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Article ; Online: A new look at the decomposition of agricultural productivity growth incorporating weather effects.

Eric Njuki / Boris E Bravo-Ureta / Christopher J O'Donnell

PLoS ONE, Vol 13, Iss 2, p e

2018 Volume 0192432

Abstract: Random fluctuations in temperature and precipitation have substantial impacts on agricultural output. However, the contribution of these changing configurations in weather to total factor productivity (TFP) growth has not been addressed explicitly in ... ...

Abstract	Random fluctuations in temperature and precipitation have substantial impacts on agricultural output. However, the contribution of these changing configurations in weather to total factor productivity (TFP) growth has not been addressed explicitly in econometric analyses. Thus, the key objective of this study is to quantify and to investigate the role of changing weather patterns in explaining yearly fluctuations in TFP. For this purpose, we define TFP to be a measure of total output divided by a measure of total input. We estimate a stochastic production frontier model using U.S. state-level agricultural data incorporating growing season temperature and precipitation, and intra-annual standard deviations of temperature and precipitation for the period 1960-2004. We use the estimated parameters of the model to compute a TFP index that has good axiomatic properties. We then decompose TFP growth in each state into weather effects, technological progress, technical efficiency, and scale-mix efficiency changes. This approach improves our understanding of the role of different components of TFP in agricultural productivity growth. We find that annual TFP growth averaged 1.56% between 1960 and 2004. Moreover, we observe substantial heterogeneity in weather effects across states and over time.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide transcriptome study using deep RNA sequencing for myocardial infarction and coronary artery calcification

Xiaoling Zhang / Jeroen G. J. van Rooij / Yoshiyuki Wakabayashi / Shih-Jen Hwang / Yanqin Yang / Mohsen Ghanbari / Daniel Bos / BIOS Consortium / Daniel Levy / Andrew D. Johnson / Joyce B. J. van Meurs / Maryam Kavousi / Jun Zhu / Christopher J. O’Donnell

BMC Medical Genomics, Vol 14, Iss 1, Pp 1-

2021 Volume 17

Abstract: Abstract Background Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and ... ...

Abstract	Abstract Background Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. Results On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls. Conclusions We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.
Keywords	Gene expression signatures ; Protein-coding gene ; Long intergenic non-coding RNA ; Myocardial infarction ; Coronary artery calcification ; Whole blood ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	572 ; 610
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Biosynthetic engineering and fermentation media development leads to gram-scale production of spliceostatin natural products in Burkholderia sp

Eustáquio, Alessandra S / Christopher J. O׳Donnell / Frank E. Koehn / Greg L. Steele / Li-Ping Chang

International Metabolic Engineering Society Metabolic engineering. 2016 Jan., v. 33

2016

Abstract: A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural ... ...

Abstract	A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/α-ketoglutarate-dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an l-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40-fold, going from the starting ~60mg/L to 2.5g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy.
Keywords	bacteria ; bioactive properties ; bioprocess engineering ; biosynthesis ; Burkholderia ; cytochrome P-450 ; drug therapy ; drugs ; fermentation ; genes ; mutants ; neoplasms ; spliceosomes
Language	English
Dates of publication	2016-01
Size	p. 67-75.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1470383-x
ISSN	1096-7184 ; 1096-7176
ISSN (online)	1096-7184
ISSN	1096-7176
DOI	10.1016/j.ymben.2015.11.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells

Cell Reports Medicine, Vol 2, Iss 5, Pp 100279- (2021)

2021

Abstract: Summary: Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by ... ...

Abstract	Summary: Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.
Keywords	notch signaling ; NOTCH3 receptor ; DLL4 ; JAG1 ; antibody drug conjugates ; cancer stem cells ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program

PLoS ONE, Vol 17, Iss

2022 Volume 5

Abstract: Background Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. Methods An ... ...

Abstract	Background Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. Methods An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. Results The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. Conclusion A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.

PLoS ONE, Vol 17, Iss 5, p e

2022 Volume 0267900

Abstract	Background Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. Methods An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. Results The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. Conclusion A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.

Aeron M Small / Jennifer E Huffman / Derek Klarin / Julie A Lynch / Themistocles Assimes / Scott DuVall / Yan V Sun / Labiba Shere / Pradeep Natarajan / Michael Gaziano / Daniel J Rader / Peter W F Wilson / Philip S Tsao / Kyong-Mi Chang / Kelly Cho / Christopher J O'Donnell / Juan P Casas / Scott M Damrauer / VA Million Veteran Program

PLoS ONE, Vol 15, Iss 11, p e

2020 Volume 0239752

Abstract: Background Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. Methods We created a genetic risk score (GRS) for PCSK9 using four single ... ...

Abstract	Background Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. Methods We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. Results Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04). Conclusions Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multivalent peptidic linker enables identification of preferred sites of conjugation for a potent thialanstatin antibody drug conjugate.

Sujiet Puthenveetil / Haiyin He / Frank Loganzo / Sylvia Musto / Jesse Teske / Michael Green / Xingzhi Tan / Christine Hosselet / Judy Lucas / L Nathan Tumey / Puja Sapra / Chakrapani Subramanyam / Christopher J O'Donnell / Edmund I Graziani

PLoS ONE, Vol 12, Iss 5, p e

2017 Volume 0178452

Abstract: Antibody drug conjugates (ADCs) are no longer an unknown entity in the field of cancer therapy with the success of marketed ADCs like ADCETRIS and KADCYLA and numerous others advancing through clinical trials. The pursuit of novel cytotoxic payloads ... ...

Abstract	Antibody drug conjugates (ADCs) are no longer an unknown entity in the field of cancer therapy with the success of marketed ADCs like ADCETRIS and KADCYLA and numerous others advancing through clinical trials. The pursuit of novel cytotoxic payloads beyond the mictotubule inhibitors and DNA damaging agents has led us to the recent discovery of an mRNA splicing inhibitor, thailanstatin, as a potent ADC payload. In our previous work, we observed that the potency of this payload was uniquely tied to the method of conjugation, with lysine conjugates showing much superior potency as compared to cysteine conjugates. However, the ADC field is rapidly shifting towards site-specific ADCs due to their advantages in manufacturability, characterization and safety. In this work we report the identification of a highly efficacious site-specific thailanstatin ADC. The site of conjugation played a critical role on both the in vitro and in vivo potency of these ADCs. During the course of this study, we developed a novel methodology of loading a single site with multiple payloads using an in situ generated multi-drug carrying peptidic linker that allowed us to rapidly screen for optimal conjugation sites. Using this methodology, we were able to identify a double-cysteine mutant ADC delivering four-loaded thailanstatin that was very efficacious in a gastric cancer xenograft model at 3mg/kg and was also shown to be efficacious against T-DM1 resistant and MDR1 overexpressing tumor cell lines.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Phenome-wide association of 1809 phenotypes and COVID-19 disease progression in the Veterans Health Administration Million Veteran Program.

Rebecca J Song / Yuk-Lam Ho / Petra Schubert / Yojin Park / Daniel Posner / Emily M Lord / Lauren Costa / Hanna Gerlovin / Katherine E Kurgansky / Tori Anglin-Foote / Scott DuVall / Jennifer E Huffman / Saiju Pyarajan / Jean C Beckham / Kyong-Mi Chang / Katherine P Liao / Luc Djousse / David R Gagnon / Stacey B Whitbourne /

Rachel Ramoni / Sumitra Muralidhar / Philip S Tsao / Christopher J O'Donnell / John Michael Gaziano / Juan P Casas / Kelly Cho / VA Million Veteran Program COVID-19 Science Initiative

PLoS ONE, Vol 16, Iss 5, p e

2021 Volume 0251651

Abstract: Background The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. ... ...

Abstract	Background The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. Methods and results We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality. Conclusions Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 10

Abstract: Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous ...

Abstract	Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.
Keywords	Science ; Q
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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