Base Pairing Promoted the Self-Organization of Genetic Coding, Catalysis, and Free-Energy Transduction
Creator:
Carter, Charles W.
Date of publication:
2024
Abstract Tesim:
How Nature discovered genetic coding is a largely ignored question, yet the answer is key to explaining the transition from biochemical building blocks to life. Other, related puzzles also fall inside the aegis enclosing the codes themselves. The peptide bond is unstable with respect to hydrolysis. So, it requires some form of chemical free energy to drive it. Amino acid activation and acyl transfer are also slow and must be catalyzed. All living things must thus also convert free energy and synchronize cellular chemistry. Most importantly, functional proteins occupy only small, isolated regions of sequence space. Nature evolved heritable symbolic data processing to seek out and use those sequences. That system has three parts: a memory of how amino acids behave in solution and inside proteins, a set of code keys to access that memory, and a scoring function. The code keys themselves are the genes for cognate pairs of tRNA and aminoacyl-tRNA synthetases, AARSs. The scoring function is the enzymatic specificity constant, kcat/kM, which measures both catalysis and specificity. The work described here deepens the evidence for and understanding of an unexpected consequence of ancestral bidirectional coding. Secondary structures occur in approximately the same places within antiparallel alignments of their gene products. However, the polar amino acids that define the molecular surface of one are reflected into core-defining non-polar side chains on the other. Proteins translated from base-paired coding strands fold up inside out. Bidirectional genes thus project an inverted structural duality into the proteome. I review how experimental data root the scoring functions responsible for the origins of coding and catalyzed activation of unfavorable chemical reactions in that duality.
Resource type:
Article
Affiliation Label Tesim:
Department of Biochemistry and Biophysics
DOI:
https://doi.org/10.17615/5dcn-1b18
Edition:
Publisher
Identifier:
https://doi.org/10.3390/life14020199
ISSN:
2075-1729
Journal Issue:
2
Journal Title:
Life
Journal Volume:
14
Keyword:
AND gating, aminoacyl-tRNA synthetase•tRNA cognate pairs, reciprocally coupled gating, protein folding, genome propagation into the proteome, ancestral gene reconstruction, origin of catalysis, origin of free-energy transduction, selection constraint surface, phylogenetics, and bidirectional genetic coding
A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment
Creator:
Beers, Jessica L., Lee, Jonghwa, Geffert, Raeanne M., and Jackson, Klarissa D.
Date of publication:
2024
Abstract Tesim:
Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies. The diverse range of experimental models and techniques has significantly contributed to the examination of potential DDIs. Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of many drugs on the market, making them frequently implicated in drug metabolism and DDIs. Consequently, there has been a growing focus on the assessment of DDI risk for CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction and an overview of the in vitro assessment of CYP-mediated DDIs.
Resource type:
Article
Affiliation Label Tesim:
Division of Pharmacotherapy and Experimental Therapeutics
DOI:
https://doi.org/10.17615/nsgk-8a60
Edition:
Publisher
Identifier:
https://doi.org/10.3390/biom14010099
ISSN:
2218-273X
Journal Issue:
1
Journal Title:
Biomolecules
Journal Volume:
14
Keyword:
cytochrome P450, drug-drug interaction, reaction phenotyping, inhibition, induction, and drug metabolism
Language Label:
English
License Label:
Attribution 4.0 International
ORCID:
Other Affiliation:
Page Start:
99
Person:
Beers, Jessica L., Lee, Jonghwa, Geffert, Raeanne M., and Jackson, Klarissa D.
We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP-/-). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP-/- mice with the PPARα agonist called fenofibrate. We found that treating CHIP-/- mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP-/- hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism.
Resource type:
Article
Affiliation Label Tesim:
UNC McAllister Heart Institute
DOI:
https://doi.org/10.17615/31w0-hj21
Edition:
Publisher
Identifier:
https://doi.org/10.3390/jcdd5030043
ISSN:
2308-3425
Journal Issue:
Journal of Cardiovascular Development and Disease
Journal Title:
5
Keyword:
Fibrosis, Autophagy, Mitophagy, Metabolism, Fibrates, Pressure overload, and Metabolomics
Language Label:
English
License Label:
Attribution 4.0 International
ORCID:
Other Affiliation:
, Indiana University School of Medicine, Duke University Medical Center, and University of Arkansas for Medical Sciences
Virological Findings and Treatment Outcomes of Cases That Developed Dolutegravir Resistance in Malawi’s National HIV Treatment Program
Creator:
van Oosterhout, Joep J., Chipungu, Chifundo, Simon, Katherine, Bisani, Pachawo, Kanise, Hope, Matola, Bilaal W., Sagno, Jean-Batiste, Songo, John, Cox, Carrie, Hosseinipour, Mina C., Heller, Tom, Steegen, Kim, Jahn, Andreas, Hoffman, Risa M., Phiri, Sam, Nyirenda, Rose, and Wallrauch, Claudia
Date of publication:
2024
Abstract Tesim:
Millions of Africans are on dolutegravir-based antiretroviral therapy (ART), but few detailed descriptions of dolutegravir resistance and its clinical management exist. We reviewed HIV drug resistance (HIVDR) testing application forms submitted between June 2019 and October 2022, data from the national HIVDR database, and genotypic test results. We obtained standardized ART outcomes and virological results of cases with dolutegravir resistance, and explored associations with dolutegravir resistance among individuals with successful integrase sequencing. All cases were on two nucleoside reverse transcriptase inhibitors (NRTIs)/dolutegravir, and had confirmed virological failure, generally with prolonged viremia. Among 89 samples with successful integrase sequencing, 24 showed dolutegravir resistance. Dolutegravir resistance-associated mutations included R263K (16/24), E138K (7/24), and G118R (6/24). In multivariable logistic regression analysis, older age and the presence of high-level NRTI resistance were significantly associated with dolutegravir resistance. After treatment modification recommendations, four individuals (17%) with dolutegravir resistance died, one self-discontinued ART, one defaulted, and one transferred out. Of the 17 remaining individuals, 12 had follow-up VL results, and 11 (92%) were <1000 copies/mL. Twenty-four cases with dolutegravir resistance among 89 individuals with confirmed virological failure suggests a considerable prevalence in the Malawi HIV program. Successful management of dolutegravir resistance was possible, but early mortality was high. More research on the management of treatment-experienced individuals with dolutegravir resistance is needed.
Resource type:
Article
Affiliation Label Tesim:
Department of Medicine
DOI:
https://doi.org/10.17615/g7dk-my47
Edition:
Publisher
Identifier:
https://doi.org/10.3390/v16010029
ISSN:
1999-4915
Journal Issue:
1
Journal Title:
Viruses
Journal Volume:
16
Keyword:
dolutegravir, antiretroviral therapy, mutations, HIV, Malawi, drug resistance, and outcomes
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Partners in Hope, Baylor College of Medicine Children’s Foundation-Malawi, The Lighthouse Trust, Ministry of Health, DREAM, Communion of St. Egidio, , National Health Laboratory Service, and University of California, Los Angeles
Page Start:
29
Person:
van Oosterhout, Joep J., Chipungu, Chifundo, Simon, Katherine, Bisani, Pachawo, Kanise, Hope, Matola, Bilaal W., Sagno, Jean-Batiste, Songo, John, Cox, Carrie, Hosseinipour, Mina C., Heller, Tom, Steegen, Kim, Jahn, Andreas, Hoffman, Risa M., Phiri, Sam, Nyirenda, Rose, and Wallrauch, Claudia
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
The Social Fabric of Watershed Management: Comparison of Citizen-Based and Agency-Based Organizations
Creator:
Cho, Sung-woo, Stedman, Richard, and Allred, Shorna B.
Date of publication:
2024
Abstract Tesim:
This research offers an exploration of the social networks within two distinct watershed groups in the Hudson River, New York State, USA: citizen-based and agency-based organizations. Through a social network analysis of their operations and interactions, this study unveils the complex dynamics and roles of individual nodes in facilitating nine types of connections, such as political and financial, within these networks. The citizen-based organization demonstrated denser and more cohesive networks, suggesting robust relationships and enhanced resilience and adaptability. In contrast, the agency-based organization exhibited more hierarchical networks. This study employs both network-level and node-level analyses to examine the social networks within watershed groups. Our network-level analysis focuses on metrics such as density, average degree, and hierarchy, while our node-level analysis examines clustering coefficients and influence. It also explores ego networks through an analysis of their density and the effective size of structural holes. Our finding is that the social networks of the two groups are quite distinct, and there is limited exchange of information and resources between them. However, we discovered that effective communication among a few well-connected individuals (e.g., those with high influence values) within each group can enhance the effectiveness and resilience of these networks. These analyses aim to provide a detailed understanding of the social dynamics within regional watershed groups.
Resource type:
Article
Affiliation Label Tesim:
Department of Geography
DOI:
https://doi.org/10.17615/a1d9-dv92
Edition:
Publisher
Identifier:
https://doi.org/10.3390/w16010111
ISSN:
2073-4441
Journal Issue:
1
Journal Title:
Water
Journal Volume:
16
Keyword:
group comparison, Hudson River in New York State, social network analysis, and watershed management
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Gachon University, Cornell University, and
Page Start:
111
Person:
Cho, Sung-woo, Stedman, Richard, and Allred, Shorna B.
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs
Creator:
Hanif, Shumaila Nida Muhammad, Durham, Phillip, Ibrahim, Mariam, Garcia-Contreras, Lucila, and Hickey, Anthony J.
Date of publication:
2023
Abstract Tesim:
CPZEN-45 is a novel compound with activity against drug-susceptible and drug-resistant tuberculosis (TB). The present study was undertaken to determine the best dose and dosing regimen of inhalable CPZEN-45 powders to use in efficacy studies with TB-infected guinea pigs. The disposition of CPZEN-45 after intravenous, subcutaneous (SC), and direct pulmonary administration (INS) was first determined to obtain their basal pharmacokinetic (PK) parameters. Then, the disposition of CPZEN-45 powders after passive inhalation using consecutive and sequential doses was evaluated. Plasma concentration versus time curves and PK parameters indicated that the absorption of CPZEN-45 after INS was faster than after SC administration (Ka = 12.94 ± 5.66 h−1 and 1.23 ± 0.55 h−1, respectively), had a longer half-life (2.06 ± 1.01 h versus 0.76 ± 0.22 h) and had higher bioavailability (67.78% and 47.73%, respectively). The plasma concentration versus time profiles and the lung tissue concentration at the end of the study period were not proportional to the dose size after one, two, and three consecutive passive inhalation doses. Three sequential passive inhalation doses maintained therapeutic concentration levels in plasma and lung tissue for a longer time than three consecutive doses (10 h vs. 3 h, respectively). Future studies to evaluate the efficacy of inhaled CPZEN-45 powders should employ sequential doses of the powder, with one nominal dose administered to animals three times per day.
Resource type:
Article
Affiliation Label Tesim:
Joint Department of Biomedical Engineering
DOI:
https://doi.org/10.17615/9jht-va23
Edition:
Publisher
Identifier:
https://doi.org/10.3390/pharmaceutics15122758
ISSN:
1999-4923
Journal Issue:
12
Journal Title:
Pharmaceutics
Journal Volume:
15
Keyword:
pharmacokinetics studies, CPZEN-45, guinea pigs, passive inhalation, insufflation, and tuberculosis
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
The University of Oklahoma Health Sciences Center, , and RTI International
Page Start:
2758
Person:
Hanif, Shumaila Nida Muhammad, Durham, Phillip, Ibrahim, Mariam, Garcia-Contreras, Lucila, and Hickey, Anthony J.
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
Programming and Reprogramming the Viscoelasticity and Magnetic Response of Magnetoactive Thermoplastic Elastomers
Creator:
Kostrov S.A., Marshall J.H., Sheiko S.S., Maw M., and Kramarenko E.Y.
Date of publication:
2023
Abstract Tesim:
We present a novel type of magnetorheological material that allows one to restructure the magnetic particles inside the finished composite, tuning in situ the viscoelasticity and magnetic response of the material in a wide range using temperature and an applied magnetic field. The polymer medium is an A-g-B bottlebrush graft copolymer with side chains of two types: polydimethylsiloxane and polystyrene. At room temperature, the brush-like architecture provides the tissue mimetic softness and strain stiffening of the elastomeric matrix, which is formed through the aggregation of polystyrene side chains into aggregates that play the role of physical cross-links. The aggregates partially dissociate and the matrix softens at elevated temperatures, allowing for the effective rearrangement of magnetic particles by applying a magnetic field in the desired direction. Magnetoactive thermoplastic elastomers (MATEs) based on A-g-B bottlebrush graft copolymers with different amounts of aggregating side chains filled with different amounts of carbonyl iron microparticles were prepared. The in situ restructuring of magnetic particles in MATEs was shown to significantly alter their viscoelasticity and magnetic response. In particular, the induced anisotropy led to an order-of-magnitude enhancement of the magnetorheological properties of the composites.
Resource type:
Article
Affiliation Label Tesim:
Department of Chemistry
DOI:
https://doi.org/10.17615/4bsa-k546
Edition:
Publisher
Identifier:
https://doi.org/10.3390/polym15234607
ISSN:
2073-4360
Journal Issue:
23
Journal Title:
Polymers
Journal Volume:
15
Keyword:
magnetorheological effect, molecular bottlebrushes, and magnetoactive elastomer
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Lomonosov Moscow State University and
Person:
Kostrov S.A., Marshall J.H., Sheiko S.S., Maw M., and Kramarenko E.Y.
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
Polymer Modeling Reveals Interplay between Physical Properties of Chromosomal DNA and the Size and Distribution of Condensin-Based Chromatin Loops
Creator:
Forest, M. Gregory, Stanton, John Donoghue, Kolbin, Daniel, Walker, Benjamin L., Adalsteinsson, David, Hult, Caitlin, and Bloom, Kerry
Date of publication:
2023
Abstract Tesim:
Transient DNA loops occur throughout the genome due to thermal fluctuations of DNA and the function of SMC complex proteins such as condensin and cohesin. Transient crosslinking within and between chromosomes and loop extrusion by SMCs have profound effects on high-order chromatin organization and exhibit specificity in cell type, cell cycle stage, and cellular environment. SMC complexes anchor one end to DNA with the other extending some distance and retracting to form a loop. How cells regulate loop sizes and how loops distribute along chromatin are emerging questions. To understand loop size regulation, we employed bead–spring polymer chain models of chromatin and the activity of an SMC complex on chromatin. Our study shows that (1) the stiffness of the chromatin polymer chain, (2) the tensile stiffness of chromatin crosslinking complexes such as condensin, and (3) the strength of the internal or external tethering of chromatin chains cooperatively dictate the loop size distribution and compaction volume of induced chromatin domains. When strong DNA tethers are invoked, loop size distributions are tuned by condensin stiffness. When DNA tethers are released, loop size distributions are tuned by chromatin stiffness. In this three-way interaction, the presence and strength of tethering unexpectedly dictates chromatin conformation within a topological domain.
Resource type:
Article
Affiliation Label Tesim:
Department of Mathematics and Department of Biology
DOI:
https://doi.org/10.17615/x8bf-ph09
Edition:
Publisher
Identifier:
https://doi.org/10.3390/genes14122193
ISSN:
2073-4425
Journal Issue:
12
Journal Title:
Genes
Journal Volume:
14
Keyword:
DNA loops, polymer modeling, crosslinkers, SMC complexes, nuclear tethers, chromatin organization, and loop regulation
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
, University of California-Irvine, and Gettysburg College
Page Start:
2193
Person:
Forest, M. Gregory, Stanton, John Donoghue, Kolbin, Daniel, Walker, Benjamin L., Adalsteinsson, David, Hult, Caitlin, and Bloom, Kerry
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
Methodological Considerations in Longitudinal Analyses of Microbiome Data: A Comprehensive Review
Creator:
Lyu, Ruiqi, Qu, Yixiang, Divaris, Kimon, and Wu, Di
Date of publication:
2024
Abstract Tesim:
Biological processes underlying health and disease are inherently dynamic and are best understood when characterized in a time-informed manner. In this comprehensive review, we discuss challenges inherent in time-series microbiome data analyses and compare available approaches and methods to overcome them. Appropriate handling of longitudinal microbiome data can shed light on important roles, functions, patterns, and potential interactions between large numbers of microbial taxa or genes in the context of health, disease, or interventions. We present a comprehensive review and comparison of existing microbiome time-series analysis methods, for both preprocessing and downstream analyses, including differential analysis, clustering, network inference, and trait classification. We posit that the careful selection and appropriate utilization of computational tools for longitudinal microbiome analyses can help advance our understanding of the dynamic host–microbiome relationships that underlie health-maintaining homeostases, progressions to disease-promoting dysbioses, as well as phases of physiologic development like those encountered in childhood.
Resource type:
Article
Affiliation Label Tesim:
Department of Biostatistics, Department of Epidemiology, and School of Dentistry
DOI:
https://doi.org/10.17615/98qd-wj88
Edition:
Publisher
Identifier:
https://doi.org/10.3390/genes15010051
ISSN:
2073-4425
Journal Issue:
1
Journal Title:
Genes
Journal Volume:
15
Keyword:
microbiome data, longitudinal analysis, review, statistical methods, and deep learning
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Carnegie Mellon University and
Page Start:
51
Person:
Lyu, Ruiqi, Qu, Yixiang, Divaris, Kimon, and Wu, Di
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)
Mechanistic Insights into Peptide Binding and Deactivation of an Adhesion G Protein-Coupled Receptor
Creator:
Miao, Yinglong and Adediwura, Victor A.
Date of publication:
2024
Abstract Tesim:
Adhesion G protein-coupled receptors (ADGRGs) play critical roles in the reproductive, neurological, cardiovascular, and endocrine systems. In particular, ADGRG2 plays a significant role in Ewing sarcoma cell proliferation, parathyroid cell function, and male fertility. In 2022, a cryo-EM structure was reported for the active ADGRG2 bound by an optimized peptide agonist IP15 and the Gs protein. The IP15 peptide agonist was also modified to antagonists 4PH-E and 4PH-D with mutations of the 4PH residue to Glu and Asp, respectively. However, experimental structures of inactive antagonist-bound ADGRs remain to be resolved, and the activation mechanism of ADGRs such as ADGRG2 is poorly understood. Here, we applied Gaussian accelerated molecular dynamics (GaMD) simulations to probe conformational dynamics of the agonist- and antagonist-bound ADGRG2. By performing GaMD simulations, we were able to identify important low-energy conformations of ADGRG2 in the active, intermediate, and inactive states, as well as explore the binding conformations of each peptide. Moreover, our simulations revealed critical peptide-receptor residue interactions during the deactivation of ADGRG2. In conclusion, through GaMD simulations, we uncovered mechanistic insights into peptide (agonist and antagonist) binding and deactivation of the ADGRG2. These findings will potentially facilitate rational design of new peptide modulators of ADGRG2 and other ADGRs.
Resource type:
Article
Affiliation Label Tesim:
Department of Pharmacology
DOI:
https://doi.org/10.17615/ra0x-tr71
Edition:
Publisher
Identifier:
https://doi.org/10.3390/molecules29010164
ISSN:
1420-3049
Journal Issue:
1
Journal Title:
Molecules
Journal Volume:
29
Keyword:
peptides, deactivation, Gaussian accelerated molecular dynamics (GaMD), adhesion G protein-coupled receptors, and drug design
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Page Start:
164
Person:
Miao, Yinglong and Adediwura, Victor A.
Publisher:
Multidisciplinary Digital Publishing Institute (MDPI)