharyngeal Carcinoma, Lih-Chyang Chen, Li-Jie Wang, Nang-Ming Tsang, David M. Ojcius, Chia-Chen Chen, Chun-Nan Ouyang, Chuen Hsueh, Ying Liang, Kai-Ping Chang, Chiu-Chin Chen, Yu-Sun Chang

All Dugoni School of Dentistry Faculty Articles

Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL-1β production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG-I inflammasomes are overexpressed in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG-I are required for IL-1β induction by EBV genomic DNA and EBV-encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 …

Reversible Inhibition Of Chlamydia Trachomatis Infection In Epithelial Cells Due To Stimulation Of P2x4 Receptors, Matthew A. Pettengill, Camila Marques-Da-Silva, Maria Luisa Avila, Verissa W. Lam, Ikechukwu Ollawa, Ali Abdul-Sater, Robson Coutinho-Silva, Georg Hacker, David M. Ojcius, Suellen D'Arc Dos Santos Oliveira

All Dugoni School of Dentistry Faculty Articles

Bacterial infections of the mucosal epithelium are a major cause of human disease. The prolonged presence of microbial pathogens stimulates inflammation of the local tissues, which leads to changes in the molecular composition of the extracellular milieu. A well-characterized molecule that is released to the extracellular milieu by stressed or infected cells is extracellular ATP and its ecto-enzymatic degradation products, which function as signaling molecules through ligation of purinergic receptors. There has been little information, however, on the effects of the extracellular metabolites on bacterial growth in inflamed tissues. Millimolar concentrations of ATP have been previously shown to inhibit irreversibly …

Secondary Structure, A Missing Component Of Sequence- Based Minimotif Definitions, David P. Sargeant, Michael R. Gryk, Mark W. Maciejewsk, Vishal Thapar, Vamsi Kundeti, Sanguthevar Rajasekaran, Pedro Romero, Keith Dunker, Shun-Cheng Li, Tomonori Kaneko, Martin Schiller

Life Sciences Faculty Research

Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis …

Knockout Of The 15 Kda Selenoprotein Protects Against Chemically-Induced Aberrant Crypt Formation In Mice, Petra A. Tsuji, Bradley A. Carlson, Salvador Naranjo-Suarez, Min-Hyuk Yoo, Xue-Ming Xu, Dmitri E. Fomenko, Vadim Gladyshev, Dolph L. Hatfield, Cindy D. Davis

Department of Biochemistry: Faculty Publications

Evidence suggests that selenium has cancer preventive properties that are largely mediated through selenoproteins. Our previous observations demonstrated that targeted down-regulation of the 15 kDa selenoprotein (Sep15) in murine colon cancer cells resulted in the reversal of the cancer phenotype. The present study investigated the effect of Sep15 knockout in mice using a chemically-induced colon cancer model. Homozygous Sep15 knockout mice, and wild type littermate controls were given four weekly subcutaneous injections of azoxymethane (10 mg/kg). Sep15 knockout mice developed significantly (pGBP-1 in humans has been associated with a highly significant, increased five-year survival rate in colorectal cancer patients. In …

Sinusoidal Endothelial Dysfunction In Non-Alcoholic Fatty Liver Disease., Sandhya Lakshmi Gopalakrishnan

Department of Biochemistry: Dissertations, Theses, and Student Research

Non-alcoholic fatty liver disease (NAFLD) is an asymptomatic increasingly common disorder that affects liver metabolism and is often the precursor for liver pathologies such as fibrosis, cirrhosis and hepato-cellular carcinoma. The liver sinusoidal endothelial cells act as a liver sieve by allowing macromolecules and chylomicrons to traverse through their fenestrations (sieve plates) to hepatocytes. Since liver sinusoidal endothelial cells (LSEC) regulate serum derived macromolecular exposure to hepatocytes, we asked what role LSEC could play in the pathogenesis of NAFLD. To investigate the early events of NAFLD we used a rat model (Sprague-Dawley) in which animals were maintained on standard and …

Proposed Coherent Trapping Of A Population Of Electrons In A C60 Molecule Induced By Laser Excitation, Thomas George, G.P. Zhang

Chemistry & Biochemistry Faculty Works

This Letter demonstrates the possibility of generating coherent population trapping in C60. Similar to a three-level Λ system, C60 has a forbidden transition between the highest occupied molecular orbital (HOMO) (|a⟩) and the lowest unoccupied molecular orbital (LUMO) (|c⟩), but a dipole-allowed transition between HOMO and LUMO+1 (|b⟩) and between |b⟩ and |c⟩. We employ two cw laser fields, one coupling and one probe. The strong coupling field is switched on first to resonantly excite the transition between |b⟩ and |c⟩. After a delay, the probe is switched on; the coherent interaction between the coupling and probe fields traps the …

The Chemical Origin Of Behavior Is Rooted In Abiogenesis, Brian C. Larson, R. Paul Jensen, Niles Lehman

Chemistry Faculty Publications and Presentations

We describe the initial realization of behavior in the biosphere, which we term behavioral chemistry. If molecules are complex enough to attain a stochastic element to their structural conformation in such as a way as to radically affect their function in a biological (evolvable) setting, then they have the capacity to behave. This circumstance is described here as behavioral chemistry, unique in its definition from the colloquial chemical behavior. This transition between chemical behavior and behavioral chemistry need be explicit when discussing the root cause of behavior, which itself lies squarely at the origins of life and is the foundation …

Cross Regulation Of Sirtuin 1, Ampk, And Ppary In Conjugated Linoleic Acid Treated Adipocytes, Shan Jiang, Wei Wang, Jess Miner, Michael E. Fromm

Department of Biochemistry: Faculty Publications

Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) reduces triglyceride (TG) levels in adipocytes through multiple pathways, with AMP-activated protein kinase (AMPK) generally facilitating, and peroxisome proliferator-activated receptor γ (PPARγ) generally opposing these reductions. Sirtuin 1 (SIRT1), a histone/protein deacetylase that affects energy homeostasis, often functions coordinately with AMPK, and is capable of binding to PPARγ, thereby inhibiting its activity. This study investigated the role of SIRT1 in the response of 3T3-L1 adipocytes to t10c12 CLA by testing the following hypotheses: 1) SIRT1 is functionally required for robust TG reduction; and 2) SIRT1, …

Phylogenetic Engineering Of The Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase Large Subunit In Chlamydomonas Reinhardtii, Boon Hoe Lim

Department of Biochemistry: Dissertations, Theses, and Student Research

Thirty-four residues in the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) may account for the kinetic differences between Rubisco enzyme from green algae and land plants. By substituting these "phylogenetic residues" as groups and combinations of groups in the large subunit of the green alga Chlamydomonas reinhardtii with those of land-plant Rubisco, the functions and relationships of these "phylogenetic groups" were determined.

A phylogenetic-group substitution at the base of catalytic loop 6 of the large subunit decreases the CO₂/O₂ specificity of the enzyme, but function is restored by a further phylogenetic-group substitution at the carboxy-terminal tail. Therefore, these …

Differential Effects Of The Hydrophobic Surfactant Proteins On The Formation Of Inverse Bicontinuous Cubic Phases, Mariya Chavarha, Ryan W. Loney, Kamlesh Kumar, Shankar B. Rananavare, Stephen B. Hall

Chemistry Faculty Publications and Presentations

Prior studies have shown that the biological mixture of the two hydrophobic surfactant proteins, SP-B and SP-C, produces faster adsorption of the surfactant lipids to an air/water interface, and that they induce 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) to form inverse bicontinuous cubic phases. SP-B has a much greater effect than SP-C on adsorption. If the two proteins induce formation of the bicontinuous structures and faster adsorption by similar mechanisms, then they should also have differential ability to form the cubic phases. To test this hypothesis, we measured small angle X-ray scattering on the individual proteins combined with POPE. SP-B replicated the doserelated …

Ivermectin Inhibits Growth Of Chlamydia Trachomatis In Epithelial Cells, Matthew A. Pettengill, Verissa W. Lam, Ikechukwu Ollawa, Camila Marques-Da-Silva, David M. Ojcius

All Dugoni School of Dentistry Faculty Articles

Ivermectin is currently approved for treatment of both clinical and veterinary infections by nematodes, including Onchocerca cervicalis in horses and Onchocerca volvulus in humans. However, ivermectin has never been shown to be effective against bacterial pathogens. Here we show that ivermectin also inhibits infection of epithelial cells by the bacterial pathogen, Chlamydia trachomatis, at doses that could be envisioned clinically for sexually-transmitted or ocular infections by Chlamydia.

Development And Validation Of A Simple Method For The Detection Of Fascaplysin In Plasma, Kenneth H. Swartz, Frederick A. Valeriote, Joseph Media, Tyler A. Johnson, Karen Tenney, Phillip Crews, Jiajiu Shaw

Natural Sciences and Mathematics | Faculty Scholarship

Fascaplysin is a cytotoxic natural product isolated from a variety of Indo-Pacific marine organisms, primarily Fascaplysinopsis sponges and Didemnum tunicates. Positive xenograft studies involving this alkaloid structural class have indicated that fascaplysin may serve as an important lead compound for preclinical development. This study was undertaken as a prelude to a full pharmacokinetics and therapeutic assessment of fascaplysin. We describe here a simple plasma preparation and a rapid HPLC method for the detection of fascaplysin in mice. The method was validated by parameters including good linear correlation, a limit of quantification of 107.1 μg/ mL, and a good precision with …

(1)H, (15)N And (13)C Backbone Resonance Assignments Of The Tpr1 And Tpr2a Domains Of Mouse Sti1., Andrzej Maciejewski, Marco A Prado, Wing-Yiu Choy

Biochemistry Publications

Hop/STI1 (Hsp-organizing protein/stress-induced-phosphoprotein 1) is a molecular co-chaperone, which coordinates Hsp70 and Hsp90 activity during client protein folding through interactions with its TPR1 and TPR2A domains. Hsp90 substrates include a diverse set of proteins, many of which have been implicated in tumorigenesis. Over-expression of Hsp90 in cancer cells stabilizes mutant oncoproteins promoting cancer cell survival. Disruption of Hsp90 and its co-chaperone machinery has become a promising strategy for the treatment of cancer. STI1 has also been described as a neurotrophic signaling molecule through its interactions with the prion protein (PrP(C)). Here, we report the (1)H, (13)C and (15)N backbone assignments …

Elastic Deformations Of The Rotary Double Motor Of Single F(O)F(1)-Atp Synthases Detected In Real Time By Förster Resonance Energy Transfer., Stefan Ernst, Monika G Düser, Nawid Zarrabi, Stanley D Dunn, Michael Börsch

Biochemistry Publications

Elastic conformational changes of the protein backbone are essential for catalytic activities of enzymes. To follow relative movements within the protein, Förster-type resonance energy transfer (FRET) between two specifically attached fluorophores can be applied. FRET provides a precise ruler between 3 and 8nm with subnanometer resolution. Corresponding submillisecond time resolution is sufficient to identify conformational changes in FRET time trajectories. Analyzing single enzymes circumvents the need for synchronization of various conformations. F(O)F(1)-ATP synthase is a rotary double motor which catalyzes the synthesis of adenosine triphosphate (ATP). A proton-driven 10-stepped rotary F(O) motor in the Escherichia coli enzyme is connected to …

Functions Of The Arabidopsis Kinesin Superfamily Of Microtubule-Based Motor Proteins, Chuanmei Zhu, Ram Dixit

Biology Faculty Publications & Presentations

Plants possess a large number of microtubule-based kinesin motor proteins. While the kinesin-2, 3, 9, and 11 families are absent from land plants, the kinesin-7 and 14 families are greatly expanded. In addition, some kinesins are specifically present only in land plants. The distinctive inventory of plant kinesins suggests that kinesins have evolved to perform specialized functions in plants. Plants assemble unique microtubule arrays during their cell cycle, including the interphase cortical microtubule array, preprophase band, anastral spindle and phragmoplast. In this review, we explore the functions of plant kinesins from a microtubule array viewpoint, focusing mainly on Arabidopsis kinesins. …

Elastic Deformations Of The Rotary Double Motor Of Single F(O)F(1)-Atp Synthases Detected In Real Time By Förster Resonance Energy Transfer., Stefan Ernst, Monika G Düser, Nawid Zarrabi, Stanley D Dunn, Michael Börsch

Biochemistry Publications

Elastic conformational changes of the protein backbone are essential for catalytic activities of enzymes. To follow relative movements within the protein, Förster-type resonance energy transfer (FRET) between two specifically attached fluorophores can be applied. FRET provides a precise ruler between 3 and 8nm with subnanometer resolution. Corresponding submillisecond time resolution is sufficient to identify conformational changes in FRET time trajectories. Analyzing single enzymes circumvents the need for synchronization of various conformations. F(O)F(1)-ATP synthase is a rotary double motor which catalyzes the synthesis of adenosine triphosphate (ATP). A proton-driven 10-stepped rotary F(O) motor in the Escherichia coli enzyme is connected to …

N-Terminal Domain Of Vacuolar Snare Vam7p Promotes Trans-Snare Complex Assembly, Hao Xu, William T. Wickner

Dartmouth Scholarship

SNARE-dependent membrane fusion in eukaryotic cells requires that the heptad-repeat SNARE domains from R- and Q-SNAREs, anchored to apposed membranes, assemble into four-helix coiled-coil bundles. In addition to their SNARE and transmembrane domains, most SNAREs have N-terminal domains (N-domains), although their functions are unclear. The N-domain of the yeast vacuolar Qc-SNARE Vam7p is a binding partner for the homotypic fusion and vacuole protein sorting complex (a master regulator of vacuole fusion) and has Phox homology, providing a phosphatidylinositol 3-phosphate (PI3P)-specific membrane anchor. We now report that this Vam7p N-domain has yet another role, one that does not depend on its …

Exploring The Role Of A Conserved Class A Residue In The Ω-Loop Of Kpc-2 Β-Lactamase: A Mechanism For Ceftazidime Hydrolysis

Chemistry Faculty Publications

Gram-negative bacteria harboring KPC-2, a class A β-lactamase, are resistant to all β-lactam antibiotics and pose a major public health threat. Arg-164 is a conserved residue in all class A β-lactamases and is located in the solvent-exposed Ω-loop of KPC-2. To probe the role of this amino acid in KPC-2, we performed site-saturation mutagenesis. When compared with wild type, 11 of 19 variants at position Arg-164 in KPC-2 conferred increased resistance to the oxyimino-cephalosporin, ceftazidime (minimum inhibitory concentration; 32→128 mg/liter) when expressed in Escherichia coli. Using the R164S variant of KPC-2 as a representative β-lactamase for more detailed analysis, we …

Insights Into Mrnp Biogenesis Provided By New Genetic Interactions Among Export And Transcription Factors, Francisco Estruch, Christine Hodge, Natalia Gómez-Navarro, Lorena Peiró-Chova, Catherine V. Heath, Charles N. Cole

Dartmouth Scholarship

The various steps of mRNP biogenesis (transcription, processing and export) are interconnected. It has been shown that the transcription machinery plays a pivotal role in mRNP assembly, since several mRNA export factors are recruited during transcription and physically interact with components of the transcription machinery. Although the shuttling DEAD-box protein Dbp5p is concentrated on the cytoplasmic fibrils of the NPC, previous studies demonstrated that it interacts physically and genetically with factors involved in transcription initiation. We investigated the effect of mutations affecting various components of the transcription initiation apparatus on the phenotypes of mRNA export mutant strains. Our results show …

Endogenous Inhibitor Proteins That Connect Ser/Thr Kinases And Phosphatases In Cell Signaling., Masumi Eto, David L Brautigan

Department of Molecular Physiology and Biophysics Faculty Papers

Protein phosphatase activity acts as a primary determinant of the extent and duration of phosphorylation of cellular proteins in response to physiological stimuli. Ser/Thr protein phosphatase-1 (PP1) belongs to the PPP superfamily, and is associated with regulatory subunits that confer substrate specificity, allosteric regulation, and subcellular compartmentalization. In addition, all eukaryotic cells contain multiple heat-stable proteins that originally were thought to inhibit phosphatase catalytic subunits released from the regulatory subunits, as a fail-safe mechanism. However, discovery of C-kinase-activated PP1 inhibitor, Mr of 17 kDa (CPI-17) required fresh thinking about the endogenous inhibitors as specific regulators of particular phosphatase complexes, acting …

Epidemiological Ins And Outs Of Helicobacter Pylori: A Review, Jibran Sualeh Muhammad, Syed Faisal Zaidi, Toshiro Sugiyama

Department of Biological & Biomedical Sciences

Helicobacter pylori infection is now recognised as a worldwide problem. It is the most common cause of chronic gastritis, and is strongly linked to peptic ulcer disease and gastric cancer. A comprehensive understanding of epidemiological ins and outs of H. pylori infection is very important in solving the patho-physiological enigma and might help in leading towards better management and prognosis of infection. This article presents a review of the literature on the epidemiology of H. pylori infection from 2006 to 2011. The authors used Medical Subject Heading (MeSH) terms 'Helicobacter' with 'epidemiology,' 'transmission' or 'risk factor' to search PubMed database. …

Taking Aim At The Start Of Translation, Medha Raina, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

No abstract provided.

Breast Tumour Initiating Cell Fate Is Regulated By Microenvironmental Cues From An Extracellular Matrix, Sharmistha Saha, Pang-Kuo Lo, Xinrui Duan, Hexin Chen, Qian Wang

Faculty Publications

Cancer stem cells, also known as tumour-initiating cells (TICs), are identified as highly tumorigenic population within tumours and hypothesized to be main regulators in tumour growth, metastasis and relapse. Evidence also suggests that a tumour microenvironment plays a critical role in the development and progression of cancer, by constantly modulating cell–matrix interactions. Scientists have tried to characterize and identify the TIC population but the actual combination of extracellular components in deciphering the fate of TICs has not been explored. The basic unanswered question is the phenotypic stability of this TIC population in a tissue extracellular matrix setting. The in vivo …

Interactome-Wide Analysis Identifies End-Binding Protein 1 As A Crucial Component For The Speck-Like Particle Formation Of Activated Absence In Melanoma 2 (Aim2) Inflammasomes, Li-Jie Wang, Chia-Wei Hsu, Chiu-Chin Chen, Ying Liang, Lih-Chyang Chen, David M. Ojcius, Ngan-Ming Tsang, Chuen Hsueh, Chih-Ching Wu, Yu-Sun Chang

All Dugoni School of Dentistry Faculty Articles

Inflammasomes are cytoplasmic receptors that can recognize intracellular pathogens or danger signals and are critical for interleukin 1β production. Although several key components of inflammasome activation have been identified, there has not been a systematic analysis of the protein components found in the stimulated complex. In this study, we used the isobaric tags for relative and absolute quantification approach to systemically analyze the interactomes of the NLRP3, AIM2, and RIG-I inflammasomes in nasopharyngeal carcinoma cells treated with specific stimuli of these interactomes (H2O2, poly (dA:dT), and EBV noncoding RNA, respectively). We identified a number of proteins that appeared to be …

Physiologically-Based Pharmacokinetic Modeling Of Acetaminophen Metabolism And Toxicity, David M. Ng, Ali Navid

STAR Program Research Presentations

Acetaminophen is a common analgesic and antipyretic. Metabolism of acetaminophen and acetaminophen-induced liver necrosis are predicted using physiologically-based pharmacokinetic (PBPK) modeling. Pharmacokinetic means the model determines where the drug is distributed in the body over time. Physiologically-based means the anatomy and physiology of the human body is reflected in the structure and functioning of the model. Acetaminophen is usually safe and effective when taken as recommended, but consumption at higher levels may lead to liver damage. Additionally, other factors such as alcoholic liver disease, smoking, and malnutrition affect the maximum safe dose of acetaminophen.