Mammalian cytochrome P450 enzymes often metabolize many pharmaceuticals and other xenobiotics, a feature that is valuable in a biotechnology setting. However, extant P450 enzymes are typically relatively unstable, with T50 values of ∼30–40 °C. Reconstructed ancestral cytochrome P450 enzymes tend to have variable substrate selectivity compared with related extant forms, but they also have higher thermostability and therefore may be excellent tools for commercial biosynthesis of important intermediates, final drug molecules, or drug metabolites. The mammalian ancestor of the cytochrome P450 1B subfamily was herein characterized structurally and functionally, revealing differences from the extant human CYP1B1 in ligand binding, metabolism, and potential molecular contributors to its thermostability. Whereas extant human CYP1B1 has one molecule of α-naphthoflavone in a closed active site, we observed that subtle amino acid substitutions outside the active site in the ancestor CYP1B enzyme yielded an open active site with four ligand copies. A structure of the ancestor with 17β-estradiol revealed only one molecule in the active site, which still had the same open conformation. Detailed comparisons between the extant and ancestor forms revealed increases in electrostatic and aromatic interactions between distinct secondary structure elements in the ancestral forms that may contribute to their thermostability. To the best of our knowledge, this represents the first structural evaluation of a reconstructed ancestral cytochrome P450, revealing key features that appear to contribute to its thermostability.

Mario Luca Morieri
Apr 1, 2020; 69:771-783
Genetics/Genomes/Proteomics/Metabolomics

Daniel Batlle
Dec 1, 2010; 59:2994-2996
Commentaries

Miriam Cnop
Dec 1, 2005; 54:S97-S107
Section III: Inflammation and beta-Cell Death

Marlou L. Dirks
Oct 1, 2016; 65:2862-2875
Metabolism

Patrick E. MacDonald
Dec 1, 2002; 51:S434-S442
Section 5: Beta-Cell Stimulus-Secretion Coupling: Hormonal and Pharmacological Modulators

As they continue to await a resolution to the Bryce Harper sweepstakes, the Giants augmented their outfield depth by signing veteran Gerardo Parra to a Minor League deal Tuesday, sources confirmed to MLB.com's Jon Paul Morosi and Mark Feinsand.

Giants president of baseball operations Farhan Zaidi knows he will eventually have to start compiling a list of potential candidates to succeed Bruce Bochy as manager, but the upcoming search isn't currently at the forefront of his mind.

30 April 2020

Corporate Members Event Webinar

Event participants

Julian Lee, Oil Strategist, Bloomberg LP London
Dr John Sfakianakis, Associate Fellow, Middle East and North Africa Programme, Chatham House; Chief Economist and Head of Research, Gulf Research Center
Professor Paul Stevens, Distinguished Fellow, Energy, Environment and Resources Programme, Chatham House
Emily Stromquist, Director, Castlereagh Associates
Chair: Dr Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

Research Event

Event participants

Brigadier General Stephen A. Cheney, CEO, American Security Project; Member, Foreign Affairs Policy Board, US Department of State
Major General Munir Muniruzzaman, President and CEO, Bangladesh Institute of Peace and Security Studies; Former Military Advisor to the President of Bangladesh 
Rear Admiral Neil Morisetti, Director of Strategy, UK Department of Science, Technology, Engineering and Public Policy; University College London; Former UK Government Climate and Energy Security Envoy
Dr Patricia Lewis, Research Director, International Security, Chatham House
Chair: Rt Hon Sir Oliver Letwin MP, Former UK Cabinet Office Minister

Just the mention of the name Marvia Providence sends a tingle to the toes and, immediately, feet start tapping and bodies begin swaying. Before you know it, all the ‘warriors’ – prayer and otherwise – are in full flight. That’s the effect of the...

Chupski dons her mask once she ventures out in public. To the bank, the supermarket, the ­pharmacy, the ATM. So far I have never even tried on the one I have. Maybe I should have worn it last Thursday mid-­morning as I stood at the entrance to the...

It could be argued that Ender Inciarte stands as the X-factor in regard to the Braves' bid to defend last year's National League East crown and experience a successful postseason.

Jackie Applebee is a GP in Tower Hamlets in London, and is concerned that the way the GP funding formula is working doesn't take account of the earlier health needs of people in deprived areas. For more about the Tower Hamlets Save Our Surgery campaign, visit their facebook page https://www.facebook.com/SaveOurGPsurgeries BMJ Voices is a...

Obioma Ezekobe is a GP in an urgent care centre in Central Middlesex Hospital. She believes that the public need to be educated about the use of NHS resources, and be taught when it is appropriate to seek care. If you would like to contribute to this collection, please email a brief audio recording to voices@bmj.com or phone +44 (20) 3058 7427...

It’s been 10 years since electronic cigarettes hit the shelves in a big way - and since there controversy has reigned about their health effects - are they less unhealthy than smoking traditional tobacco cigarettes, and will they increase nicotine dependence? Its to that last point that new research, published on BMJ.com is looking into -...

In the UK - type 2 diabetes now affects between 5-10% of the population - and accounts for around 10% of our total NHS budget. For the individuals affected, treatments are effective at helping control glucose levels - however, the sequela associated with the disease - vascular problems, and a life expectancy that’s 6 years shorter - are still an...

A study published by The BMJ today reports a possible association between intake of highly processed (“ultra-processed”) food in the diet and cancer. Ultra-processed foods include packaged baked goods and snacks, fizzy drinks, sugary cereals, ready meals and reconstituted meat products - often containing high levels of sugar, fat, and salt, but...

In the second of our EBM round-ups, Carl Heneghan, Helen Macdonald and Duncan Jarvies are joined by Deborah Cohen, investigative journalist and scourge of device manufacturers. We're giving our verdict on the sensitivity and specificity of ketone testing for hyperemesis, and the advice to drinking more water to prevent recurrent UTIs in...

An “author pays” publishing model is the only fair way to make biomedical research findings accessible to all, say David Sanders, professor of gastroenterology at Sheffield University, but James Ashton and worries that it can lead to bias in the evidence base towards commercially driven results - as those are the researchers who can pay for open...

Direct-to-consumer genetic tests are sold online and in shops as a way to “find out what your DNA says". They insights into ancestry or disease risks; others claim to provide information on personality, athletic ability, and child talent. However, interpretation of genetic data is complex and context dependent, and DTC genetic tests may produce...

Miriam Cnop
Dec 1, 2005; 54:S97-S107
Section III: Inflammation and beta-Cell Death

This study aims to model genetic, immunologic, metabolomics, and proteomic biomarkers for development of islet autoimmunity (IA) and progression to type 1 diabetes in a prospective high-risk cohort. We studied 67 children: 42 who developed IA (20 of 42 progressed to diabetes) and 25 control subjects matched for sex and age. Biomarkers were assessed at four time points: earliest available sample, just prior to IA, just after IA, and just prior to diabetes onset. Predictors of IA and progression to diabetes were identified across disparate sources using an integrative machine learning algorithm and optimization-based feature selection. Our integrative approach was predictive of IA (area under the receiver operating characteristic curve [AUC] 0.91) and progression to diabetes (AUC 0.92) based on standard cross-validation (CV). Among the strongest predictors of IA were change in serum ascorbate, 3-methyl-oxobutyrate, and the PTPN22 (rs2476601) polymorphism. Serum glucose, ADP fibrinogen, and mannose were among the strongest predictors of progression to diabetes. This proof-of-principle analysis is the first study to integrate large, diverse biomarker data sets into a limited number of features, highlighting differences in pathways leading to IA from those predicting progression to diabetes. Integrated models, if validated in independent populations, could provide novel clues concerning the pathways leading to IA and type 1 diabetes.

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (P_interaction = 3.7 x 10^–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

An application earlier this year by Mahoe Gaming Enterprises Limited (MGEL) has not benefited from any preferential treatment by the Betting, Gaming and Lotteries Commission (BGLC). That was the finding of ex-commissioner of the Integrity...

WASHINGTON, CMC – The World Bank has predicted the sharpest decline of remittances to Latin America and the Caribbean, saying that global remittances on a whole are projected to fall by about 20 percent in 2020 due to the economic crisis...

Reds starting pitcher Anthony DeSclafani hated how his 2018 season ended and didn't need any motivation to make improvements over the winter.

THE EDITOR, Madam: THE JAMAICA Council for Persons with Disabilities (JCPD) – an agency of the Ministry of Labour...

At the outset, author Ivy Slater shares the existential crisis that spurred her to change careers. Slater’s psychosocial experience after the passing of her father and the stagnation she experienced at her printing business proved exhaustively...

2 July 2014 , Volume 90, Number 4

1 December 2014

Invitation Only Research Event

Event participants

Dr Ashwini Swain, Fellow, CUTS Institute for Regulation and Competition
Glada Lahn, Senior Research Fellow, Energy, Environment and Resources, Chatham House
Dr Gareth Price, Senior Research Fellow, Asia Programme, Chatham House

Invitation Only Research Event

Event participants

Moïse Katumbi Chapwe, Governor, Katanga Province, Democratic Republic of the Congo

Invitation Only Research Event

A rise in mortality is a price worth paying to restart the US economy, President Trump has said, as many states flout advice from scientists and reopen beaches, cinemas, or hair salons while new...

The University of Iowa recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) new-drug application (NDA) process that ultimately resulted in approval of ⁶⁸Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for ⁶⁸Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the ⁶⁸Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents.

Autoimmunity against pancreatic β-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4⁺ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4⁺ T cells, and improved regulation of CD4⁺ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin.

The Jamaica Stock Exchange (JSE) Combined Index regained lost ground on Tuesday with an advance/decline ratio of 28/38 The JSE index advanced marginally 1,154.11 points or 0.32 per cent to close at 360,497.91. The JSE Main Market Index was up...

The Jamaica Stock Exchange (JSE) Combined Index continued its mild rally on Wednesday with an advance/decline ratio of 34/29 The JSE index advanced marginally 1,983.51points or 0.55 per cent to close at 362,481.42. The JSE Main Market Index was up...

OP-ED CONTRIBUTION: COVID-19 AND THE ECONOMY FOR MOST countries in the Caribbean, the current testing for COVID-19 has not reached levels suitable for ascertaining an accurate picture of the state of outbreak and spread of the infection. This...

With immigration increasingly visible in the news and the political space in the United States and internationally, getting access to accurate, high-quality data is essential to understand immigration’s demographic effects and impacts on the economy, education and labor systems, and communities. This event marks the release of the Immigration Data Matters guide.

Marking the release of MPI President Andrew Selee's latest book, speakers explore emerging trends in migration, economic interdependence, technology innovation, and cultural exchange that are transforming the relationship between the United States and Mexico, and the policy implications of these changes for the future.

At this release of an updated version of the popular Immigration Data Matters guide, presenters discuss how to navigate and access the increasing number of data sources on immigration and immigrants in the United States and internationally.