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1,232 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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3. DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders

Author: Melissa Lim, Thang Do Cong, Lauren M. Orr, Ethan S. Toriki, Andrew C. Kile, James W. Papatzimas, Elijah Lee, Yihan Lin, and Daniel K. Nomura
Subjects: Chemistry, QD1-999
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. 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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14. 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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15. 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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16. 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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17. 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. Naik, K. Prashanth, M. Rao, N.M. Rao, N. Sadhu, D. Shah, M. Sharma, P. Shiva, S. Singhal, S. Suresh, V. Vanajakshamma, S.G. Panse, Y. Koretsune, S. Kanamori, K. Yamamoto, K. Kumagai, Y. Katsuda, K. Sadamatsu, F. Toyota, Y. Mizuno, I. Misumi, H. Noguchi, S. Ando, T. Suetsugu, M. Minamoto, Hiroshi Oda, K. Shiraishi, S. Adachi, K. Chiba, H. Norita, M. Tsuruta, T. Koyanagi, H. Ando, T. Higashi, K. Okada, S. Azakami, S. Komaki, K. Kumeda, T. Murayama, J. Matsumura, Y. Oba, R. Sonoda, K. Goto, K. Minoda, Y. Haraguchi, H. Suefuji, H. Miyagi, H. Kato, Tadashi Nakamura, Tsugihiro Nakamura, H. Nandate, R. Zaitsu, Yoshihisa Fujiura, A. Yoshimura, H. Numata, J. Ogawa, H. Tatematsu, Y. Kamogawa, K. Murakami, Y. Wakasa, M. Yamasawa, H. Maekawa, S. Abe, H. Kihara, S. Tsunoda, Katsumi Saito, Kazuyuki Saito, T. Fudo, K. Obunai, H. Tachibana, I. Oba, T. Kuwahata, S. Higa, M. Gushiken, T. Eto, H. Yoshida, D. Ikeda, Yoshitake Fujiura, M. Ishizawa, M. Nakatsuka, K. Murata, C. Ogurusu, M. Shimoyama, M. 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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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18. Toward abiotic sugar synthesis from CO2 electrolysis

Author: Stefano Cestellos-Blanco, Sheena Louisia, Michael B. Ross, Yifan Li, Nathan E. Soland, Tyler C. Detomasi, Jessica N. Cestellos Spradlin, Daniel K. Nomura, and Peidong Yang
Subjects: General Energy
Published: 2022
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19. 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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20. 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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21. 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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22. Erratum for Ahyong et al., '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: Microbiology, QR1-502
Published: 2019
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23. 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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24. 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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25. Figure 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: Supplemental data
Published: 2023
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26. 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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27. 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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28. 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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29. 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

30. 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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31. 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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32. 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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33. 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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34. 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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35. 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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36. 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

37. Advances in covalent drug discovery

Author: Lydia Boike, Nathaniel J. Henning, and Daniel K. Nomura
Subjects: Pharmacology, 5.1 Pharmaceuticals, Drug Discovery, General Medicine, Pharmacology & Pharmacy, Development of treatments and therapeutic interventions, Biological Sciences, Medical and Health Sciences, Cancer
Abstract: Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through 'electrophile-first' approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field.
Published: 2022

38. Tyrosinase-Mediated Synthesis of Nanobody-Cell Conjugates

Author: Johnathan C. Maza, Derek M. García-Almedina, Lydia E. Boike, Noah X. Hamlish, Daniel K. Nomura, and Matthew B. Francis
Subjects: General Chemical Engineering, General Chemistry
Abstract: A convenient enzymatic strategy is reported for the modification of cell surfaces. Using a tyrosinase enzyme isolated from
Published: 2022

39. Vortex breakdown in swirling Burke–Schumann flames

Author: Benjamin W. Keeton, Keiko K. Nomura, Antonio L. Sánchez, and Forman A. Williams
Subjects: Mechanical Engineering, General Chemical Engineering, Physical and Theoretical Chemistry
Published: 2022
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40. Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function

Author: Martin Valdearcos, Megan M. Robblee, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu, and Suneil K. Koliwad
Subjects: Biology (General), QH301-705.5
Abstract: Diets rich in saturated fat produce inflammation, gliosis, and neuronal stress in the mediobasal hypothalamus (MBH). Here, we show that microglia mediate this process and its functional impact. Although microglia and astrocytes accumulate in the MBH of mice fed a diet rich in saturated fatty acids (SFAs), only the microglia undergo inflammatory activation, along with a buildup of hypothalamic SFAs. Enteric gavage specifically with SFAs reproduces microglial activation and neuronal stress in the MBH, and SFA treatment activates murine microglia, but not astrocytes, in culture. Moreover, depleting microglia abrogates SFA-induced inflammation in hypothalamic slices. Remarkably, depleting microglia from the MBH of mice abolishes inflammation and neuronal stress induced by excess SFA consumption, and in this context, microglial depletion enhances leptin signaling and reduces food intake. We thus show that microglia sense SFAs and orchestrate an inflammatory process in the MBH that alters neuronal function when SFA consumption is high.
Published: 2014
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41. Recurrence rate of intramucosal gastric cancer with positive vertical margin due to lesion damage during endoscopic submucosal dissection

Author: Masanobu Kitagawa, J Hayasaka, Y Ochiai, Y Fukuma, Shu Hoteya, N Inoshita, K Nomura, Y Suzuki, Satoshi Yamashita, M Tanaka, H Odagiri, Akira Matsui, and Daisuke Kikuchi
Subjects: medicine.medical_specialty, Endoscopic Mucosal Resection, Resection, Lesion, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, medicine, Humans, Neoplasm, Retrospective Studies, business.industry, Significant difference, Cancer, Endoscopic submucosal dissection, medicine.disease, Confidence interval, Early Gastric Cancer, Treatment Outcome, Gastric Mucosa, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Radiology, Neoplasm Recurrence, Local, medicine.symptom, business
Abstract: Background and study aim: In principle, additional surgery is performed after endoscopic submucosal dissection for early gastric cancer if the vertical margin is positive, regardless of lesion damage. The recurrence rate of vertical margin-positive lesions due to lesion damage after endoscopic submucosal dissection is unknown, and unnecessary surgeries may be performed. In this study, we investigated whether there was a difference in the recurrence rate between vertical margin-positive lesions due to lesion damage and vertical margin-negative lesions. Patients and methods: We included 1,294 intramucosal gastric cancer lesions that were resected by endoscopic submucosal dissection between January 2008 and December 2016, without additional surgery. The lesions were divided into the Damage and No damage groups based on vertical margin status. The Damage group had only one non-curative indication: a positive vertical margin due to lesion damage. The No damage group had no non curative indications. We compared the recurrence rate between the Damage and No damage groups. Results: The recurrence rates of the Damage and No damage groups were 0% (0/23; 95% confidence interval: 0-14.8%) and 0% (0/1,271; 95% confidence interval: 0-0.003%), respectively, with no statistically significant difference. Conclusions: In intramucosal gastric cancer, the recurrence rate of vertical margin-positive lesions due to lesion damage was 0%, which did not differ from that of vertical margin-negative lesions with curative resection. Follow-up, instead of additional surgery, may be an option for patients with non-curative resection when the only non-curative indication is a positive vertical margin due to lesion damage.
Published: 2021
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42. Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB

Author: Elizabeth A. King, Yoojin Cho, Nathan S. Hsu, Dustin Dovala, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, and Daniel K. Nomura
Subjects: Pharmacology, Clinical Biochemistry, Drug Discovery, Molecular Medicine, Molecular Biology, Biochemistry
Published: 2023
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43. Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling

Author: Daniel I. Benjamin, Pieter Both, Joel S. Benjamin, Christopher W. Nutter, Jenna H. Tan, Jengmin Kang, Leo A. Machado, Julian D. D. Klein, Antoine de Morree, Soochi Kim, Ling Liu, Hunter Dulay, Ludovica Feraboli, Sharon M Louie, Daniel K Nomura, and Thomas A. Rando
Subjects: Blood Glucose, p53, ketosis, fasting, Physiology, muscle, Endocrinology, Diabetes and Metabolism, Medical Biochemistry and Metabolomics, Regenerative Medicine, Article, Myoblasts, Endocrinology & Metabolism, Endocrinology, HDAC, stem cells, MuSC, Humans, quiescence, Molecular Biology, 3-Hydroxybutyric Acid, Stem Cells, Muscles, Cell Biology, Fasting, Ketosis, Stem Cell Research, BHB, Stem Cell Research - Nonembryonic - Non-Human, Biochemistry and Cell Biology, Tumor Suppressor Protein p53, diet
Abstract: SummaryShort-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically β-hydroxybutyrate, directly promote MuSC deep quiescence via a non-metabolic mechanism. We show that β-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
Published: 2022

44. Bypassing the Pentose Phosphate Pathway: Towards Modular Utilization of Xylose.

Author: Kulika Chomvong, Stefan Bauer, Daniel I Benjamin, Xin Li, Daniel K Nomura, and Jamie H D Cate
Subjects: Medicine, Science
Abstract: The efficient use of hemicellulose in the plant cell wall is critical for the economic conversion of plant biomass to renewable fuels and chemicals. Previously, the yeast Saccharomyces cerevisiae has been engineered to convert the hemicellulose-derived pentose sugars xylose and arabinose to d-xylulose-5-phosphate for conversion via the pentose phosphate pathway (PPP). However, efficient pentose utilization requires PPP optimization and may interfere with its roles in NADPH and pentose production. Here, we developed an alternative xylose utilization pathway that largely bypasses the PPP. In the new pathway, d-xylulose is converted to d-xylulose-1-phosphate, a novel metabolite to S. cerevisiae, which is then cleaved to glycolaldehyde and dihydroxyacetone phosphate. This synthetic pathway served as a platform for the biosynthesis of ethanol and ethylene glycol. The use of d-xylulose-1-phosphate as an entry point for xylose metabolism opens the way for optimizing chemical conversion of pentose sugars in S. cerevisiae in a modular fashion.
Published: 2016
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45. Manumycin Polyketides Act as Molecular Glues Between UBR7 and P53

Author: Scott M. Brittain, Xiaoyou Liang, Mikiko Okumura, Lynn M. McGregor, Yosuke Isobe, Daniel K. Nomura, Thomas J. Maimone, Ross White, Markus Schirle, William C. Forrester, John A. Tallarico, Michael D. Jones, and Jeffrey Mckenna
Subjects: natural products, Molecular Conformation, chemistry.chemical_compound, molecular glues, Drug Discovery, 0303 health sciences, Tumor, biology, Molecular Structure, Chemistry, 030302 biochemistry & molecular biology, Limiting, Small molecule, Ubiquitin ligase, Gene Expression Regulation, Neoplastic, Cross-Linking Reagents, Gene Knockdown Techniques, Female, Biochemistry & Molecular Biology, Polyunsaturated Alkamides, Ubiquitin-Protein Ligases, Static Electricity, Breast Neoplasms, Antineoplastic Agents, covalent ligands, Computational biology, Polyenes, manumycin, Article, Cell Line, 03 medical and health sciences, Structure-Activity Relationship, Medicinal and Biomolecular Chemistry, E3 ligases, Cell Line, Tumor, Humans, Chemoproteomics, asukamycin, Molecular Biology, protein-protein interaction (PPI), undruggable, 030304 developmental biology, activity-based protein profiling, Neoplastic, Natural product, Cell Biology, Anticancer mechanism, chemoproteomics, Gene Expression Regulation, Polyketides, biology.protein, Breast cancer cells, Biochemistry and Cell Biology, Tumor Suppressor Protein p53
Abstract: Molecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multi-covalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells and engage in molecular glue interactions with the neo-substrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal a novel anti-cancer mechanism of this natural product family and highlight the potential for combining chemoproteomics and multi-covalent natural products for the discovery of new molecular glues.
Published: 2020

46. Neuronal modulation of hepatic lipid accumulation induced by bingelike drinking

Author: Suneil K. Koliwad, Rachel T. Cheang, Frederic Woodward Hopf, Xiaoyi Yuan, Allison W. Xu, Matthew T Maier, Sharon M. Louie, Scott A. Wegner, Anna Vilhelmsson, Ernie Yulyaningsih, Maria Ibars, Daniel K. Nomura, Holger K. Eltzschig, and Luz Perez
Subjects: Male, 0301 basic medicine, Sympathetic nervous system, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, Hypothalamus, Neuropeptide, Binge drinking, Binge Drinking, Mice, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Animals, Agouti-Related Protein, Neurons, business.industry, Fatty liver, Lipid Metabolism, medicine.disease, Adenosine, Adenosine Receptor A2b, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Liver, Alcoholic fatty liver, Steatosis, business, 030217 neurology & neurosurgery, Research Article, Fatty Liver, Alcoholic, medicine.drug
Abstract: Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A2Bsignaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.
Published: 2020
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47. Temperature-induced phase transitions in the correlated quantum Hall state of bilayer graphene

Author: M. Tanaka, K. Watanabe, T. Taniguchi, K. Nomura, S. Tarucha, and M. Yamamoto
Published: 2022
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48. γ -ray spectroscopy of low-lying yrast and non-yrast states in neutron-rich Kr94,95,96

Author: R.-B. Gerst, A. Blazhev, K. Moschner, P. Doornenbal, A. Obertelli, K. Nomura, J.-P. Ebran, S. Hilaire, J. Libert, G. Authelet, H. Baba, D. Calvet, F. Château, S. Chen, A. Corsi, A. Delbart, J.-M. Gheller, A. Giganon, A. Gillibert, V. Lapoux, T. Motobayashi, M. Niikura, N. Paul, J.-Y. Roussé, H. Sakurai, C. Santamaria, D. Steppenbeck, R. Taniuchi, T. Uesaka, T. Ando, T. Arici, F. Browne, A. M. Bruce, R. Caroll, L. X. Chung, M. L. Cortés, M. Dewald, B. Ding, F. Flavigny, S. Franchoo, M. Górska, A. Gottardo, J. Jolie, A. Jungclaus, J. Lee, M. Lettmann, B. D. Linh, J. Liu, Z. Liu, C. Lizarazo, S. Momiyama, S. Nagamine, N. Nakatsuka, C. R. Nita, C. Nobs, L. Olivier, R. Orlandi, Z. Patel, Zs. Podolyák, M. Rudigier, T. Saito, C. Shand, P.-A. Söderström, I. Stefan, V. Vaquero, V. Werner, K. Wimmer, and Z. Xu
Published: 2022
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49. Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

Author: Nathaniel J. Henning, Andrew G. Manford, Jessica N. Spradlin, Scott M. Brittain, Erika Zhang, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, Michael Rape, and Daniel K. Nomura
Subjects: Proteasome Endopeptidase Complex, Binding Sites, Dasatinib, Fusion Proteins, bcr-abl, Ubiquitin-Protein Ligase Complexes, Cell Cycle Proteins, General Chemistry, Azepines, Triazoles, Biochemistry, Catalysis, Recombinant Proteins, Article, Cell Line, Mice, Colloid and Surface Chemistry, Acetamides, Proteolysis, Animals, Humans, Cysteine, Carrier Proteins, Protein Kinase Inhibitors, Protein Binding, Transcription Factors
Abstract: Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number of E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress. By targeting C186 in FEM1B, EN106 disrupts recognition of the key reductive stress substrate of FEM1B, FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications by demonstrating that a PROTAC linking EN106 to the BET Bromodomain inhibitor JQ1 or the kinase inhibitor dasatinib leads to the degradation of BRD4 and BCR-ABL, respectively. Our study showcases a covalent ligand that targets a natural E3 ligase-substrate binding site and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters suitable for TPD applications.
Published: 2022

50. 57P Two cases of adult rhabdomyosarcoma of the head and neck successfully treated with pazopanib

Author: Y. Okita, H. Okuyama, A. Murakami, K. Nomura, I. Kita, S. Tsukamoto, T. Nishiuchi, and A. Tsuji
Subjects: Cancer Research, Oncology
Published: 2023
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