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Article ; Online: An improved method for the incorporation of fluoromethyl ketones into solid phase peptide synthesis techniques.

Joshi, Dhira / Milligan, Jennifer C / Zeisner, Theresa U / O'Reilly, Nicola / Diffley, John F X / Papageorgiou, George

RSC advances

2021 Volume 11, Issue 33, Page(s) 20457–20464

Abstract: An improved and expedient technique for the synthesis of peptidyl-fluoromethyl ketones is described. The methodology is based on prior coupling of an aspartate fluoromethyl ketone to a linker and mounting it onto resin-bound methylbenzhydrylamine ... ...

Abstract	An improved and expedient technique for the synthesis of peptidyl-fluoromethyl ketones is described. The methodology is based on prior coupling of an aspartate fluoromethyl ketone to a linker and mounting it onto resin-bound methylbenzhydrylamine hydrochloride. Subsequently, by utilising standard Fmoc peptide procedures, a number of short Z-protected peptides were synthesised and assessed as possible inhibitors of the main protease from SARS-CoV-2 (3CL
Language	English
Publishing date	2021-06-08
Publishing country	England
Document type	Journal Article
ISSN	2046-2069
ISSN (online)	2046-2069
DOI	10.1039/d1ra03046a
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Article: An improved method for the incorporation of fluoromethyl ketones into solid phase peptide synthesis techniques

Joshi, Dhira / Milligan, Jennifer C. / Zeisner, Theresa U. / O'Reilly, Nicola / Diffley, John F. X. / Papageorgiou, George

RSC advances. 2021 June 08, v. 11, no. 33

2021

Abstract	An improved and expedient technique for the synthesis of peptidyl-fluoromethyl ketones is described. The methodology is based on prior coupling of an aspartate fluoromethyl ketone to a linker and mounting it onto resin-bound methylbenzhydrylamine hydrochloride. Subsequently, by utilising standard Fmoc peptide procedures, a number of short Z-protected peptides were synthesised and assessed as possible inhibitors of the main protease from SARS-CoV-2 (3CLᵖʳᵒ).
Keywords	Severe acute respiratory syndrome coronavirus 2 ; aspartic acid ; peptides ; proteinases
Language	English
Dates of publication	2021-0608
Size	p. 20457-20464.
Publishing place	The Royal Society of Chemistry
Document type	Article
ISSN	2046-2069
DOI	10.1039/d1ra03046a
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Article ; Online: Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study.

Lowenthal, Elizabeth D / Chapman, Jennifer / Ohrenschall, Rachel / Calabrese, Katherine / Baltrusaitis, Kristin / Heckman, Barbara / Yin, Dwight E / Agwu, Allison L / Harrington, Conn / Van Solingen-Ristea, Rodica M / McCoig, Cynthia C / Adeyeye, Adeola / Kneebone, Jared / Chounta, Vasiliki / Smith-Anderson, Christiana / Camacho-Gonzalez, Andres / D'Angelo, Jessica / Bearden, Allison / Crauwels, Herta /

Huang, Jenny / Buisson, Sarah / Milligan, Ryan / Ward, Shawn / Bolton-Moore, Carolyn / Gaur, Aditya H

The lancet. HIV

2024 Volume 11, Issue 4, Page(s) e222–e232

Abstract: Background: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents ( ... ...

Abstract	Background: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. Methods: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections. Interpretation: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV. Funding: National Institutes of Health and ViiV Healthcare.
MeSH term(s)	Adult ; Child ; Humans ; Adolescent ; Rilpivirine/therapeutic use ; Anti-HIV Agents/therapeutic use ; HIV Infections/drug therapy ; Quality of Life ; Anti-Retroviral Agents/therapeutic use ; HIV Seropositivity/drug therapy ; HIV-1 ; Pain/drug therapy ; Pyridones ; Diketopiperazines
Chemical Substances	Rilpivirine (FI96A8X663) ; Anti-HIV Agents ; cabotegravir (HMH0132Z1Q) ; Anti-Retroviral Agents ; Pyridones ; Diketopiperazines
Language	English
Publishing date	2024-03-27
Publishing country	Netherlands
Document type	Multicenter Study ; Clinical Trial, Phase II ; Clinical Trial, Phase I ; Journal Article
ISSN	2352-3018
ISSN (online)	2352-3018
DOI	10.1016/S2352-3018(23)00301-6
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase.

Bertolin, Agustina P / Weissmann, Florian / Zeng, Jingkun / Posse, Viktor / Milligan, Jennifer C / Canal, Berta / Ulferts, Rachel / Wu, Mary / Drury, Lucy S / Howell, Michael / Beale, Rupert / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2425–2443

Abstract: The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. ...

Abstract	The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. Repurposing existing drugs with known pharmacological safety profiles is a fast and cost-effective approach to identify novel treatments. The COVID-19 etiologic agent is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded positive-sense RNA virus. Coronaviruses rely on the enzymatic activity of the replication-transcription complex (RTC) to multiply inside host cells. The RTC core catalytic component is the RNA-dependent RNA polymerase (RdRp) holoenzyme. The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologues in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified three novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Benzoates/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Chlorocebus aethiops ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Drug Evaluation, Preclinical ; Enzyme Assays ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; Holoenzymes/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Suramin/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Benzoates ; Bridged Bicyclo Compounds, Heterocyclic ; Holoenzymes ; NS8 protein, SARS-CoV-2 ; Small Molecule Libraries ; Viral Nonstructural Proteins ; 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid (56887611DJ) ; Suramin (6032D45BEM) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; NSP7 protein, SARS-CoV-2 (EC 2.7.7.48)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210200
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Article ; Online: The Role of Immune Responses in HIV Mother-to-Child Transmission.

Milligan, Caitlin / Slyker, Jennifer A / Overbaugh, Julie

Advances in virus research

2017 Volume 100, Page(s) 19–40

Abstract: HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still ...

Abstract	HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still occurs and better understanding of the basic biology and immunology of transmission will aid in future prevention and treatment efforts. MTCT is a unique setting given that the transmission pair is known and the infant receives passively transferred HIV-specific antibodies from the mother while in utero. Thus, infant exposure to HIV occurs in the face of HIV-specific antibodies, especially during delivery and breastfeeding. This review highlights the immune correlates of protection in HIV MTCT including humoral (neutralizing antibodies, antibody-dependent cellular cytotoxicity, and binding epitopes), cellular, and innate immune factors. We further discuss the future implications of this research as it pertains to opportunities for passive and active vaccination with the ultimate goal of eliminating HIV MTCT.
MeSH term(s)	Adaptive Immunity ; Anti-HIV Agents/therapeutic use ; Antibiotic Prophylaxis ; HIV/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/prevention & control ; HIV Infections/transmission ; Humans ; Immunity, Innate ; Immunization, Passive ; Infectious Disease Transmission, Vertical/prevention & control ; Vaccination
Chemical Substances	Anti-HIV Agents
Language	English
Publishing date	2017-11-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	195-8
ISSN	1557-8399 ; 0065-3527
ISSN (online)	1557-8399
ISSN	0065-3527
DOI	10.1016/bs.aivir.2017.10.001
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Article: Critical Research Needs for Forage Fish within Inner Shelf Marine Ecosystems

Rivers, James W. / Bailey Guerrero, Jennifer / Brodeur, Richard D. / Krutzikowsky, Gregory K. / Adrean, Lindsay J. / Heppell, Scott A. / Jacobson, Kym C. / Milligan, Kristen / Nelson, S. Kim / Roby, Daniel D. / Sydeman, William J. / Torres, Leigh G. / Barth, John A.

Fisheries. 2022 May, v. 47, no. 5

2022

Abstract: Forage fish are a critical component of marine ecosystems because they integrate energy across trophic levels within marine food webs. Many studies have highlighted the importance of this group, and past research efforts have focused largely on studying ... ...

Abstract	Forage fish are a critical component of marine ecosystems because they integrate energy across trophic levels within marine food webs. Many studies have highlighted the importance of this group, and past research efforts have focused largely on studying forage fish within offshore and estuarine areas. In contrast, limited information is available for forage fish on the inner continental shelf (<50 m water depth), where they encounter a range of anthropogenic stressors and support critical apex predator populations, including species of conservation concern. We highlight the importance of forage fish within inner shelf marine ecosystems using examples from the Northern California Current and describe outstanding research needs for forage fish within this topical area. Addressing these research needs is a critical step for maintaining productive forage fish populations within inner shelf ecosystems considering the social‐, management‐, and climate‐driven changes that are expected to impact coastal regions in the coming decades.
Keywords	anthropogenic stressors ; continental shelf ; energy ; estuaries ; forage fish ; Pacific Ocean
Language	English
Dates of publication	2022-05
Size	p. 213-221.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	430448-2
ISSN	0363-2415
ISSN	0363-2415
DOI	10.1002/fsh.10725
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Article ; Online: HIV risk behaviour, viraemia, and transmission across HIV cascade stages including low-level viremia: Analysis of 14 cross-sectional population-based HIV Impact Assessment surveys in sub-Saharan Africa.

Edun, Olanrewaju / Okell, Lucy / Chun, Helen / Bissek, Anne-Cecile Z / Ndongmo, Clement B / Shang, Judith D / Brou, Hermann / Ehui, Eboi / Ekra, Alexandre K / Nuwagaba-Biribonwoha, Harriet / Dlamini, Sindisiwe S / Ginindza, Choice / Eshetu, Frehywot / Misganie, Yimam G / Desta, Sileshi Lulseged / Achia, Thomas N O / Aoko, Appolonia / Jonnalagadda, Sasi / Wafula, Rose /

Asiimwe, Fred M / Lecher, Shirley / Nkanaunena, Kondwani / Nyangulu, Mtemwa K / Nyirenda, Rose / Beukes, Anita / Klemens, Johannes O / Taffa, Negussie / Abutu, Andrew A / Alagi, Matthias / Charurat, Man E / Dalhatu, Ibrahim / Aliyu, Gambo / Kamanzi, Collins / Nyagatare, Celestine / Rwibasira, Gallican N / Jalloh, Mohamed F / Maokola, Werner M / Mgomella, George S / Kirungi, Wilford L / Mwangi, Christina / Nel, Jennifer A / Minchella, Peter A / Gonese, Gloria / Nasr, Melodie A / Bodika, Stephane / Mungai, Elisabeth / Patel, Hetal K / Sleeman, Katrina / Milligan, Kyle / Dirlikov, Emilio / Voetsch, Andrew C / Shiraishi, Ray W / Imai-Eaton, Jeffrey W

PLOS global public health

2024 Volume 4, Issue 4, Page(s) e0003030

Abstract: As antiretroviral treatment (ART) coverage for people living with HIV (PLHIV) increases, HIV programmes require up-to-date information about evolving HIV risk behaviour and transmission risk, including those with low-level viremia (LLV; >50 to ≤1000 ... ...

Abstract	As antiretroviral treatment (ART) coverage for people living with HIV (PLHIV) increases, HIV programmes require up-to-date information about evolving HIV risk behaviour and transmission risk, including those with low-level viremia (LLV; >50 to ≤1000 copies/mL), to guide prevention priorities. We aimed to assess differences in sexual risk behaviours, distribution of viral load (VL) and proportion of transmission across PLHIV subgroups. We analysed data from Population-based HIV Impact Assessment surveys in 14 sub-Saharan African countries during 2015-2019. We estimated adjusted prevalence ratios (aPR) of self-reported HIV high-risk behaviour (multiple partners and condomless sex) across cascade stages via generalised estimation equations. We modelled the proportions of transmission from each subgroup using relative self-reported sexual risk, a Hill function for transmission rate by VL, and proportions within cascade stages from surveys and UNAIDS country estimates for 2010-2020. Compared to PLHIV with undetectable VL (≤50 copies/mL), undiagnosed PLHIV (aPR women: 1.28 [95% CI: 1.08-1.52]; men: 1.61 [1.33-1.95]) and men diagnosed but untreated (2.06 [1.52-2.78]) were more likely to self-report high-risk sex. High-risk behaviour was not significantly associated with LLV. Mean VL was similar among undiagnosed, diagnosed but untreated, and on ART but non-suppressed sub-groups. Across surveys, undiagnosed and diagnosed but untreated contributed most to transmission (40-91% and 1-41%, respectively), with less than 1% from those with LLV. Between 2010 and 2020, the proportion of transmission from individuals on ART but non-suppressed increased. In settings with high ART coverage, effective HIV testing, ART linkage, and retention remain priorities to reduce HIV transmission. Persons with LLV are an increasing share of PLHIV but their contribution to HIV transmission was small. Improving suppression among PLHIV on ART with VL ≥1000 copies/mL will become increasingly important.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ISSN	2767-3375
ISSN (online)	2767-3375
DOI	10.1371/journal.pgph.0003030
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Article ; Online: Toward a Cenozoic history of atmospheric CO

Hönisch, Bärbel / Royer, Dana L / Breecker, Daniel O / Polissar, Pratigya J / Bowen, Gabriel J / Henehan, Michael J / Cui, Ying / Steinthorsdottir, Margret / McElwain, Jennifer C / Kohn, Matthew J / Pearson, Ann / Phelps, Samuel R / Uno, Kevin T / Ridgwell, Andy / Anagnostou, Eleni / Austermann, Jacqueline / Badger, Marcus P S / Barclay, Richard S / Bijl, Peter K /

Chalk, Thomas B / Scotese, Christopher R / de la Vega, Elwyn / DeConto, Robert M / Dyez, Kelsey A / Ferrini, Vicki / Franks, Peter J / Giulivi, Claudia F / Gutjahr, Marcus / Harper, Dustin T / Haynes, Laura L / Huber, Matthew / Snell, Kathryn E / Keisling, Benjamin A / Konrad, Wilfried / Lowenstein, Tim K / Malinverno, Alberto / Guillermic, Maxence / Mejía, Luz María / Milligan, Joseph N / Morton, John J / Nordt, Lee / Whiteford, Ross / Roth-Nebelsick, Anita / Rugenstein, Jeremy K C / Schaller, Morgan F / Sheldon, Nathan D / Sosdian, Sindia / Wilkes, Elise B / Witkowski, Caitlyn R / Zhang, Yi Ge / Anderson, Lloyd / Beerling, David J / Bolton, Clara / Cerling, Thure E / Cotton, Jennifer M / Da, Jiawei / Ekart, Douglas D / Foster, Gavin L / Greenwood, David R / Hyland, Ethan G / Jagniecki, Elliot A / Jasper, John P / Kowalczyk, Jennifer B / Kunzmann, Lutz / Kürschner, Wolfram M / Lawrence, Charles E / Lear, Caroline H / Martínez-Botí, Miguel A / Maxbauer, Daniel P / Montagna, Paolo / Naafs, B David A / Rae, James W B / Raitzsch, Markus / Retallack, Gregory J / Ring, Simon J / Seki, Osamu / Sepúlveda, Julio / Sinha, Ashish / Tesfamichael, Tekie F / Tripati, Aradhna / van der Burgh, Johan / Yu, Jimin / Zachos, James C / Zhang, Laiming

Science (New York, N.Y.)

2023 Volume 382, Issue 6675, Page(s) eadi5177

Abstract: The geological record encodes the relationship between climate and atmospheric carbon dioxide ( ... ...

Abstract	The geological record encodes the relationship between climate and atmospheric carbon dioxide (CO
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.adi5177
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Article ; Online: Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later.

Milligan, Emma C / Olstad, Katherine / Williams, Caitlin A / Mallory, Michael / Cano, Patricio / Cross, Kaitlyn A / Munt, Jennifer E / Garrido, Carolina / Lindesmith, Lisa / Watanabe, Jennifer / Usachenko, Jodie L / Hopkins, Lincoln / Immareddy, Ramya / Shaan Lakshmanappa, Yashavanth / Elizaldi, Sonny R / Roh, Jamin W / Sammak, Rebecca L / Pollard, Rachel E / Yee, JoAnn L /

Science translational medicine

2023 Volume 15, Issue 685, Page(s) eadd6383

Abstract: The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against ... ...

Abstract	The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.
MeSH term(s)	Animals ; Humans ; Infant ; SARS-CoV-2 ; COVID-19 Vaccines ; Macaca mulatta ; COVID-19 ; Viral Vaccines ; BNT162 Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; Viral Vaccines ; BNT162 Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.add6383
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Article: Fuel use during glycogenesis in rainbow trout (Oncorhynchus mykiss Walbaum) white muscle studied in vitro.

Kam, Jennifer C / Milligan, C Louise

The Journal of experimental biology

2006 Volume 209, Issue Pt 5, Page(s) 871–880

Abstract: The purpose of this study was to examine fuel used during muscle glycogenesis in rainbow trout Oncorhynchus mykiss using an in vitro muscle slice preparation to test the hypothesis that intracellular lactate is the major glycogenic substrate and the ... ...

Abstract	The purpose of this study was to examine fuel used during muscle glycogenesis in rainbow trout Oncorhynchus mykiss using an in vitro muscle slice preparation to test the hypothesis that intracellular lactate is the major glycogenic substrate and the muscle relies upon extracellular substrates for oxidation. Fish were exhaustively exercised to reduce muscle glycogen content, muscle slices were taken from exhausted fish and incubated for 1 h in medium containing various substrates at physiological concentrations. 14C-labeled lactate, glycerol or palmitate was added and 14C incorporation into muscle glycogen and/or CO2 was measured. Lactate clearance in the absence of net glycogenesis suggests that when suitable oxidizable extracellular substrates were lacking, intracellular lactate was oxidized. Only muscle incubated in lactate, glycerol or palmitate synthesized glycogen, with the greatest synthesis in muscle incubated in lactate plus glycerol. The major fate of these extracellular substrates was oxidative, with lactate oxidized at rates 10 times that of palmitate and 100 times that of glycerol. Neither extracellular lactate nor glycerol contributed significantly to glycogenesis, with lactate carbon contributing less than 0.1% of the total glycogen synthesized, and glycerol less than 0.01%. There was 100 times more extracellular lactate-carbon incorporated into CO2 than into glycogen. In the presence of extracellular lactate, palmitate or glycerol, intracellular lactate was spared an oxidative fate, allowing it to serve as the primary substrate for in situ glycogenesis, with oxidation of extracellular substrates driving ATP synthesis. The primary fate of extracellular lactate is clearly oxidative, while that of intracellular, glycolytically derived lactate is glycogenic, which suggests intracellular compartmentation of lactate metabolism.
MeSH term(s)	Animals ; Energy Metabolism ; Female ; Glycerol/metabolism ; Glycogen/metabolism ; Lactic Acid/metabolism ; Male ; Muscle Fibers, Fast-Twitch/metabolism ; Oncorhynchus mykiss/metabolism ; Oxidation-Reduction ; Palmitic Acid/metabolism ; Substrate Specificity
Chemical Substances	Palmitic Acid (2V16EO95H1) ; Lactic Acid (33X04XA5AT) ; Glycogen (9005-79-2) ; Glycerol (PDC6A3C0OX)
Language	English
Publishing date	2006-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218085-6
ISSN	1477-9145 ; 0022-0949
ISSN (online)	1477-9145
ISSN	0022-0949
DOI	10.1242/jeb.02071
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In stock of ZB MED Cologne/Königswinter

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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