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Article ; Online: Reply to: [{Th(C

Boronski, Josef T / Seed, John A / Hunger, David / Woodward, Adam W / van Slageren, Joris / Wooles, Ashley J / Natrajan, Louise S / Kaltsoyannis, Nikolas / Liddle, Stephen T

Nature

2022 Volume 603, Issue 7902, Page(s) E21–E22

MeSH term(s)	Chlorine
Chemical Substances	Chlorine (4R7X1O2820)
Language	English
Publishing date	2022-03-23
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-04320-6
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Article ; Online: Molly reborn in C++ and R.

Woodward, S J R / Beukes, P C / Hanigan, M D

Animal : an international journal of animal bioscience

2020 Volume 14, Issue S2, Page(s) s250–s256

Abstract: ... Language) programming language, Molly has been translated into C++. This paper describes the translation process and ...

Abstract	The dairy cow model 'Molly' is a mixed discrete event-continuous system model that simulates feeding, metabolism and lactation of dairy cows. Decades of model development have resulted in a valuable tool in dairy science. Due to the deprecation of the ACSL (Advanced Continuous Simulation Language) programming language, Molly has been translated into C++. This paper describes the translation process and discusses the advantages of the new implementation, one of which is the ability to run Molly within RStudio, a popular integrated development environment (IDE) for data science.
MeSH term(s)	Animals ; Cattle ; Computer Simulation ; Diet ; Female ; Lactation ; Milk ; Software
Language	English
Publishing date	2020-02-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2257920-5
ISSN	1751-732X ; 1751-7311
ISSN (online)	1751-732X
ISSN	1751-7311
DOI	10.1017/S1751731120000270
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Article ; Online: C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis.

McCabe, John J / Walsh, Cathal / Gorey, Sarah / Harris, Katie / Hervella, Pablo / Iglesias-Rey, Ramon / Jern, Christina / Li, Linxin / Miyamoto, Nobukazu / Montaner, Joan / Pedersen, Annie / Purroy, Francisco / Rothwell, Peter M / Sudlow, Catherine / Ueno, Yuji / Vicente-Pascual, Mikel / Whiteley, William / Woodward, Mark / Kelly, Peter J

Stroke

2023 Volume 54, Issue 5, Page(s) 1289–1299

Abstract: ... in current guidelines.: Methods: We investigated the association between hsCRP (high-sensitivity C ...

Abstract	Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase log Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.
MeSH term(s)	Humans ; Interleukin-6 ; C-Reactive Protein/analysis ; Ischemic Attack, Transient/prevention & control ; Prospective Studies ; Stroke/prevention & control ; Ischemic Stroke ; Recurrence
Chemical Substances	Interleukin-6 ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.122.040529
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Article ; Online: C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis

McCabe, John J / Walsh, Cathal / Gorey, Sarah / Harris, Katie / Hervella, Pablo / Iglesias-Rey, Ramon / Jern, Christina / Li, Linxin / Miyamoto, Nobukazu / Montaner, Joan / Pedersen, Annie / Purroy, Francisco F / Rothwell, Peter M / Sudlow, Cathie L / Ueno, Yuji / Vicente-Pascual, Mikel / Whiteley, Will N / Woodward, Mark / Kelly, Peter J

Neurology

2023 Volume 102, Issue 2, Page(s) e208016

Abstract: ... high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic ...

Abstract	Background and objectives: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention. Methods: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after log Results: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, Discussion: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.
MeSH term(s)	Humans ; Anti-Inflammatory Agents/therapeutic use ; Atherosclerosis/pathology ; C-Reactive Protein/analysis ; Cerebral Infarction/pathology ; Interleukin-6/analysis ; Stroke/drug therapy ; Stroke/pathology ; Systematic Reviews as Topic ; Recurrence
Chemical Substances	Anti-Inflammatory Agents ; C-Reactive Protein (9007-41-4) ; Interleukin-6
Language	English
Publishing date	2023-12-19
Publishing country	United States
Document type	Journal Article ; Meta-Analysis
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208016
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Article ; Online: FAAH-Catalyzed C-C Bond Cleavage of a New Multitarget Analgesic Drug.

Ligresti, Alessia / Silvestri, Cristoforo / Vitale, Rosa Maria / Martos, Jose L / Piscitelli, Fabiana / Wang, Jenny W / Allarà, Marco / Carling, Robert W / Luongo, Livio / Guida, Francesca / Illiano, Anna / Amoresano, Angela / Maione, Sabatino / Amodeo, Pietro / Woodward, David F / Di Marzo, Vincenzo / Marino, Gennaro

ACS chemical neuroscience

2018 Volume 10, Issue 1, Page(s) 424–437

Abstract: ... resulting in the cleavage of the C-C bond between the oxazole and the carboxyamide moieties, instead ... of the carbamate intermediate, thus confirming the cleavage of the aforementioned C-C bond. Quantum mechanics ...

Abstract	The discovery of extended catalytic versatilities is of great importance in both the chemistry and biotechnology fields. Fatty acid amide hydrolase (FAAH) belongs to the amidase signature superfamily and is a major endocannabinoid inactivating enzyme using an atypical catalytic mechanism involving hydrolysis of amide and occasionally ester bonds. FAAH inhibitors are efficacious in experimental models of neuropathic pain, inflammation, and anxiety, among others. We report a new multitarget drug, AGN220653, containing a carboxyamide-4-oxazole moiety and endowed with efficacious analgesic and anti-inflammatory activities, which are partly due to its capability of achieving inhibition of FAAH, and subsequently increasing the tissue concentrations of the endocannabinoid anandamide. This inhibitor behaves as a noncompetitive, slowly reversible inhibitor. Autoradiography of purified FAAH incubated with AGN220653, opportunely radiolabeled, indicated covalent binding followed by fragmentation of the molecule. Molecular docking suggested a possible nucleophilic attack by FAAH-Ser241 on the carbonyl group of the carboxyamide-4-oxazole moiety, resulting in the cleavage of the C-C bond between the oxazole and the carboxyamide moieties, instead of either of the two available amide bonds. MRM-MS analyses only detected the Ser241-assisted formation of the carbamate intermediate, thus confirming the cleavage of the aforementioned C-C bond. Quantum mechanics calculations were fully consistent with this mechanism. The study exemplifies how FAAH structural features and mechanism of action may override the binding and reactivity propensities of substrates. This unpredicted mechanism could pave the way to the future development of a completely new class of amidase inhibitors, of potential use against pain, inflammation, and mood disorders.
MeSH term(s)	Amidohydrolases/metabolism ; Analgesics/administration & dosage ; Analgesics/chemistry ; Analgesics/metabolism ; Animals ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic/chemistry ; Bridged Bicyclo Compounds, Heterocyclic/metabolism ; Carbon/chemistry ; Carbon/metabolism ; Catalysis ; Cinnamates/administration & dosage ; Cinnamates/chemistry ; Cinnamates/metabolism ; Drug Delivery Systems/methods ; Mice ; Molecular Docking Simulation/methods ; Neuralgia/drug therapy ; Neuralgia/metabolism ; Rats
Chemical Substances	AGN 211377 ; Analgesics ; Bridged Bicyclo Compounds, Heterocyclic ; Cinnamates ; Carbon (7440-44-0) ; Amidohydrolases (EC 3.5.-) ; fatty-acid amide hydrolase (EC 3.5.1.-)
Language	English
Publishing date	2018-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.8b00315
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Article: Molly reborn in C++ and R

Woodward, S. J. R / Beukes, P. C / Hanigan, M. D

Animal. 2020 Aug., v. 14, no. S2

2020

Abstract: ... Language) programming language, Molly has been translated into C++. This paper describes the translation process and ...

Abstract	The dairy cow model ‘Molly’ is a mixed discrete event-continuous system model that simulates feeding, metabolism and lactation of dairy cows. Decades of model development have resulted in a valuable tool in dairy science. Due to the deprecation of the ACSL (Advanced Continuous Simulation Language) programming language, Molly has been translated into C++. This paper describes the translation process and discusses the advantages of the new implementation, one of which is the ability to run Molly within RStudio, a popular integrated development environment (IDE) for data science.
Keywords	dairy cows ; dairy science ; lactation ; metabolism
Language	English
Dates of publication	2020-08
Size	p. s250-s256.
Publishing place	Cambridge University Press
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2257920-5
ISSN	1751-732X ; 1751-7311
ISSN (online)	1751-732X
ISSN	1751-7311
DOI	10.1017/S1751731120000270
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Protein dose-sparing effect of AS01B adjuvant in a randomized preventive HIV vaccine trial of ALVAC-HIV (vCP2438) and adjuvanted bivalent subtype C gp120.

Chirenje, Zvavahera Mike / Laher, Fatima / Dintwe, One / Muyoyeta, Monde / deCamp, Allan C / He, Zonglin / Grunenberg, Nicole / Laher Omar, Faatima / Seaton, Kelly E / Polakowski, Laura / Woodward Davis, Amanda S / Maganga, Lucas / Baden, Lindsey R / Mayer, Kenneth / Kalams, Spyros / Keefer, Michael / Edupuganti, Srilatha / Rodriguez, Benigno / Frank, Ian /

Scott, Hyman / Stranix-Chibanda, Lynda / Gurunathan, Sanjay / Koutsoukos, Marguerite / Van Der Meeren, Olivier / DiazGranados, Carlos A / Paez, Carmen / Andersen-Nissen, Erica / Kublin, James / Corey, Lawrence / Ferrari, Guido / Tomaras, Georgia / McElrath, M Juliana

The Journal of infectious diseases

2023

Abstract: ... subtype C gp120 Env protein at two dose levels in healthy HIV-uninfected adults. Trial registration URL ... received either placebo, ALVAC-HIV (vCP2438) with 200μg of bivalent subtype C gp120 adjuvanted with MF59 or ... AS01B, or ALVAC-HIV (vCP2438) with 40μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary ...

Abstract	Background: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled HIV vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at two dose levels in healthy HIV-uninfected adults. Trial registration URL https://clinicaltrials.gov/ct2/show/NCT03122223 and registration number NCT03122223. Methods: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. Results: We enrolled 160 participants, 55% females, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40μg gp120/AS01B group were higher than in either of the 200μg gp120 groups. Conclusions: The 40μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses.
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad434
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Article ; Online: Using C-DFT to develop an e-ReaxFF force field for acetophenone radical anion.

Penrod, Katheryn A / Burgess, Maximiliano Aldo / Akbarian, Dooman / Dabo, Ismaila / Woodward, W H Hunter / van Duin, Adri C T

The Journal of chemical physics

2021 Volume 155, Issue 21, Page(s) 214104

Abstract: ... to its aromaticity and positive electron affinity. In this work, constrained density functional theory (C-DFT) was ... chemistry. Then, C-DFT geometry optimizations were performed wherein an excess electron was constrained ... to each atom of acetophenone. The resulting C-DFT energy values for the various electronic positions were added ...

Abstract	Increased electricity usage over the past several decades has accelerated the need for efficient high-voltage power transmission with reliable insulating materials. Cross-linked polyethylene (XLPE) prepared via dicumyl peroxide (DCP) cross-linking has emerged as the insulator of choice for modern power cables. Although DCP cross-linking generates the desired XLPE product in high yield, other by-products are also produced. One such by-product, acetophenone, is particularly intriguing due to its aromaticity and positive electron affinity. In this work, constrained density functional theory (C-DFT) was utilized to develop an e-ReaxFF force field suitable for describing the acetophenone radical anion. Initial parameters were taken from the 2021 Akbarian e-ReaxFF force field, which was developed to describe XLPE chemistry. Then, C-DFT geometry optimizations were performed wherein an excess electron was constrained to each atom of acetophenone. The resulting C-DFT energy values for the various electronic positions were added to the e-ReaxFF training set. Next, an analogous set of structures was energy-minimized using e-ReaxFF, and equilibrium mixture compositions for the two methods were compared at multiple temperatures. Iterative fitting against C-DFT energy data was performed until satisfactory agreement was achieved. To test force field performance, molecular dynamics simulations were performed in e-ReaxFF and the resulting electronic distributions were qualitatively compared to unconstrained-DFT spin density data. By expanding our e-ReaxFF force field for XLPE, namely, adding the capability to describe acetophenone and its interactions with an excess electron, we move one step closer to a comprehensive molecular understanding of XLPE chemistry in a high-voltage power cable.
Language	English
Publishing date	2021-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/5.0064705
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Article ; Online: Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer.

Woodward, Emma R / van Veen, Elke M / Forde, Claire / Harkness, Elaine F / Byers, Helen J / Ellingford, Jamie M / Burghel, George J / Schlech, Helene / Bowers, Naomi L / Wallace, Andrew J / Howell, Sacha J / Howell, Anthony / Lalloo, Fiona / Newman, William G / Smith, Miriam J / Gareth Evans, D

Genetics in medicine : official journal of the American College of Medical Genetics

2021 Volume 23, Issue 10, Page(s) 1969–1976

Abstract: ... the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated ...

Abstract	Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results: Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2_PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20-39 = 11/520, P = 0.04) but not for CHEK2_1100delC (MS < 15 = 29/1,762, MS 20-39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P = 0.002). Conclusion: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.
MeSH term(s)	Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Checkpoint Kinase 2/genetics ; Fanconi Anemia Complementation Group N Protein/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Odds Ratio ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics
Chemical Substances	Fanconi Anemia Complementation Group N Protein ; PALB2 protein, human ; Checkpoint Kinase 2 (EC 2.7.1.11) ; CHEK2 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2021-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1038/s41436-021-01234-6
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Article ; Online: Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection.

Tang, Qing / Precit, Mimi R / Thomason, Maureen K / Blanc, Sophie F / Ahmed-Qadri, Fariha / McFarland, Adelle P / Wolter, Daniel J / Hoffman, Lucas R / Woodward, Joshua J

Cell host & microbe

2022 Volume 30, Issue 7, Page(s) 961–974.e6

Abstract: ... disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c ... in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting ... Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent ...

Abstract	Antimicrobials can impact bacterial physiology and host immunity with negative treatment outcomes. Extensive exposure to antifolate antibiotics promotes thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), commonly associated with worse clinical outcomes. We show that antibiotic-mediated disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c-di-AMP), consequently inducing host STING activation and inflammation. An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis. Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent manner. Murine lung infection with TD-SCVs revealed STING-dependent elevation of proinflammatory cytokines, causing higher airway neutrophil infiltration and activation compared with normal-colony S. aureus and hemin-dependent SCVs. Collectively, our results suggest that thymidine metabolism disruption in Firmicutes leads to elevated c-di-AMP-mediated STING-dependent inflammation, with potential impacts on antibiotic usage and infection outcomes.
MeSH term(s)	Animals ; Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/metabolism ; Cyclic AMP/metabolism ; Dinucleoside Phosphates ; Folic Acid Antagonists/metabolism ; Inflammation ; Mice ; Staphylococcal Infections/microbiology ; Staphylococcus aureus/metabolism ; Thymidine/metabolism
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Dinucleoside Phosphates ; Folic Acid Antagonists ; cyclic diadenosine phosphate ; Cyclic AMP (E0399OZS9N) ; Thymidine (VC2W18DGKR)
Language	English
Publishing date	2022-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2022.03.028
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