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3,349 results on '"K Nomura"'

1. X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction

Author

Peixiang Zhang, Joseph J. Munier, Carrie B. Wiese, Laurent Vergnes, Jenny C. Link, Fahim Abbasi, Emilio Ronquillo, Katherine Scheker, Antonio Muñoz, Yu-Lin Kuang, Elizabeth Theusch, Meng Lu, Gabriela Sanchez, Akinyemi Oni-Orisan, Carlos Iribarren, Michael J. McPhaul, Daniel K. Nomura, Joshua W. Knowles, Ronald M. Krauss, Marisa W. Medina, and Karen Reue

Subjects
Science
Abstract

Abstract Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Published
2024
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2. Collectivity at the prolate-oblate transition: The 21+ lifetime of 190W

Author

E. Şahin, V. Werner, A.K. Mistry, M. Rudigier, K. Nomura, J. Jolie, N. Pietralla, P.H. Regan, G. Ağgez, H.M. Albers, U. Ahmed, Ö. Aktaş, A. Algora, S. Alhomaidhi, C. Appleton, T. Arıcı, M. Armstrong, A. Banerjee, J. Benito, G. Benzoni, A. Blazhev, P. Boutachkov, A.M. Bruce, B. Cederwall, M.M.R. Chishti, M.L. Cortés, F. Crespi, B. Das, T. Davinson, T. Dickel, M. Doncel, A. Ertoprak, A. Esmaylzadeh, L.M. Fraile, E.R. Gamba, J. Gerl, M. Górska, J. Ha, E. Haettner, O. Hall, H. Heggen, C. Hornung, N. Hubbard, S. Jazrawi, P.R. John, C.E. Jones, V. Karayonchev, E. Kazantseva, R. Kern, L. Knafla, I. Kojouharov, P. Koseoglou, G. Kosir, D. Kostyleva, N. Kurz, N. Kuzminchuk, M. Llanos-Expósito, R. Lozeva, D. Mengoni, T.J. Mertzimekis, M. Mikolajczuk, A.I. Morales, I. Mukha, J.R. Murias, B.S. Nara-Singh, S.E.A. Orrigo, J. Pellumaj, S. Pelonis, S. Pietri, S. Pigliapoco, Zs. Podolyák, M. Polettini, K. Rezynkina, H.A. Rösch, H. Schaffner, Ch. Scheidenberger, L. Sexton, P.-A. Söderström, Y.K. Tanaka, J.J. Valiente-Dobón, P. Vasileiou, J. Vasiljević, J. Vesic, H. Weick, J. Wiederhold, A. Yaneva, G. Zhang, J. Zhao, and A. Zyriliou

Subjects
Nuclear structure, γ-ray spectroscopy, Isomer spectroscopy, Shape phase transition, DESPEC, NUSTAR, Physics, QC1-999
Abstract

The neutron-rich rare isotope 190W is discussed as a candidate for a prolate-oblate transitional nucleus with maximum γ-softness. The collectivity of this isotope is assessed for the first time by the measurement of the reduced E2 transition probability of its first 2+ state to the ground state. The experiment employed the FAst TIming Array (FATIMA), comprised of 36 LaBr3(Ce) scintillators, which was part of the DESPEC setup at GSI, Darmstadt. The 41+ and 21+ states of 190W were populated subsequently to the decay of its 127(12) μs isomeric Jπ=10− state. The mean lifetime of the 21+ state was determined to be τ=274(28) ps, which corresponds to a B(E2;21+→01+) value of 95(10) W.u. The results motivated a revision of previous calculations within an energy-density functional-based interacting boson model-2 approach, yielding E2 transition properties and spectroscopic quadrupole moments for tungsten isotopes. From comparison to theory, the new data suggest that 190W is at the transition from prolate to oblate structure along the W isotopic chain, which had previously been discussed as a nuclear shape-phase transition.

Published
2024
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4. Neutron scattering and neural-network quantum molecular dynamics investigation of the vibrations of ammonia along the solid-to-liquid transition

Author

T. M. Linker, A. Krishnamoorthy, L. L. Daemen, A. J. Ramirez-Cuesta, K. Nomura, A. Nakano, Y. Q. Cheng, W. R. Hicks, A. I. Kolesnikov, and P. D. Vashishta

Subjects
Science
Abstract

Abstract Vibrational spectroscopy allows us to understand complex physical and chemical interactions of molecular crystals and liquids such as ammonia, which has recently emerged as a strong hydrogen fuel candidate to support a sustainable society. We report inelastic neutron scattering measurement of vibrational properties of ammonia along the solid-to-liquid phase transition with high enough resolution for direct comparisons to ab-initio simulations. Theoretical analysis reveals the essential role of nuclear quantum effects (NQEs) for correctly describing the intermolecular spectrum as well as high energy intramolecular N-H stretching modes. This is achieved by training neural network models using ab-initio path-integral molecular dynamics (PIMD) simulations, thereby encompassing large spatiotemporal trajectories required to resolve low energy dynamics while retaining NQEs. Our results not only establish the role of NQEs in ammonia but also provide general computational frameworks to study complex molecular systems with NQEs.

Published
2024
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5. MITOCHONDRIAL FRAGMENTATION IS A NEW THERAPEUTIC TARGET AND DIAGNOSTIC CRITERIA FOR MYELODYSPLASTIC SYNDROMES.

Author

Y. Kamimura-Aoyagi, Y. Harada, K. Nomura, N. Matsunuma, K. Yuki, H. Kobayashi, Y. Hayashi, A. Hijikata, and H. Harada

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: Myelodysplastic syndromes (MDS) are characterized by persistent of cytopenia, gene abnormalities, and dysplasia. Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear. Methods: Recently, we established a new MDS with low blasts (MDS-LB) model (CBLΔE8/9-RUNX1S291fs mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) . Results: MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P

Published
2024
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6. N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics

Author

Tin-Yan Koo, Hinyuk Lai, Daniel K. Nomura, and Clive Yik-Sham Chung

Subjects
Science
Abstract

Abstract Cysteine has been exploited as the binding site of covalent drugs. Its high sensitivity to oxidation is also important for regulating cellular processes. To identify new ligandable cysteines which can be hotspots for therapy and to better study cysteine oxidations, we develop cysteine-reactive probes, N-acryloylindole-alkynes (NAIAs), which have superior cysteine reactivity owing to delocalization of π electrons of the acrylamide warhead over the whole indole scaffold. This allows NAIAs to probe functional cysteines more effectively than conventional iodoacetamide-alkyne, and to image oxidized thiols by confocal fluorescence microscopy. In mass spectrometry experiments, NAIAs successfully capture new oxidized cysteines, as well as a new pool of ligandable cysteines and proteins. Competitive activity-based protein profiling experiments further demonstrate the ability of NAIA to discover lead compounds targeting these cysteines and proteins. We show the development of NAIAs with activated acrylamide for advancing proteome-wide profiling and imaging ligandable cysteines and oxidized thiols.

Published
2023
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7. Diurnal decline in the photosynthetic capacity of uppermost leaves in an eggplant canopy grown in a horticultural greenhouse

Author

K. NOMURA, M. SAITO, M. ITO, S. YAMANE, T. IWAO, I. TADA, T. YAMAZAKI, S. ONO, D. YASUTAKE, and M. KITANO

Subjects
co2-photosynthesis curve, diurnal variation, farquhar-von caemmerer-berry photosynthesis model, horticultural crop, photosynthesis limitation, triose phosphate utilization, Botany, QK1-989
Abstract

Parameters representing leaf photosynthetic capacity, namely, the maximal carboxylation rate (Vcmax), maximal electron transport rate (Jmax), and triose phosphate-utilization rate (Tp), can vary depending on various factors. The present study investigated diurnal variations in Vcmax, Jmax, and Tp of uppermost leaves of soil-grown, well-watered eggplant in a greenhouse based on the simultaneous measurements of leaf gas exchange and chlorophyll fluorescence. The values of net photosynthetic rates and electron transport rates plotted against intercellular CO2 concentrations were noticeably higher in the morning than in the afternoon. Significant differences were detected among the values of Vcmax, Jmax, and Tp obtained at different times of day (08:30, 11:00, 13:30, and 16:00 h). All three parameters tended to decline as the time of day advanced; compared to the values at 08:30 h, Vcmax, Jmax, and Tp declined by approximately 15% at 16:00 h. Among the three parameters, Tp appeared to be the most sensitive to time.

Published
2022
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8. Psychometric Properties of the Parent Versions of the Japanese Versions of the Strength and Difficulties Questionnaire: A study on Health Checkups for 5-Year-Old Children in Japan

Author

K. Yokoyama and K. Nomura

Subjects
Psychiatry, RC435-571
Abstract

Introduction In Japan, the effectiveness of health checkups for children aged 5 years has attracted attention as the basis for a support system for early detection and support of children with developmental disabilities. However, these have not yet become statutory health checkups, and their assessment has not been standardized. This study employed the Strength and Difficulties Questionnaire (SDQ) in examining the health of a 5-year-old child. This study aims to demonstrate the scores’ distribution and obtain the standard land and cutoff values of the SDQ. Objectives From 2010 to 2012, children reaching 5 years of age in Kanie-cho, Aichi Prefecture, Japan, underwent a health checkup. Of the 888 children for whom parental consent was obtained, 884 responses without missing values (453 boys: 51.2%, 430 girls: 48.6%) were included in the analysis. Methods SDQ and medical questionnaires for 5-year-old children were sent to the parents with a formal request for approval for the child to participate in the study. Further, the parents were asked to respond to the questionnaire. The Ethics Committee of the Graduate School of Education and Developmental Sciences, Nagoya University approved this study (No.298). Results A confirmatory factor analysis using the maximum likelihood method revealed a factor structure almost identical to that of Goodman (JCPP 1997; 38 581-586). Nonetheless, items 3, 10, 11, 13, 14, and 22 showed high loadings on factors different from those in the original version. Similar to the original version, we set our criteria so that Some and High Needs would be approximately 10% each. Furthermore, we calculated the percentage of children who fell into these categories and found that the scores that fell into the Need category differed from those in the previous study(Table 1). Image: Conclusions Although the five-factor structure of the SDQ was generally accepted, as pointed out in previous studies (Matsuishi et al. Brain Dev 2008;30 410-415 : Iida et al. 2014; 33-41), differences in expression between English and Japanese and cultural differences may have influenced the results. Therefore, it is necessary to be careful in interpreting the results. Additionally, the differences in the Need classification indicated that the difficulty level tends to be slightly lower in the 5-year-old children’s health checkups and that boys may be more likely to recognize the “Hyperactivity/inattention” problem. Based on these results, it is necessary to consider more effective ways of using the SDQ in 5-year-old children’s health checkups, such as evaluating the SDQ scores in combination with the actual condition of the children at the time of the checkup. Disclosure of Interest None Declared

Published
2023
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9. Follow-up Study Tracking Children’s Development from Preschool till Middle School

Author

K. Nomura and K. Yokoyama

Subjects
Psychiatry, RC435-571
Abstract

Introduction Screening for early detection of health issues and support are provided to children needing developmental support. In Japan, a significant percentage of infants requiring support are identified during health checkups. Sometimes, however, problems are first observed when children are of school age. It is, therefore, important to identify the age at which children need early support. Objectives Of the children born in 2005 in Kanie-cho, in Japan, 106 participated in the survey at all time points: age 5, first grade, fifth grade, and eighth grade. Methods The medical checkup results of the participants at age 5 were used to determine who among them needed support After entering school, the participants who scored less than 70 points on the Children’s Global Assessment Scale, where their adjustment was assessed based on the interview with the homeroom teacher, were considered maladjusted. Results The results are presented in Table 1. Thirty participants needed supports at age 5; of these, 20 (66.7%) were maladjusted at any point in their school years—19 (95%) in the first grade, 14 (70%) till the fifth grade, and five (25%) till the eighth grade. Of the 76 participants who did not need support in early childhood, 24 (31.6%) were maladjusted at some point in their school years—nine (37.5%) experienced maladjustment in the first grade, but none of them continued to be maladjusted till the fifth grade, and 14 (58.3%) who were not maladjusted in the first grade experienced it in the fifth or eighth grade (adolescents). Thus, the participants maladjusted in their school years were categorized as follows: 1. The developmental disorders group (experiencing maladjustment throughout since early childhood): 19 2. The “first grade problem” group (experiencing transient problems only in the first grade): 9 3. The adolescent group (experiencing problems during adolescence): 14 Image: Conclusions Since maladjusted children with developmental disabilities are identified in early childhood, support can be provided before they reach school age. Many children with developmental disabilities improve their adjustment as they grow up. It is thus advisable to take a long-term perspective in dealing with problematic behaviors. From late school age to adolescence, problems unrelated to developmental disabilities emerge. By listening to the child’s upbringing, it may be possible to ascertain whether or not the problem stems from a developmental disability. Disclosure of Interest None Declared

Published
2023
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10. Correction to 'Rational Chemical Design of Molecular Glue Degraders'

Author

Ethan S. Toriki, James W. Papatzimas, Kaila Nishikawa, Dustin Dovala, Andreas O. Frank, Matthew J. Hesse, Daniela Dankova, Jae-Geun Song, Megan Bruce-Smythe, Heidi Struble, Francisco J. Garcia, Scott M. Brittain, Andrew C. Kile, Lynn M. McGregor, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, and Daniel K. Nomura

Subjects
Chemistry, QD1-999
Published
2023
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11. Ab initio study on the possible magnetic topological semimetallic state in MnMg2O4

Author

S. Tomita, D.-P. Yao, H. Tsuchiura, and K. Nomura

Subjects
Physics, QC1-999
Abstract

We study the electronic state of an inverse spinel compound MnMg2O4 based on first-principles calculations. The high-spin state is realized in Mn ions on the diamond lattice, resulting in that this material is found to be a half-metallic semimetal with the minority spin-gap about 3eV, and also with line nodes in the Brillouin zone. The intrinsic anomalous Hall conductivity (AHC) is also computed as a function of the chemical potential of the system assuming the rigid band structure, and is found to exhibit a peak structure with a maximum value of 200 S/cm at only 15 meV above the Fermi level. The relation between the large AHC and Berry curvature in the Brillouin zone is also discussed.

Published
2022
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12. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones

Author

Candice B. Herber, William C. Krause, Liping Wang, James R. Bayrer, Alfred Li, Matthew Schmitz, Aaron Fields, Breanna Ford, Zhi Zhang, Michelle S. Reid, Daniel K. Nomura, Robert A. Nissenson, Stephanie M. Correa, and Holly A. Ingraham

Subjects
Science
Abstract

Estrogen promotes negative energy balance and preserves skeletal physiology. Here the authors show that loss of estrogen signalling after ablating estrogen receptor alpha (ERa) in specific hypothalamic neuronal populations leads to a marked sex-dependent increase in bone mass in female mice.

Published
2019
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13. Artificial Intelligence in Quantitative Chest Imaging Analysis for Occupational Lung Disease

Author

Narufumi Suganuma, Shinichi Yoshida, Yuma Takeuchi, Yoshua K. Nomura, and Kazuhiro Suzuki

Subjects
Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Abstract

Occupational lung disease manifests complex radiologic findings which have long been a challenge for computer-assisted diagnosis (CAD). This journey started in the 1970s when texture analysis was developed and applied to diffuse lung disease. Pneumoconiosis appears on radiography as a combination of small opacities, large opacities, and pleural shadows. The International Labor Organization International Classification of Radiograph of Pneumoconioses has been the main tool used to describe pneumoconioses and is an ideal system that can be adapted for CAD using artificial intelligence (AI). AI includes machine learning which utilizes deep learning or an artificial neural network. This in turn includes a convolutional neural network. The tasks of CAD are systematically described as classification, detection, and segmentation of the target lesions. Alex-net, VGG16, and U-Net are among the most common algorithms used in the development of systems for the diagnosis of diffuse lung disease, including occupational lung disease. We describe the long journey in the pursuit of CAD of pneumoconioses including our recent proposal of a new expert system.

Published
2023
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14. Rational Chemical Design of Molecular Glue Degraders

Author

Ethan S. Toriki, James W. Papatzimas, Kaila Nishikawa, Dustin Dovala, Andreas O. Frank, Matthew J. Hesse, Daniela Dankova, Jae-Geun Song, Megan Bruce-Smythe, Heidi Struble, Francisco J. Garcia, Scott M. Brittain, Andrew C. Kile, Lynn M. McGregor, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, and Daniel K. Nomura

Subjects
General Chemical Engineering, General Chemistry
Published
2023
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15. 4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor

Author

Ofer Moldavski, Peter-James H. Zushin, Charles A. Berdan, Robert J. Van Eijkeren, Xuntian Jiang, Mingxing Qian, Daniel S. Ory, Douglas F. Covey, Daniel K. Nomura, Andreas Stahl, Ethan J. Weiss, and Roberto Zoncu

Subjects
oxysterol, SREBP1c, liver-X-Receptor, de-novo-lipogenesis, lipid droplets, insulin, Biochemistry, QD415-436
Abstract

Oxysterols are oxidized derivatives of cholesterol that play regulatory roles in lipid biosynthesis and homeostasis. How oxysterol signaling coordinates different lipid classes such as sterols and triglycerides remains incompletely understood. Here, we show that 4β-hydroxycholesterol (HC) (4β-HC), a liver and serum abundant oxysterol of poorly defined functions, is a potent and selective inducer of the master lipogenic transcription factor, SREBP1c, but not the related steroidogenic transcription factor SREBP2. By correlating tracing of lipid synthesis with lipogenic gene expression profiling, we found that 4β-HC acts as a putative agonist for the liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of the LXR, 4β-HC induced expression of the lipogenic program downstream of SREBP1c and triggered de novo lipogenesis both in primary hepatocytes and in the mouse liver. In addition, 4β-HC acted in parallel to insulin-PI3K–dependent signaling to stimulate triglyceride synthesis and lipid-droplet accumulation. Thus, 4β-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.

Published
2021
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17. A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication

Author

Hesong Han, Albert Vallejo Gracia, Joachim J. Røise, Lydia Boike, Kristoffer Leon, Ursula Schulze-Gahmen, Michael R. Stentzel, Teena Bajaj, Dake Chen, I.-Che Li, Maomao He, Kamyar Behrouzi, Zahra Khodabakhshi, Daniel K. Nomura, Mohammad R. K. Mofrad, G. Renuka Kumar, Melanie Ott, and Niren Murthy

Subjects
Vaccine Related, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Biodefense, Prevention, General Chemical Engineering, Chemical Sciences, General Chemistry, Development of treatments and therapeutic interventions, Lung
Abstract

Covalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 have great potential as antivirals, but their non-specific reactivity with thiols has limited their development. In this report, we performed an 8000 molecule electrophile screen against PLpro and identified an α-chloro amide fragment, termed compound 1, which inhibited SARS-CoV-2 replication in cells, and also had low non-specific reactivity with thiols. Compound 1 covalently reacts with the active site cysteine of PLpro, and had an IC50 of 18 μM for PLpro inhibition. Compound 1 also had low non-specific reactivity with thiols and reacted with glutathione 1-2 orders of magnitude slower than other commonly used electrophilic warheads. Finally, compound 1 had low toxicity in cells and mice and has a molecular weight of only 247 daltons and consequently has great potential for further optimization. Collectively, these results demonstrate that compound 1 is a promising lead fragment for future PLpro drug discovery campaigns.

Published
2023
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18. Prompt Response Function (PRF) of Lifetime Measurement in the 2+ State of 192Os Nuclei Energy Levels from Triple-Gamma Coincidence Techniques

Author

Terver Daniel, Stanimir Kisyov, Patrick Regan, Nicu Marginean, Zsolt Podolyak, R. Marginean, K. Nomura, M. Rudigier, R. Mihai, V. Werner, R. J. Carroll, Laila Gurgi, A. Oprea, Tom Berry, A. Serban, C. R. Nita, C. Sotty, R. Suvaila, A. Turturica, C. Costache, L. Stan, A. Olacel, M. Boromiza, S. Toma, S. J. Gemanam, F. Gbaorun, I. Ochala, and E. C. Hemba

Subjects
Prompt response, Full width at half maximum, Lifetime, Scintillators, Physics, QC1-999
Abstract

The effective prompt response function full width at half maximum, PRF FWHM of 637 ps (obtained from the prompt gamma pairs of 477 keV and 700 keV associated with the yrast 2+ state in 206Po), and 1007 ps (obtained from the Compton gamma pairs of 189 keV and 237 keV associated with the 192Os(18O,16O)194Os 2 neutron transfer reaction) were used in fitting the time difference spectra obtained from the gamma coincident pairs of 206 keV and 374 keV in a symmetrised LaBr3(Ce) associated with the gamma transitions in 192Os, using the Half-life program. The values of half-life measured by fitting these PRF FWHM of 637 ps and 1007 ps separately show an excellent agreement of 282(16) ps and 272(21) ps, respectively, which correspond to the global half-life value of 282(4) ps for the 192Os. The mean value of 277(12) ps from these two measurements was used in calculating the B(E2; IL ->IL-2) of 4233(114) e2fm4, which is equivalent to be 81(19) W.u.

Published
2020
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19. Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry

Author

Jitendra PS. Sawhney, Veerappa A. Kothiwale, Vikas Bisne, Rajashekhar Durgaprasad, Praveen Jadhav, Manoj Chopda, Velam Vanajakshamma, Ramdhan Meena, Govindan Vijayaraghavan, Kamaldeep Chawla, Jagan Allu, Karen S. Pieper, A. John Camm, Ajay K. Kakkar, Jean-Pierre Bassand, David A. Fitzmaurice, Samuel Z. Goldhaber, Shinya Goto, Sylvia Haas, Werner Hacke, Lorenzo G. Mantovani, Frank Misselwitz, Alexander G.G. Turpie, Martin van Eickels, Freek W.A. Verheugt, Gloria Kayani, Keith A.A. Fox, Bernard J. Gersh, Hector Lucas Luciardi, Harry Gibbs, Marianne Brodmann, Frank Cools, Antonio Carlos Pereira Barretto, Stuart J. Connolly, Alex Spyropoulos, John Eikelboom, Ramon Corbalan, Dayi Hu, Petr Jansky, Jørn Dalsgaard Nielsen, Hany Ragy, Pekka Raatikainen, Jean-Yves Le Heuzey, Harald Darius, Matyas Keltai, Sanjay Kakkar, Jitendra Pal Singh Sawhney, Giancarlo Agnelli, Giuseppe Ambrosio, Yukihiro Koretsune, Carlos Jerjes Sánchez Díaz, Hugo Ten Cate, Dan Atar, Janina Stepinska, Elizaveta Panchenko, Toon Wei Lim, Barry Jacobson, Seil Oh, Xavier Viñolas, Marten Rosenqvist, Jan Steffel, Pantep Angchaisuksiri, Ali Oto, Alex Parkhomenko, Wael Al Mahmeed, David Fitzmaurice, D.Y. Hu, K.N. Chen, Y.S. Zhao, H.Q. Zhang, J.Z. Chen, S.P. Cao, D.W. Wang, Y.J. Yang, W.H. Li, Y.H. Yin, G.Z. Tao, P. Yang, Y.M. Chen, S.H. He, Ying Wang, Yong Wang, G.S. Fu, X. Li, T.G. Wu, X.S. Cheng, X.W. Yan, R.P. Zhao, M.S. Chen, L.G. Xiong, P. Chen, Y. Jiao, Y. Guo, L. Xue, F.Z. Wang, H. Li, Z.M. Yang, C.L. Bai, J. Chen, J.Y. Chen, X. Chen, S. Feng, Q.H. Fu, X.J. Gao, W.N. Guo, R.H. He, X.A. He, X.S. Hu, X.F. Huang, B. Li, J. Li, L. Li, Y.H. Li, T.T. Liu, W.L. Liu, Y.Y. Liu, Z.C. Lu, X.L. Luo, T.Y. Ma, J.Q. Peng, X. Sheng, X.J. Shi, Y.H. Sun, G. Tian, K. Wang, L. Wang, R.N. Wu, Q. Xie, R.Y. Xu, J.S. Yang, L.L. Yang, Q. Yang, Y. Ye, H.Y. Yu, J.H. Yu, T. Yu, H. Zhai, Q. Zhan, G.S. Zhang, Q. Zhang, R. Zhang, Y. Zhang, W.Y. Zheng, B. Zhou, Z.H. Zhou, X.Y. Zhu, S. Kakkar, J.P.S. Sawhney, P. Jadhav, R. Durgaprasad, A.G. Ravi Shankar, R.K. Rajput, K. Bhargava, R. Sarma, A. Srinivas, D. Roy, U.M. Nagamalesh, M. Chopda, R. Kishore, G. Kulkarni, P. Chandwani, R.A. Pothiwala, M. Padinhare Purayil, S. Shah, K. Chawla, V.A. Kothiwale, B. Raghuraman, G. Vijayaraghavan, V.M. Vijan, G. Bantwal, V. Bisne, A. Khan, J.B. Gupta, S. Kumar, D. Jain, S. Abraham, D. Adak, A. Barai, H. Begum, P. Bhattacharjee, M. Dargude, D. Davies, B. Deshpande, P. Dhakrao, V. Dhyani, S. Duhan, M. Earath, A. Ganatra, S. Giradkar, V. Jain, R. Karthikeyan, L. Kasala, S. Kaur, S. Krishnappa, A. Lawande, B. Lokesh, N. Madarkar, R. Meena, P. More, D. 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Grässjö, S. Hahn, P. Jaensson, B. Jansson, J.-H. Jansson, R.-M. Kangert, A. Koch, D. Kusiak, A. Lettenström, A. Lindberg, C.-J. Lindholm, A. Mannermyr, K. Mansson, M. Millborg, C. Nilsson, A.-M. Ohlin, A. Olofsson, A. Osberg, A. Pedersen, K. Risbecker, K. Rosenberg, J. Samuelsson, M. Shayesteh, K. Skoglund, M. Stjernberg, C. Thorsen, J. Steffel, J.H. Beer, J. Debrunner, D. Amstutz, J. Bruegger, G. Elise, A. Grau, A. Guinand, I. Henriette, E. Saga, S. Winnik, A. Parkhomenko, I. Rudyk, V. Tseluyko, O. Karpenko, S. Zhurba, I. Kraiz, I. Kupnovytska, N. Serediuk, Y. Mostovoy, O. Ushakov, O. Koval, I. Kovalskyi, Y. Svyshchenko, O. Sychov, M. Stanislavchuk, O. Kraydashenko, A. Yagensky, S. Tykhonova, I. Fushtey, R. Belegai, G. Berko, L. Burdeuna, O. Chabanna, I. Daniuk, A. Ivanov, E. Kamenska, P. Kaplan, O. Khyzhnyak, S. Kizim, O. Matova, O. Medentseva, V. Mochonyi, M. Mospan, V. Nemtsova, T. Ovdiienko, O. Palamarchuk, M. Pavelko, R. Petrovskyy, D. Plevak, O. Proshak, S. Pyvovar, L. Rasputina, O. Romanenko, O. Romanova, A. Sapatyi, O. Shumakov, R. Stets, L. Todoriuk, V. Varenov, D. Fitzmaurice, N. Chauhan, D. Goodwin, P. Saunders, R. Evans, J. Leese, P.S. Jhittay, A. Ross, M.S. Kainth, G. Pickavance, J. McDonnell, A. Williams, T. Gooding, H. Wagner, S. Suryani, A. Singal, S. Sircar, R. Bilas, P. Hutchinson, A. Wakeman, M. Stokes, N. Paul, M. Aziz, C. Ramesh, P. Wilson, S. Franklin, S. Fairhead, J. Thompson, V. St Joseph, G. Taylor, D. Tragen, D. Seamark, C. Paul, M. Richardson, A. Jefferies, H. Sharp, H. Jones, C. Giles, M. Page, O. Oginni, J. Aldegather, S. Wetherwell, W. Lumb, P. Evans, F. Scouller, N. Macey, Y. Stipp, R. West, S. Thurston, P. Wadeson, J. Matthews, P. Pandya, A. Gallagher, T. Railton, B. Sinha, D. Russell, J.A. Davies, P. Ainsworth, C.P. Jones, P. Weeks, J. Eden, D. Kernick, W. Murdoch, L. Lumley, R.P. Patel, S.W. Wong, M. Saigol, K. Ladha, K. Douglas, D.F. Cumberlidge, C. Bradshaw, G. Van Zon, K.P. Jones, M.J. Thomas, E. Watson, B. Sarai, N. Ahmad, W. Willcock, J. Cairns, S. Sathananthan, N. de Kare-Silver, A. Gilliland, E. Strieder, A. Howitt, B. Vishwanathan, N. Bird, D. Gray, M. Clark, J. Bisatt, J. Litchfield, E. Fisher, T. Fooks, A.R. Kelsall, E. Alborough, J. Wakeling, M. Parfitt, K. Milne, S. Rogers, R. Priyadharshan, J.L. Oliver, E. Davies, S. Abushal, M. Jacobs, C. Hutton, N.I. Walls, R. Thompson, C. Chigbo, S.M.A. Zaidi, M. Howard, K.C. Butter, S. Barrow, H. Little, I.U. Haq, L. Gibbons, S. Glencross, A.J. McLeod, K. Poland, C. Mulholland, A. Warke, P. Conn, G. Burns, R.N. Smith, S. Lowe, R. Kamath, H.S. Dau, J. Webster, I. Hodgins, S. Vercoe, P.C. Roome, H. Pinnock, J.R.A. Patel, A. Ali, N. Hart, R. Davies, E. Stuart, C.A. Neden, M. Danielsen, R. Heath, P. Sharma, S. Galloway, C. Hawkins, R. Oliver, M. Aylward, S. Mannion, M. Braddick, D. Edwards, A.C. Rothwell, A. Sabir, F. Choudhary, S. Khalaque, A. Wilson, S. Peters, W. Coulson, N. Roberts, A. Heer, S. Coates, B. Ward, D. Jackson, S. Walton, D. Shepherd, M. Sterry, T. Wong, M. Boon, R. Bunney, R. Haria-Shah, R.T. Baron, S. Davies, T. Schatzberger, N. Hargreaves, T. Stephenson, H. Choi, R. Batson, L. Lucraft, T. Myhill, S. Estifano, D. Geatch, J. Wilkinson, R. Veale, K. Forshaw, T. Davies, K. Zaman, P. Vinson, C. Liley, M. Bandrapalli, P. McGinty, R. Wastling, P. McEleny, A. Beattie, P. Cooke, M. Wong, J. Gunasegaram, M. Pugsley, S. Ahmad, C. A'Court, J. Ayers, J. Bennett, S. Cartwright, S. Dobson, C. Dooldeniya, A. Flynn, R. Fox, J. Goram, A. Halpin, A. Hay, P. Jacobs, L. Jeffers, L. Lomax, I. Munro, R. Muvva, M. Nadaph, K. Powell, S. Randfield, D. Redpath, R. Reed, M. Rickenbach, G. Rogers, P.B. Saunders, C. Seamark, J. Shewring, P. Simmons, H. Simper, H. Stoddart, A. Sword, N. Thomas, A. Thomson, H. Gibbs, A. Blenkhorn, B. Singh, W. Van Gaal, W. Abhayaratna, R. Lehman, P. Roberts-Thomson, J. Kilian, D. Coulshed, A. Catanchin, D. Colquhoun, H. Kiat, D. Eccleston, J. French, L. Zimmett, B. Ayres, T. Phan, P. Blombery, D. Crimmins, D. O'Donnell, A. Choi, P. Astridge, M. Arstall, N. Jepson, M. Binnekamp, A. Lee, J. Rogers, G. Starmer, P. Carroll, J. Faunt, A. Aggarwala, L. Barry, C. Batta, R. Beveridge, A. Black, M. Bonner, J. Boys, E. Buckley, M. Campo, L. Carlton, A. Connelly, B. Conway, D. Cresp, H. Dimitri, S. Dixon, M. Dolman, M. Duroux, M. Eskandari, R. Eslick, A. Ferreira-Jardim, T. Fetahovic, D. Fitzpatrick, R. Geraghty, J. Gibbs, T. Grabek, M.H. Modi, K. Hayes, M.P. Hegde, L. Hesketh, B. Hoffmann, B. Jacobson, K. Johnson, C. Juergens, I. Kassam, V. Lawlor, M. Lehman, S. Lehman, D. Leung, S. Mackay, M. MacKenzie, C. McCarthy, C. McIntosh, L. McKeon, H. Morrison, C. Mussap, J.-D. Myers, V. Nagalingam, G. Oldfield, V. O'May, J. Palmer, L. Parsons, K. Patching, T. Patching, V. Paul, M. Plotz, S. Preston, H. Rashad, M. Ratcliffe, S. Raynes, J. Rose, L. Sanders, M. Seremetkoska, H. Setio, S. Shone, P. Shrestha, C. Singh, C. Singleton, N. Stoyanov, S. Sutcliffe, K. Swaraj, J. Tarrant, S. Thompson, I.M. Tsay, M. Vorster, A. Waldman, L. Wallis, E. Wilford, K. Wong, S.J. Connolly, A. Spyropoulos, J. Eikelboom, R. Luton, M. Gupta, A.S. Pandey, S. Cheung, R. Leader, P. Beaudry, F. Ayala-Paredes, J. Berlingieri, J. Heath, G. Poirier, M. Du Preez, R. Nadeau, G. Dresser, R. Dhillon, T. Hruczkowski, B. Schweitzer, B. Coutu, P. Angaran, P. MacDonald, S. Vizel, S. Fikry, R. Parkash, A. Lavoie, J. Cha, B. Ramjattan, J. Bonet, K. Ahmad, L. Aro, T. Aves, K. Beaudry, C. Bergeron, J. Bigcanoe, N. Bignell, L. Breakwell, E. Burke, L. Carroll, B. Clarke, T. Cleveland, S. Daheb, P. Dehghani, I. Denis, Z. Djaidani, P. Dorian, S. Douglass, J. Dunnigan, A. Ewert, D. Farquhar, A. Fearon, L. Ferleyko, D. Fournier, B. Fox, M.-C. Grenier, W. Gulliver, K. Haveman, C. Hines, K. Hines, A.M. Jackson, C. Jean, G. Jethoo, R. Kahlon, S. Kelly, R. Kim, V. Korley, J. Kornder, L. Kwan, J. Largy, C. Lewis, S. Lewis, I. Mangat, R. Moor, J. Navratil, I. Neas, J. Otis, R. Otis, M. Pandey, F. Petrie, A. Pinter, M. Raines, P. Roberts, M. Robinson, G. Sas, S. Schulman, L. Snell, S. Spearson, J. Stevenson, T. Trahey, S. Wong, D. Wright, H. Ragy, A. Abd El-Aziz, S.K. Abou Seif, M.G. El Din, S. El Etriby, A. Elbahry, A. El-Etreby, M. Elkhadem, A. Katta, T. Khairy, A. Mowafy, M. Nawar, A. Ohanissian, A. Reda, M. Reda, H. Salem, N. Sami, S. Samir, M. Setiha, M. Sobhy, A. Soliman, N. Taha, M. Tawfik, E. Zaatout, D. Kettles, J. Bayat, H. Siebert, A. Horak, Y. Kelfkens, R. Garda, T. Pillay, M. Guerra, L. van Zyl, H. Theron, A. Murray, R. Louw, D. Greyling, P. Mntla, V. Ueckermann, R. Loghdey, S. Ismail, F. Ahmed, J. Engelbrecht, A. Ramdass, S. Maharajh, W. Oosthuysen, G. Angel, C. Bester, M. Booysen, C. Boshoff, C. Cannon, S. Cassimjee, C. Chami, G. Conway, A. Davids, L. de Meyer, G. Du Plessis, T. Ellis, L. Henley, M. Karsten, E. Loyd, J. Marks, L. Mavhusa, M. Mostert, A. Page, L. Rikhotso, M. Salie, J. Sasto, F. Shaik, A. Skein, L. Smith, G. Tarr, T. Tau, F. van Zyl, W. Al Mahmeed, G. Yousef, A. Agrawal, M. Nathani, M. Ibrahim, E.M. Esheiba, R. Singh, A. Naguib, M. Abu-Mahfouz, M. Al Omairi, A. Al Naeemi, R. Maruthanayagam, N. Bazargani, A. Wassef, R. Gupta, M. Khan, B. Subbaraman, A. Abdul, A. Al Mulla, S. El Bardisy, P. Haridas, S. Jadhav, K. Magdaluyo, M. Makdad, I. Maqsood, R. Mohamed, N. Sharma, R. Sharma, M. Thanzeel, S.Z. Goldhaber, R. Canosa, P. Rama, E. Blumberg, J. Garcia, P. Mullen, V. Wilson, A. Quick, K. Ferrick, W.M. Kutayli, M. Cox, M. Franco, S. Falkowski, R. Mendelson, M. Williams, S. Miller, S. Beach, A. Alfieri, T. Gutowski, I. Haque, R. Reddy, W. Ahmed, P. Delafontaine, D. Diercks, D. Theodoro, K. Remmel, M. Alberts, R. Ison, H. Noveck, P. Duffy, S. Pitta, D. Nishijima, C. Treasure, N. Asafu-Adjaye, K. Ball, M. Bartlett, M. Bentley, S. Bowers, A. Brown, A. Browne, J. Cameron-Watts, M. Canova, D. Cassidy, K. Cervellione, S. Congal, J. DePauw, A. Dickerson, M. Eley, L. Evans, S. Felpel, K. Ferdinand, D. Fielder, P. Gentry, A. Haideri, F. Hakimi, T. Harbour, E. Hartranft, B. Hawkins, M. Headlee, L. Henson, C. Herrick, T. Hicks, S. Jasinski, A. Jones, L. Jones, P. Jones, S. Karl, M. Keeling, J. Kerr, P. Knowles, J. Langdon, M. Lay, J.A. Lee, T. Lincoln, E. Malone, A. Merliss, D. Merritt, J. Minardo, B. Mooso, C. Orosco, V. Palumbo, M. Parker, T. Parrott, S. Paserchia, G. Pearl, J. Peterson, N. Pickelsimer, T. Purcell, J. Raynor, S. Raziano, C. Richard, T. Richardson, C. Robertson, A. Sage, T. Sanghera, P. Shaw, J. Shoemaker, K. Smith, B. Stephanie, A. Thatcher, H. Theobald, N. Thompson, L. Treasure, T. Tripti, C. Verdi, and V. Worthy

Subjects
Surgery, RD1-811, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Published
2018
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22. Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors

Author

Justin A. De Leon, Jiazhang Qiu, Christopher J. Nicolai, Jessica L. Counihan, Kevin C. Barry, Li Xu, Rosalie E. Lawrence, Brian M. Castellano, Roberto Zoncu, Daniel K. Nomura, Zhao-Qing Luo, and Russell E. Vance

Subjects
mTORC1, Legionella pneumophila, effector, amino acids, T4SS, amino-acids, Biology (General), QH301-705.5
Abstract

All pathogens must acquire nutrients from their hosts. The intracellular bacterial pathogen Legionella pneumophila, the etiological agent of Legionnaires’ disease, requires host amino acids for growth within cells. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved master regulator of host amino acid metabolism. Here, we identify two families of translocated L. pneumophila effector proteins that exhibit opposing effects on mTORC1 activity. The Legionella glucosyltransferase (Lgt) effector family activates mTORC1, through inhibition of host translation, whereas the SidE/SdeABC (SidE) effector family acts as mTORC1 inhibitors. We demonstrate that a common activity of both effector families is to inhibit host translation. We propose that the Lgt and SidE families of effectors work in concert to liberate host amino acids for consumption by L. pneumophila.

Published
2017
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23. Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Author

Maxwell A. Ruby, Julie Massart, Devon M. Hunerdosse, Milena Schönke, Jorge C. Correia, Sharon M. Louie, Jorge L. Ruas, Erik Näslund, Daniel K. Nomura, and Juleen R. Zierath

Subjects
obesity, hepatic steatosis, carboxylesterase, lipidomics, insulin resistance, activity-based protein profiling, inflammation, diacylglycerol, serine hydrolase, Biology (General), QH301-705.5
Abstract

Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.

Published
2017
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24. A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics

Author

Vida Ahyong, Charles A. Berdan, Thomas P. Burke, Daniel K. Nomura, and Matthew D. Welch

Subjects
Rickettsia, isoprenoids, metabolic parasitism, Microbiology, QR1-502
Abstract

ABSTRACT Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles’ heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth. IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles’ heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism.

Published
2019
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26. Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis

Author

Lydia Zhang, Michelle Tang, Xavier Tao, Qian Shao, Vienna Thomas, Saki Shimizu, Miki Kasano, Yoshinori Ishikawa, Takayuki Inukai, and Daniel K. Nomura

Abstract

Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibiting cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive covalent ligand EN25 that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, leading to inhibition of GCL activity, lowering of cellular GSH levels, and impaired cell viability in ARID1A-deficient cancer cells that are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit the GSH synthesis in cancer cells to target vulnerable cancer cell types.

Published
2023
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27. Discovery of Potent Pyrazoline‐Based Covalent SARS‐CoV‐2 Main Protease Inhibitors**

Author

Patrick Moon, Charlotte M. Zammit, Qian Shao, Dustin Dovala, Lydia Boike, Nathaniel J. Henning, Mark Knapp, Jessica N. Spradlin, Carl C. Ward, Helene Wolleb, Daniel Fuller, Gabrielle Blake, Jason P. Murphy, Feng Wang, Yipin Lu, Stephanie A. Moquin, Laura Tandeske, Matthew J. Hesse, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, F. Dean Toste, and Daniel K. Nomura

Subjects
Organic Chemistry, Molecular Medicine, Molecular Biology, Biochemistry
Published
2023
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28. Supplementary Methods from Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles

Author

David A. Frank, Paula T. Hammond, Daniel K. Nomura, Daphne A. Haas-Kogan, Alexander R. Ivanov, Douglas S. Richardson, Sharmistha Pal, Elizabeth A. Grossman Moore, Daniel F. Costa, Santiago Correa, Natalie Boehnke, Susana P. Egusquiaguirre, Lisa N. Heppler, and Isidora Tošić

Abstract

Supplementary Methods

Published
2023
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29. Supplementary Table 2 from Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles

Author

David A. Frank, Paula T. Hammond, Daniel K. Nomura, Daphne A. Haas-Kogan, Alexander R. Ivanov, Douglas S. Richardson, Sharmistha Pal, Elizabeth A. Grossman Moore, Daniel F. Costa, Santiago Correa, Natalie Boehnke, Susana P. Egusquiaguirre, Lisa N. Heppler, and Isidora Tošić

Abstract

Supplementary Table 2

Published
2023
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31. Data from Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles

Author

David A. Frank, Paula T. Hammond, Daniel K. Nomura, Daphne A. Haas-Kogan, Alexander R. Ivanov, Douglas S. Richardson, Sharmistha Pal, Elizabeth A. Grossman Moore, Daniel F. Costa, Santiago Correa, Natalie Boehnke, Susana P. Egusquiaguirre, Lisa N. Heppler, and Isidora Tošić

Abstract

The oncogenic transcription factor STAT3 is aberrantly activated in 70% of breast cancers, including nearly all triple-negative breast cancers (TNBCs). Because STAT3 is difficult to target directly, we considered whether metabolic changes driven by activated STAT3 could provide a therapeutic opportunity. We found that STAT3 prominently modulated several lipid classes, with most profound effects on N-acyl taurine and arachidonic acid, both of which are involved in plasma membrane remodeling. To exploit these metabolic changes therapeutically, we screened a library of layer-by-layer (LbL) nanoparticles (NPs) differing in the surface layer that modulates interactivity with the cell membrane. We found that poly-l-glutamic acid (PLE)–coated NPs bind to STAT3-transformed breast cancer cells with 50% greater efficiency than to nontransformed cells, and the heightened PLE-NP binding to TNBC cells was attenuated by STAT3 inhibition. This effect was also observed in densely packed three-dimensional breast cancer organoids. As STAT3-transformed cells show greater resistance to cytotoxic agents, we evaluated whether enhanced targeted delivery via PLE-NPs would provide a therapeutic advantage. We found that cisplatin-loaded PLE-NPs induced apoptosis of STAT3-driven cells at lower doses compared with both unencapsulated cisplatin and cisplatin-loaded nontargeted NPs. In addition, because radiation is commonly used in breast cancer treatment, and may alter cellular lipid distribution, we analyzed its effect on PLE-NP–cell binding. Irradiation of cells enhanced the STAT3-targeting properties of PLE-NPs in a dose-dependent manner, suggesting potential synergies between these therapeutic modalities. These findings suggest that cellular lipid changes driven by activated STAT3 may be exploited therapeutically using unique LbL NPs.

Published
2023
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34. Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design

Author

Annika C. S. Page, Spencer O. Scholz, Katherine N. Keenan, Jessica N. Spradlin, Bridget P. Belcher, Scott M. Brittain, John A. Tallarico, Jeffrey M. McKenna, Markus Schirle, Daniel K. Nomura, and F. Dean Toste

Subjects
Chemical Sciences, General Chemistry
Abstract

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an iPr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived iPr acyl silanes were shown to selectively label recombinant BRD4-BD1 and FKBP12, respectively, with minimal background. Together, these data highlight the untapped potential of acyl silanes as a novel, tunable scaffold for photoaffinity labeling.

Published
2022
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36. Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells

Author

Flor A. Gowans, Danny Q. Thach, Yangzhi Wang, Belen E. Altamirano Poblano, Dustin Dovala, John A. Tallarico, Jeffrey M. McKenna, Markus Schirle, Thomas J. Maimone, and Daniel K. Nomura

Abstract

SummaryOphiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets—cysteine C53 of HIG2DA and lysine K72 of COX5A—that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.

Published
2023
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37. Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3

Author

Bridget P. Belcher, Paulo A. Machicao, Binqi Tong, Emily Ho, Julia Friedli, Brian So, Helen Bui, Yosuke Isobe, Thomas J. Maimone, and Daniel K. Nomura

Subjects
Article
Abstract

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strainGymnascella dankaliensishave been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Published
2023
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38. A Cellular Platform for Production of C4Monomers

Author

Matthew A. Davis, Vivian Yaci Yu, Beverly Fu, Miao Wen, Edward J. Koleski, Joshua Silverman, Charles A. Berdan, Daniel K. Nomura, and Michelle C. Y. Chang

Abstract

Living organisms carry out a wide range of remarkable functions, including the synthesis of thousands of simple and complex chemical structures for cellular growth and maintenance. The manipulation of this reaction network has allowed for the genetic engineering of cells for targeted chemical synthesis, but it remains challenging to alter the program underlying their fundamental chemical behavior. By taking advantage of the unique ability of living systems to use evolution to find solutions to complex problems, we have achieved ~95% theoretical yield of three C4commodity chemicals,n-butanol, 1,3-butanediol, and 4-hydroxy-2-butanone. Genomic sequencing of the evolved strains identifiedpcnBandrpoBCas two gene loci that are able to alter carbon flow by remodeling the transcriptional landscape of the cell, highlighting the potential of synthetic pathways as a tool to identify metabolic control points.

Published
2023
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39. S wift heavy ion irradiation-induced amorphous iron and Fe–Si oxide phases in metallic 57 Fe layer vacuum deposited on surface of SiO2 /Si

Author

E. Kuzmann, K. Nomura, S. Stichleutner, A. Nakanishi, J. Pechousek, L. Machala, Z. Homonnay, R. Vondrasek, V. A. Skuratov, L. Krupa, O. Malina, T. Ingr, and S. Kubuki

Subjects
Mechanics of Materials, Mechanical Engineering, General Materials Science, Condensed Matter Physics
Abstract

57Fe conversion electron Mössbauer (CEM) spectroscopy, SEM and magnetization measurements were used to study the effect of swift heavy ion irradiation on metallic 57Fe (10 nm) thin layer vacuum deposited onto SiO2/Si. About 85% of the total iron content of the surface layer detected by CEM was present as metallic, crystalline alpha iron before the irradiation, while upon irradiation with 160 MeV Xe ions, with a fluence of 5 × 1013 ion cm−2, ~ 21% was converted to amorphous iron and ~ 47% to silicon-containing iron oxide phases. The presence of pure iron in the amorphous state was evidenced by CEM in agreement with magnetization measurements. Temperature dependence of CEM measurements and the FC/ZFC curves of the irradiated deposit indicated superparamagnetic nature of the iron-silicon-oxide phases. The results are discussed in terms of the thermal spike model for the formation of the amorphous iron phase that can be essential for the formation of silicon-iron-oxides. Graphical abstract

Published
2023

40. Metabolomic Markers of Phthalate Exposure in Plasma and Urine of Pregnant Women

Author

Michael Zhou, Breanna Ford, Douglas Lee, Gwen Tindula, Karen Huen, Vy Tran, Asa Bradman, Robert Gunier, Brenda Eskenazi, Daniel K. Nomura, and Nina Holland

Subjects
targeted metabolomics, endocrine disruptors, phthalates, in utero exposure, inflammation, pregnancy, Public aspects of medicine, RA1-1270
Abstract

Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (q-values 0.0001–0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma (p = 0.01–0.0004), while Mevalonic acid was positively associated (p = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI (p = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring.

Published
2018
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41. Dependence of Brown Adipose Tissue Function on CD36-Mediated Coenzyme Q Uptake

Author

Courtney M. Anderson, Melissa Kazantzis, Jinshan Wang, Subramaniam Venkatraman, Renata L.S. Goncalves, Casey L. Quinlan, Ryan Ng, Martin Jastroch, Daniel I. Benjamin, Biao Nie, Candice Herber, An-Angela Ngoc Van, Michael J. Park, Dawee Yun, Karen Chan, Angela Yu, Peter Vuong, Maria Febbraio, Daniel K. Nomura, Joseph L. Napoli, Martin D. Brand, and Andreas Stahl

Subjects
Biology (General), QH301-705.5
Abstract

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.

Published
2015
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43. Targeted Protein Degradation through E2 Recruitment

Author

Nafsika Forte, Dustin Dovala, Matthew J. Hesse, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, and Daniel K. Nomura

Subjects
Molecular Medicine, General Medicine, Biochemistry
Abstract

Targeted protein degradation (TPD) with Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds consisting of protein targeting ligands linked to recruiters of E3 ubiquitin ligases, has arisen as a powerful therapeutic modality to induce the proximity of target proteins with E3 ligases to ubiquitinate and degrade specific proteins in cells. Thus far, PROTACs have primarily exploited the recruitment of E3 ubiquitin ligases or their substrate adapter proteins but have not exploited the recruitment of more core components of the ubiquitin-proteasome system (UPS). In this study, we used covalent chemoproteomic approaches to discover a covalent recruiter against the E2 ubiquitin conjugating enzyme UBE2D—EN67—that targets an allosteric cysteine, C111, without affecting the enzymatic activity of the protein. We demonstrated that this UBE2D recruiter could be used in heterobifunctional degraders to degrade neo-substrate targets in a UBE2D-dependent manner, including BRD4 and the androgen receptor. Overall, our data highlight the potential for the recruitment of core components of the UPS machinery, such as E2 ubiquitin conjugating enzymes, for TPD, and underscore the utility of covalent chemoproteomic strategies for identifying novel recruiters for additional components of the UPS.

Published
2022
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44. Rational Chemical Design of Molecular Glue Degraders

Author

Ethan S. Toriki, James W. Papatzimas, Kaila Nishikawa, Dustin Dovala, Lynn M. McGregor, Matthew J. Hesse, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, and Daniel K. Nomura

Abstract

Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor Ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of Ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Covalent chemoproteomic profiling of this CDK4 degrader revealed covalent interactions with cysteine 32 of the RING family E3 ubiquitin ligase RNF126. Structural modification of our initial covalent scaffold led to an improved CDK4 degrader with the development of a but-2-ene, 1,4-dione (“fumarate”) handle that showed improved interactions with RNF126. Thereafter, we worked to identify the minimum covalent motif required for interaction with RNF126, which we then transplanted onto chemically related and un-related protein-targeting ligands. This strategy successfully produced molecules which induced the degradation of several proteins across diverse protein classes, including BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, and SMARCA2. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders.

Published
2022
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45. N-Acryloylindole-alkyne (NAIA) enables profiling new ligandable hotspots in chemoproteomics experiments and imaging thiol oxidation

Author

Hinyuk Lai, Tin-Yan Koo, Daniel K. Nomura, and Clive Yik-Sham CHUNG

Abstract

We report a new class of compounds, N-acryloylindole-alkynes (NAIAs), as promising cysteine-reactive probes for proteome-wide cysteine profiling and imaging of thiol oxidative modifications. NAIAs showed superior cysteine reactivity owing to delocalization of π electrons of the acrylamide warhead over the whole indole scaffold, resulting in its activation for faster reaction with cysteines. This allows NAIAs to ligand functional cysteines more effectively than IAA, as well as to image oxidized thiols in cells facing oxidative stress by confocal fluorescence microscopy. In MS-based ABPP experiments, NAIAs successfully captured a new pool of ligandable cysteines and proteins even compared to the current state-of-the-art cysteine profiling data. Competitive ABPP experiments further demonstrate the ability of NAIA to discover hit compounds targeting these new cysteines and proteins. This work should initiate development of new cysteine-reactive probes, particularly those with activated acrylamide, for advancing cysteine imaging and profiling, and covalent ligand screening for drug research.

Published
2022
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46. Ligandability of E3 Ligases for Targeted Protein Degradation Applications

Author

Daniel K. Nomura, Bridget P. Belcher, and Carl C. Ward

Subjects
biology, medicine.diagnostic_test, Chemistry, Proteolysis, Druggability, Computational biology, Protein degradation, Biochemistry, Small molecule, Article, Ubiquitin ligase, Ubiquitin, Proteasome, Proteome, biology.protein, medicine
Abstract

Targeted protein degradation (TPD) using Proteolysis Targeting Chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ heterobifunctional or monovalent small molecules, respectively, to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. While TPD is an attractive therapeutic strategy for expanding the druggable proteome, only a relatively small number of E3 ligases out of the >600 E3 ligases encoded by the human genome have been exploited by small molecules for TPD applications. Here, we review the existing E3 ligases that have thus far been successfully exploited for TPD and discuss chemoproteomics-enabled covalent screening strategies for discovering new E3 ligase recruiters. We also provide a chemoproteomic map of reactive cysteines within hundreds of E3 ligases which may represent potential ligandable sites that can be pharmacologically interrogated to uncover additional E3 ligase recruiters.

Published
2021
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48. Cellobiose Consumption Uncouples Extracellular Glucose Sensing and Glucose Metabolism in Saccharomyces cerevisiae

Author

Kulika Chomvong, Daniel I. Benjamin, Daniel K. Nomura, and Jamie H. D. Cate

Subjects
PMA1, cellobiose, glucose sensors, metabolomics, Microbiology, QR1-502
Abstract

ABSTRACT Glycolysis is central to energy metabolism in most organisms and is highly regulated to enable optimal growth. In the yeast Saccharomyces cerevisiae, feedback mechanisms that control flux through glycolysis span transcriptional control to metabolite levels in the cell. Using a cellobiose consumption pathway, we decoupled glucose sensing from carbon utilization, revealing new modular layers of control that induce ATP consumption to drive rapid carbon fermentation. Alterations of the beta subunit of phosphofructokinase-1 (PFK2), H+-plasma membrane ATPase (PMA1), and glucose sensors (SNF3 and RGT2) revealed the importance of coupling extracellular glucose sensing to manage ATP levels in the cell. Controlling the upper bound of cellular ATP levels may be a general mechanism used to regulate energy levels in cells, via a regulatory network that can be uncoupled from ATP concentrations under perceived starvation conditions. IMPORTANCE Living cells are fine-tuned through evolution to thrive in their native environments. Genome alterations to create organisms for specific biotechnological applications may result in unexpected and undesired phenotypes. We used a minimal synthetic biological system in the yeast Saccharomyces cerevisiae as a platform to reveal novel connections between carbon sensing, starvation conditions, and energy homeostasis.

Published
2017
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49. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1

Author

Hijai R. Shin, Y. Rose Citron, Lei Wang, Laura Tribouillard, Claire S. Goul, Robin Stipp, Yusuke Sugasawa, Aakriti Jain, Nolwenn Samson, Chun-Yan Lim, Oliver B. Davis, David Castaneda-Carpio, Mingxing Qian, Daniel K. Nomura, Rushika M. Perera, Eunyong Park, Douglas F. Covey, Mathieu Laplante, Alex S. Evers, and Roberto Zoncu

Subjects
Multidisciplinary, Proteome, General Science & Technology, 1.1 Normal biological development and functioning, GTPase-Activating Proteins, Mechanistic Target of Rapamycin Complex 1, Article, Receptors, G-Protein-Coupled, G-Protein-Coupled, Cholesterol, Underpinning research, Receptors, Humans, Lysosomes, Monomeric GTP-Binding Proteins
Abstract

Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein–coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)–activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.

Published
2022

50. X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction

Author

Peixiang Zhang, Joseph J. Munier, Laurent Vergnes, Carrie B. Wiese, Jenny C. Link, Fahim Abbasi, Emilio Ronquillo, Antonio Muñoz, Yu-Lin Kuang, Meng Liu, Gabriela Sanchez, Akinyemi Oni-Orisan, Carlos Iribarren, Michael J. McPhaul, Daniel K. Nomura, Joshua W. Knowles, Ronald M. Krauss, Marisa W. Medina, and Karen Reue

Abstract

SummaryStatin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. We determined that female mice are more susceptible than males to glucose intolerance, fasting hyperglycemia, and muscle weakness after short-term statin treatment. Lipidomic, transcriptomic, and biochemical analyses identified reduced docosahexaenoic acid (DHA) levels, and impaired redox tone and mitochondrial respiration specifically in statin-treated female mice. Statin adverse effects could be prevented in females by complementation with a source of DHA. Statin adverse effects segregated with XX chromosome complement, and specifically dosage of the Kdm5c gene, which regulates fatty acid gene expression and has differential expression levels in females and males. In humans, we found that women experience more severe reductions than men in DHA levels after short-term statin administration, and that DHA reduction was correlated with increases in fasting glucose levels. Furthermore, induced pluripotent stem cells derived from women, but not men, who developed NOD exhibited impaired mitochondrial function when treated with statin. Overall, our studies identify biochemical mechanisms, biomarkers, and a genetic risk factor for susceptibility to statin adverse effects, and point to DHA supplementation as a preventive co-therapy.

Published
2022
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