597 results on '"Martin, O."'
Search Results
2. The Dynamics of Per- and Polyfluoroalkyl Substances (PFAS) at Interfaces in Porous Media: A Computational Roadmap from Nanoscale Molecular Dynamics Simulation to Macroscale Modeling
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Kaveh Sookhak Lari, Greg B. Davis, Anand Kumar, John L. Rayner, Xiang-Zhao Kong, and Martin O. Saar
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Chemistry ,QD1-999 - Published
- 2024
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3. IGF-1 and IGFBP-1 as Possible Predictors of Response to Lifestyle Intervention—Results from Randomized Controlled Trials
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Nina M. T. Meyer, Stefan Kabisch, Ulrike Dambeck, Caroline Honsek, Margrit Kemper, Christiana Gerbracht, Ayman M. Arafat, Andreas L. Birkenfeld, Peter E. H. Schwarz, Jürgen Machann, Martin A. Osterhoff, Martin O. Weickert, and Andreas F. H. Pfeiffer
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IGF axis ,lifestyle intervention ,intervention response ,prediabetes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lifestyle interventions can prevent type 2 diabetes (T2DM). However, some individuals do not experience anticipated improvements despite weight loss. Biomarkers to identify such individuals at early stages are lacking. Insulin-like growth factor 1 (IGF- 1) and Insulin-like growth factor binding protein 1(IGFBP-1) were shown to predict T2DM onset in prediabetes. We assessed whether these markers also predict the success of lifestyle interventions, thereby possibly guiding personalized strategies. We analyzed the fasting serum levels of IGF-1, IGFBP-1, and Insulin-like growth factor binding protein 2 (IGFBP-2) in relation to changes in metabolic and anthropometric parameters, including intrahepatic lipids (IHLs) and visceral adipose tissue (VAT) volume, measured by magnetic resonance imaging (MRI), in 345 participants with a high risk for prediabetes (54% female; aged 36–80 years). Participants were enrolled in three randomized dietary intervention trials and assessed both at baseline and one year post-intervention. Statistical analyses were performed using IBM SPSS Statistics (version 28), and significance was set at p < 0.05. Within the 1-year intervention, overall significant improvements were observed. Stratifying individuals by baseline IGF-1 and IGFBP-1 percentiles revealed significant differences: higher IGF-1 levels were associated with more favorable changes compared to lower levels, especially in VAT and IHL. Lower baseline IGFBP-1 levels were associated with greater improvements, especially in IHL and 2 h glucose. Higher bioactive IGF-1 levels might predict better metabolic outcomes following lifestyle interventions in prediabetes, potentially serving as biomarkers for personalized interventions.
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- 2024
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4. Helicobacter pylori and Pro-Inflammatory Protein Biomarkers in Myocardial Infarction with and without Obstructive Coronary Artery Disease
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Jonatan Wärme, Martin O. Sundqvist, Marcus Hjort, Stefan Agewall, Olov Collste, Christina Ekenbäck, Mats Frick, Loghman Henareh, Claes Hofman-Bang, Jonas Spaak, Peder Sörensson, Shams Y-Hassan, Per Svensson, Bertil Lindahl, Robin Hofmann, and Per Tornvall
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myocardial infarction ,coronary artery disease ,MINOCA ,Helicobacter pylori ,inflammation ,biomarkers ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. Helicobacter pylori (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA (n = 99) in Sweden were included, complemented by matched subjects with MI-CAD (n = 99) and controls (n = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively (p = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.
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- 2023
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5. Helicobacter Pylori Virulence Factor Cytotoxin-Associated Gene A (CagA) Induces Vascular Calcification in Coronary Artery Smooth Muscle Cells
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Martin O. Sundqvist, Jonatan Wärme, Robin Hofmann, Sven-Christian Pawelzik, and Magnus Bäck
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vascular calcification ,Helicobacter pylori ,cytotoxin-associated gene A ,coronary artery smooth muscle cells ,cardiovascular disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Helicobacter pylori (H. pylori) has been associated with cardiovascular diseases. The pro-inflammatory H. pylori virulence factor cytotoxin-associated gene A (CagA) has been detected in serum exosomes of H. pylori-infected subjects and may exert systemic effects throughout the cardiovascular system. The role of H. pylori and CagA in vascular calcification was hitherto unknown. The aim of this study was to determine the vascular effects of CagA through human coronary artery smooth muscle cell (CASMC) osteogenic and pro-inflammatory effector gene expression as well as interleukin 1β secretion and cellular calcification. CagA upregulated bone morphogenic protein 2 (BMP-2) associated with an osteogenic CASMC phenotype switch and induced increased cellular calcification. Furthermore, a pro-inflammatory response was observed. These results support that H. pylori may contribute to vascular calcification through CagA rendering CASMCs osteogenic and inducing calcification.
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- 2023
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6. Synthesis, Characterization, and DNA-Binding Kinetics of New Pd(II) and Pt(II) Thiosemicarbazone Complexes: Spectral, Structural, and Anticancer Evaluation
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Simon N. Mbugua, Lydia W. Njenga, Ruth A. Odhiambo, Shem O. Wandiga, Mervin Meyer, Nicole Sibuyi, Roger A. Lalancette, and Martin O. Onani
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Chemistry ,QD1-999 - Abstract
In a bid to come up with potential anticancer agents, a class of thiosemicarbazone ligands bearing substituted thiophene were synthesized followed by complexation with various Pd(II) and Pt(II) metal precursors. The ligands (E)-1-((thiophen-2-yl)methylene)thiosemicarbazide (L1), (E)-1-((4-bromothiophen-2-yl)methylene)thiosemicarbazide (L2), and (E)-1-((5-bromothiophen-2-yl)methylene)thiosemicarbazide (L3) were synthesized by condensation reactions and obtained in good yields. Complexation of L1 and L2 with Pd(cod)Cl2 gave C1 (C6H7Cl2N3PdS2) and C2 (C6H6BrCl2N3PdS2), respectively. Complexation of L1 with K2PtCl4 gave C3 (C6H7Cl2N3PtS2), while L3 with K2PtCl2[(PPh)3]2 gave C4 (C24H21BrClN3PPtS2). The structures and coordination for all compounds were established by FTIR, 1H-NMR, 13C-NMR, UV-Vis, elemental analysis, and single-crystal X-ray diffraction studies for ligand L1. Tuning of the spectral and anticancer activity of the compounds was investigated by changing the position of the bromide substituent, metal center, and the σ or π-donor/acceptor strength of the groups surrounding the metal center. The compounds had low to moderate anticancer potency with their spectral and structural properties correlating with the corresponding anticancer activity profiles. DNA binding modes were studied by spectroscopy and were comparable to known DNA intercalators. Structure-activity profiles were evident especially between C1 and C2 differing by the presence of a Br in position 5 of thiophene ring, which caused a remarkable increase in IC50 values, from 14.71 ± 0.016 (C1) to 43.08 ± 0.001(C2) in Caco-2 cells, 1.973 ± 0.048 (C1) to 59.56 ± 0.010 (C2) in MCF-7 cells, 16.65 ± 0.051 (C1) to 72.25 ± 0.003 (C2) in HeLa cells, 14.64 ± 0.037 (C1) to 94.34 ± 0.003 (C2) in HepG2, and 14.05 ± 0.042 (C1) to >100(C2) in PC-3 cells.
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- 2020
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7. Advances in Nanotechnology towards Development of Silver Nanoparticle-Based Wound-Healing Agents
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Zimkhitha B. Nqakala, Nicole R. S. Sibuyi, Adewale O. Fadaka, Mervin Meyer, Martin O. Onani, and Abram M. Madiehe
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antimicrobial agents ,nanotechnology ,silver-based therapy ,silver nanoparticles ,wound healing ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Since antiquity, silver-based therapies have been used in wound healing, wound care and management of infections to provide adequate healing. These therapies are associated with certain limitations, such as toxicity, skin discolouration and bacterial resistance, which have limited their use. As a result, new and innovative wound therapies, or strategies to improve the existing therapies, are sought after. Silver nanoparticles (AgNPs) have shown the potential to circumvent the limitations associated with conventional silver-based therapies as described above. AgNPs are effective against a broad spectrum of microorganisms and are less toxic, effective at lower concentrations and produce no skin discolouration. Furthermore, AgNPs can be decorated or coupled with other healing-promoting materials to provide optimum healing. This review details the history and impact of silver-based therapies leading up to AgNPs and AgNP-based nanoformulations in wound healing. It also highlights the properties of AgNPs that aid in wound healing and that make them superior to conventional silver-based wound treatment therapies.
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- 2021
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8. Mechanisms of Central Hypogonadism
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Thomas M. Barber, Ioannis Kyrou, Gregory Kaltsas, Ashley B. Grossman, Harpal S Randeva, and Martin O. Weickert
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hypogonadism ,prolactin ,leptin ,Kallmann syndrome ,stress ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.
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- 2021
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9. Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air–liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells
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Martin O. Leonard, Lyle Armstrong, Maria Georgiou, Elena Tasinato, Jelle van den Bor, Majlinda Lako, Ivo Djidrovski, Medicinal chemistry, and AIMMS
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Primary (chemistry) ,Airway epithelium ,Air liquid interface ,Chemistry ,Health, Toxicology and Mutagenesis ,Air–liquid interface ,Cell Biology ,respiratory system ,Toxicity assessment ,Toxicology ,respiratory tract diseases ,Cell biology ,Transcriptome ,Induced pluripotent stem cells ,Toxicity ,Respiratory epithelium ,Induced pluripotent stem cell ,Transcriptomics ,Drug metabolism - Abstract
Abstract The airway epithelium represents the main barrier between inhaled air and the tissues of the respiratory tract and is therefore an important point of contact with xenobiotic substances into the human body. Several studies have recently shown that in vitro models of the airway grown at an air–liquid interface (ALI) can be particularly useful to obtain mechanistic information about the toxicity of chemical compounds. However, such methods are not very amenable to high throughput since the primary cells cannot be expanded indefinitely in culture to obtain a sustainable number of cells. Induced pluripotent stem cells (iPSCs) have become a popular option in the recent years for modelling the airways of the lung, but despite progress in the field, such models have so far not been assessed for their ability to metabolise xenobiotic compounds and how they compare to the primary bronchial airway model (pBAE). Here, we report a comparative analysis by TempoSeq (oligo-directed sequencing) of an iPSC-derived airway model (iBAE) with a primary bronchial airway model (pBAE). The iBAE and pBAE were differentiated at an ALI and then evaluated in a 5-compound screen with exposure to a sub-lethal concentration of each compound for 24 h. We found that despite lower expression of xenobiotic metabolism genes, the iBAE similarly predicted the toxic pathways when compared to the pBAE model. Our results show that iPSC airway models at ALI show promise for inhalation toxicity assessments with further development. Graphical abstract
- Published
- 2022
10. Dietary Influences on the Microbiota–Gut–Brain Axis
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Thomas M. Barber, Georgios Valsamakis, George Mastorakos, Petra Hanson, Ioannis Kyrou, Harpal S. Randeva, and Martin O. Weickert
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gut microbiota ,brain ,diet ,appetite ,metabolism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Over unimaginable expanses of evolutionary time, our gut microbiota have co-evolved with us, creating a symbiotic relationship in which each is utterly dependent upon the other. Far from confined to the recesses of the alimentary tract, our gut microbiota engage in complex and bi-directional communication with their host, which have far-reaching implications for overall health, wellbeing and normal physiological functioning. Amongst such communication streams, the microbiota–gut–brain axis predominates. Numerous complex mechanisms involve direct effects of the microbiota, or indirect effects through the release and absorption of the metabolic by-products of the gut microbiota. Proposed mechanisms implicate mitochondrial function, the hypothalamus–pituitary–adrenal axis, and autonomic, neuro-humeral, entero-endocrine and immunomodulatory pathways. Furthermore, dietary composition influences the relative abundance of gut microbiota species. Recent human-based data reveal that dietary effects on the gut microbiota can occur rapidly, and that our gut microbiota reflect our diet at any given time, although much inter-individual variation pertains. Although most studies on the effects of dietary macronutrients on the gut microbiota report on associations with relative changes in the abundance of particular species of bacteria, in broad terms, our modern-day animal-based Westernized diets are relatively high in fats and proteins and impoverished in fibres. This creates a perfect storm within the gut in which dysbiosis promotes localized inflammation, enhanced gut wall permeability, increased production of lipopolysaccharides, chronic endotoxemia and a resultant low-grade systemic inflammatory milieu, a harbinger of metabolic dysfunction and many modern-day chronic illnesses. Research should further focus on the colony effects of the gut microbiota on health and wellbeing, and dysbiotic effects on pathogenic pathways. Finally, we should revise our view of the gut microbiota from that of a seething mass of microbes to one of organ-status, on which our health and wellbeing utterly depends. Future guidelines on lifestyle strategies for wellbeing should integrate advice on the optimal establishment and maintenance of a healthy gut microbiota through dietary and other means. Although we are what we eat, perhaps more importantly, we are what our gut microbiota thrive on and they thrive on what we eat.
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- 2021
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11. Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction
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Thomas M. Barber, Ioannis Kyrou, Harpal S. Randeva, and Martin O. Weickert
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insulin resistance ,obesity ,metabolic dysfunction ,cognitive dysfunction ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Obesity mediates most of its direct medical sequelae through the development of insulin resistance (IR). The cellular effects of insulin occur through two main postreceptor pathways that are the phosphatidylinositol 3-kinase (PI3-K) and the mitogen-activated protein kinase (MAP-K) pathways. Obesity-related IR implicates the PI3-K pathway that confers the metabolic effects of insulin. Numerous and complex pathogenic pathways link obesity with the development of IR, including chronic inflammation, mitochondrial dysfunction (with the associated production of reactive oxygen species and endoplasmic reticulum stress), gut microbiota dysbiosis and adipose extracellular matrix remodelling. IR itself plays a key role in the development of metabolic dysfunction, including hypertension, dyslipidaemia and dysglycaemia. Furthermore, IR promotes weight gain related to secondary hyperinsulinaemia, with a resulting vicious cycle of worsening IR and its metabolic sequelae. Ultimately, IR underlies obesity-related conditions such as type 2 diabetes mellitus (T2D) and polycystic ovary syndrome (PCOS). IR also underlies many obesity-related malignancies, through the effects of compensatory hyperinsulinaemia on the relatively intact MAP-K insulin pathway, which controls cellular growth processes and mitoses. Furthermore, the emergent data over recent decades support an important role of obesity- and T2D-related central IR in the development of cognitive dysfunction, including effects on hippocampal synaptic plasticity. Importantly, IR is largely reversible through the optimisation of lifestyle factors that include regular engagement in physical activity with the avoidance of sedentariness, improved diet including increased fibre intake and sleep sufficiency. IR lies at the key crossroad between obesity and both metabolic and cognitive dysfunction. Given the importance of IR in the pathogenesis of many 21st century chronic diseases and its eminent reversibility, it is important that we all embrace and facilitate optimised lifestyles to improve the future health and wellbeing of the populace.
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- 2021
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12. Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma
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Jan Borén, Levent M. Akyürek, Per Fogelstrand, Matias Ekstrand, Joakim Karlsson, Max Levin, Malin Levin, Keith E. Mostov, Lars Ny, Martin O. Bergo, Jonas Nilsson, Sara Bjursten, Zhiyuan Zhao, Kristell Le Gal, Andrew J. Ewald, and Ankur Pandita
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Male ,Skin Neoplasms ,Angiogenesis ,MMP9 ,Matrix metalloproteinase ,Medical and Health Sciences ,Pathology and Forensic Medicine ,Mice ,chemistry.chemical_compound ,80 and over ,Genetics ,Pathology ,medicine ,Animals ,Humans ,2.1 Biological and endogenous factors ,PTEN ,Tensin ,Aetiology ,Intussusceptive angiogenesis ,Melanoma ,Neovascularization ,Aged ,Cancer ,Aged, 80 and over ,Pathologic ,Neovascularization, Pathologic ,biology ,Regular Article ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor ,Matrix Metalloproteinase 9 ,chemistry ,Cancer research ,biology.protein ,Heterografts ,Female ,Biotechnology - Abstract
Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor-driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.
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- 2021
13. Crystal structure of 2,2′-(propane-1,3-dilylbis(azaneylylidene))bis(methanylylidene)bis(4-methylphenol), C19H22N2O2
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Paul K. Tarus, Martin O. Onani, Samuel T. Lutta, Roger A. Lalancette, and Daniel M. Orang’o
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Inorganic Chemistry ,chemistry.chemical_compound ,Chemistry ,Propane ,Polymer chemistry ,General Materials Science ,Crystal structure ,Condensed Matter Physics - Abstract
C19H22N2O2, monoclinic, P21/c (no. 14), a = 19.3063(4) Å, b = 5.83200(10) Å, c = 14.7996(3) Å, β = 92.715(1)°, V = 1664.48(6) Å3, Z = 4, R gt (F) = 0.0423, wR ref (F 2) = 0.1102, T = 100(2) K.
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- 2021
14. Crystal structure of 2,2′-(butane-1,4-diylbis(azanylylidene))bis(methanylylidene))bis(4-methoxyphenol), C20H24N2O4
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Martin O. Onani, Samuel T. Lutta, Paul K. Tarus, Daniel M. Orang’o, and Roger A. Lalancette
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Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,4-Methoxyphenol ,General Materials Science ,Butane ,Crystal structure ,Condensed Matter Physics ,Medicinal chemistry - Abstract
C20H24N2O4, monoclinic, P21/n (no. 14), a = 11.0474(3) Å, b = 6.0853(2) Å, c = 13.9881(4) Å, β = 104.271(2)°, V = 911.36(5) Å3, Z = 2, R gt (F) = 0.0290, wR ref (F 2) = 0.0728, T = 100(2) K.
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- 2021
15. A novel roadmap connecting the 1H-MRS total choline resonance to all hallmarks of cancer following targeted therapy
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Egidio Iorio, Francis G. Blankenberg, Jason A. Koutcher, Franca Podo, Joseph F. Norfray, and Martin O. Leach
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0301 basic medicine ,lcsh:Medical physics. Medical radiology. Nuclear medicine ,Programmed cell death ,Cell signaling ,medicine.medical_treatment ,lcsh:R895-920 ,Targeted therapy ,Choline ,Unfolded protein response ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Magnetic resonance spectroscopy ,medicine ,Radiology, Nuclear Medicine and imaging ,Cancer ,medicine.disease ,030104 developmental biology ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Biomarker (medicine) ,Biomarkers - Abstract
This review describes a cellular adaptive stress signalling roadmap connecting the 1H magnetic resonance spectroscopy (MRS) total choline peak at 3.2 ppm (tCho) to cancer response after targeted therapy (TT). Recent research on cell signalling, tCho metabolism, and TT of cancer has been retrospectively re-examined. Signalling research describes how the unfolded protein response (UPR), a major stress signalling network, transduces, regulates, and rewires the total membrane turnover in different cancer hallmarks after a TT stress. In particular, the UPR signalling maintains or increases total membrane turnover in all pro-survival hallmarks, whilst dramatically decreases turnover during apoptosis, a pro-death hallmark. Recent research depicts the TT-induced stress as a crucial event responsible for interrupting UPR pro-survival pathways, leading to an UPR-mediated cell death. The 1H-MRS tCho resonance represents the total mobile precursors and products during the enzymatic modification of phosphatidylcholine membrane abundance. The tCho profile represents a biomarker that noninvasively monitors TT-induced enzymatic changes in total membrane turnover in a wide variety of existing and new anticancer treatments targeting specific layers of the UPR signalling network. Our overview strongly suggests further evaluating and validating the 1H-MRS tCho peak as a powerful noninvasive imaging biomarker of cancer response in TT clinical trials.
- Published
- 2021
16. Toward a New Therapy for Rapidly Aging Children
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Mohamed X. Ibrahim and Martin O. Bergo
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Chemistry ,business.industry ,General Chemical Engineering ,Medicine ,General Chemistry ,business ,QD1-999 ,First Reactions - Published
- 2021
17. Heterolytic Scission of Hydrogen Within a Crystalline Frustrated Lewis Pair
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Luke L. Daemen, Bojana Ginovska, Anibal J. Ramirez-Cuesta, Abhijeet J. Karkamkar, Madison B. Martinez, Timo Repo, Mark E. Bowden, Konstantin Chernichenko, Martin O. Jones, Seth A. Miller, Tom Autrey, Gregory K. Schenter, Noemi Leick, and Department of Chemistry
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Hydrogen ,116 Chemical sciences ,Ab initio ,chemistry.chemical_element ,Crystal structure ,010402 general chemistry ,FE ,01 natural sciences ,Heterolysis ,Frustrated Lewis pair ,ACTIVATION ,Inorganic Chemistry ,Crystal ,DESIGN ,Physical and Theoretical Chemistry ,Bond cleavage ,H-2 ,010405 organic chemistry ,CATALYTIC-HYDROGENATION ,REACTIVITY ,0104 chemical sciences ,Crystallography ,chemistry ,biological sciences ,CO2 ,COMPLEXES ,C6F5 ,Single crystal - Abstract
We report the heterolysis of molecular hydrogen under ambient conditions by the crystalline frustrated Lewis pair (FLP) 1-{2-[bis (pentafluorophenyOboryl] phenyl -2, 2,6,6-tetrame-thylpiperidine (KCAT). The gas-solid reaction provides an approach to prepare the solvent-free, polycrystalline ion pair KCATH2 through a single crystal to single crystal transformation. The crystal lattice of KCATH2 increases in size relative to the parent KCAT by approximately 2%. Microscopy was used to follow the transformation of the highly colored red/orange KCAT to the colorless KCATH2 over a period of 2 h at 300 K under a flow of H-2 gas. There is no evidence of crystal decrepitation during hydrogen uptake. Inelastic neutron scattering employed over a temperature range from 4-200 K did not provide evidence for the formation of polarized H-2 in a precursor complex within the crystal at low temperatures and high pressures. However, at 300 K, the INS spectrum of KCAT transformed to the INS spectrum of KCATH2. Calculations suggest that the driving force is more favorable in the solid state compared to the solution or gas phase, but the addition of H-2 into the KCAT crystal is unfavorable. Ab Initio methods were used to calculate the INS spectra of KCAT, KCATH2, and a possible precursor complex of H-2 in the pocket between the B and N of crystalline KCAT. Ex-situ NMR showed that the transformation from KCAT to KCATH2 is quantitative and our results suggest that the hydrogen heterolysis process occurs via H-2 diffusion into the FLP crystal with a rate-limiting movement of H-2 from inactive positions to reactive sites.
- Published
- 2020
18. Quantitative Genetic Analysis of Hydroxycinnamic Acids in Maize (Zea mays L.) for Plant Improvement and Production of Health-Promoting Compounds
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Carolyn J. Butts-Wilmsmeyer, Martin O. Bohn, and Rita H. Mumm
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0106 biological sciences ,Abiotic component ,chemistry.chemical_classification ,food.ingredient ,Chemistry ,Food additive ,010401 analytical chemistry ,food and beverages ,Growing season ,General Chemistry ,Hydroxycinnamic acid ,01 natural sciences ,0104 chemical sciences ,Ferulic acid ,Test weight ,chemistry.chemical_compound ,food ,Genetic variation ,Food science ,General Agricultural and Biological Sciences ,010606 plant biology & botany ,Hybrid - Abstract
Hydroxycinnamic acids, including ferulic acid and p-coumaric acid, have been tied to multiple positive health and agronomic benefits. However, little work has been done to improve the concentration of hydroxycinnamic acids in maize. We evaluated a set of 12 commercially important maize (Zea mays L.) inbred lines and 66 hybrids derived from their crosses for hydroxycinnamic acid concentration in the grain, grain yield, and test weight. The grain was obtained from replicated field experiments, which were conducted for 3 years. Both ferulic acid and p-coumaric acid were found to be highly heritable, and most of the genetic variation was additive. Grain yield and test weight were not correlated with hydroxycinnamic acid concentration. These findings suggest that breeding maize for improved hydroxycinnamic acid concentration is feasible. Maize hybrids with high hydroxycinnamic acid concentrations in the grain could be useful for the production of dietary supplements or all-natural food additives while imparting enhanced resistance to biotic and abiotic stresses during the growing season and grain storage.
- Published
- 2020
19. New Palladium(II) and Platinum(II) Complexes Based on Pyrrole Schiff Bases: Synthesis, Characterization, X-ray Structure, and Anticancer Activity
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Martin O. Onani, Lydia W. Njenga, Simon N. Mbugua, Shem O. Wandiga, Roger A. Lalancette, Mervin Meyer, Nicole Remaliah Samantha Sibuyi, and Ruth A. Odhiambo
- Subjects
Schiff base ,biology ,General Chemical Engineering ,Molar conductivity ,chemistry.chemical_element ,General Chemistry ,biology.organism_classification ,Binding constant ,Medicinal chemistry ,Article ,HeLa ,chemistry.chemical_compound ,Chemistry ,chemistry ,Bromide ,Methylene ,Platinum ,QD1-999 ,Palladium - Abstract
New palladium (Pd)II and platinum (Pt)II complexes (C1-C5) from the Schiff base ligands, R-(phenyl)methanamine (L1), R-(pyridin-2-yl)methanamine (L2), and R-(furan-2-yl)methanamine (L3) (R-(E)-N-((1H-pyrrol-2-yl) methylene)) are herein reported. The complexes (C1-C5) were characterized by FTIR, 1H and 13C NMR, UV-vis, and microanalyses. Single-crystal X-ray crystallographic analysis was performed for the two ligands (L1-L2) and a Pt complex. Both L1 and L2 belong to P21/n monoclinic and P-1 triclinic space systems, respectively. The complex C5 belongs to the P21/c monoclinic space group. The investigated molar conductivity of the complexes in DMSO gave the range 4.0-8.8 μS/cm, suggesting neutrality, with log P values ≥ 1.2692 ± 0.004, suggesting lipophilicity. The anticancer activity and mechanism of the complexes were investigated against various human cancerous (Caco-2, HeLa, HepG2, MCF-7, and PC-3) and noncancerous (MCF-12A) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Apopercentage assays, respectively. C5 demonstrated strong DNA-binding affinity for calf thymus DNA (CT-DNA) with a binding constant of 8.049 × 104 M-1. C3 reduced cell viability of all the six cell lines, which included five cancerous cell lines, by more than 80%. The C5 complex also demonstrated remarkably high selectivity with no cytotoxic activity toward the noncancerous breast cell line but reduced the viability of the five cancerous cell lines, which included one breast cancer cell line, by more than 60%. Further studies are required to evaluate the selective toxicity of these two complexes and to fully understand their mechanism of action.
- Published
- 2020
20. Synthesis, characterization and antibacterial activity studies of new 2-pyrral-L-amino acid Schiff base palladium (II) complexes
- Author
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Phumuzile Dube, Eunice A. Nyawade, Martin O. Onani, and Samantha Meyer
- Subjects
General Chemical Engineering ,chemistry.chemical_element ,02 engineering and technology ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Industrial and Manufacturing Engineering ,chemistry.chemical_compound ,Staphylococcus epidermidis ,Materials Chemistry ,medicine ,Imidazole ,Indole test ,chemistry.chemical_classification ,Schiff base ,biology ,General Chemistry ,021001 nanoscience & nanotechnology ,biology.organism_classification ,0104 chemical sciences ,Amino acid ,chemistry ,Staphylococcus aureus ,0210 nano-technology ,Antibacterial activity ,Palladium ,Nuclear chemistry - Abstract
Three new 2-pyrral amino acid Schiff base palladium (II) complexes were synthesized, characterized and their activity against six bacterial species was investigated. The ligands: Potassium 2-pyrrolidine-L-methioninate (L1), Potassium 2-pyrrolidine-L-histidinate (L2) and Potassium 2-pyrrolidine-L-tryptophanate (L3) were synthesized and reacted with dichloro(1,5-cyclooctadiene)palladium(II) to form new palladium (II) complexes C1, C2 and C3, respectively. 1H NMR, FTIR, UV–Vis, elemental analysis and conductivity measurements were used to characterize the products. The antibacterial activities of the compounds were evaluated against Gram-positive Staphylococcus aureus (S. aureus, ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591), Staphylococcus epidermidis (S. epidermidis, ATCC 12228) and Streptococcus pyogenes (S. pyogenes, ATCC 19615) and, gram-negative Pseudomonas aeruginosa (P. aeruginosa, ATCC 27853) and Klebsiella pneumoniae (K. pneumoniae, ATCC 13883) using the agar well diffusion assay and microtitre plate serial dilution method. The palladium complexes were active against the selected bacteria with the imidazole ring containing complex C2 and indole heterocyclic ring containing complex C3 showing the highest activity.
- Published
- 2020
21. The Gestational Effects of Maternal Appetite Axis Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review
- Author
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Angelos Dimas, Anastasia Politi, George Papaioannou, Thomas M. Barber, Martin O. Weickert, Dimitris K. Grammatopoulos, Sudhesh Kumar, Sophia Kalantaridou, and Georgios Valsamakis
- Subjects
fetal adiposity ,gut hormones ,QH301-705.5 ,Appetite ,Review ,leptin ,Catalysis ,Inorganic Chemistry ,Fetal Development ,Gastrointestinal Hormones ,maternal hyperphagia ,Fetus ,Pregnancy ,Birth Weight ,Humans ,Obesity ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Pregnancy Complications ,Chemistry ,ghrelin ,IGF-1 ,Female ,GLP-1 ,RC - Abstract
Increased maternal food intake is considered a normal pregnancy adjustment. However, the overavailability of nutrients may lead to dysregulated fetal development and increased adiposity, with long-lasting effects on offspring in later life. Several gut-hormone molecules regulate maternal appetite, with both their orexigenic and anorectic effects being in a state of sensitive equilibrium. The aim of this manuscript is to systematically review literature on the effects of maternal gut-hormone molecules on fetal growth and metabolism, birth weight and the later metabolic health of offspring. Maternal serum ghrelin, leptin, IGF-1 and GLP-1 appear to influence fetal growth; however, a lack of consistent and strong correlations of maternal appetite axis hormones with birth weight and the concomitant correlation with fetal and birth waist circumference may suggest that these molecules primarily mediate fetal energy deposition mechanisms, preparing the fetus for survival after birth. Dysregulated intrauterine environments seem to have detrimental, sex-dependent effects on fetal energy stores, affecting not only fetal growth, fat mass deposition and birth weight, but also future metabolic and endocrine wellbeing of offspring.
- Published
- 2022
22. Sequestration of Heavy Metal Pollutants by Fe3O4-based Composites
- Author
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Martin O. Onani and Linda Ouma
- Subjects
Pollutant ,Materials science ,Magnetism ,Metal ions in aqueous solution ,Metal ,chemistry.chemical_compound ,Adsorption ,chemistry ,visual_art ,visual_art.visual_art_medium ,Water treatment ,Composite material ,Groundwater ,Magnetite - Abstract
Heavy metal pollution poses a grave environmental threat. Some of the most toxic metals are highly mobile and, therefore, easily transported through ground water systems, thus, affecting large areas. Over the last decade, adsorption has been greatly focused on as a strategy for contaminated water treatment. Its versatility and relative ease of application have been a major determinant of its preference. Nanosized adsorbents have high surface areas and are size tunable and, hence, have been favored in adsorption applications. The magnetic properties of nanosized magnetite (Fe3O4) have made them particularly favorable. Magnetite composites with various materials have widely been applied in the adsorptive treatment of real and synthetic water containing heavy metal pollutants. This review outlines the application of Fe3O4 nanoparticles and Fe3O4 organic composites in the adsorption of heavy metal ions in aqueous solution. The reviewed articles indicate that the formation of Fe3O4 inorganic–organic composites improves the adsorption efficiencies of the composites and improves their applicability by providing magnetic separability. The presence of Fe3O4 nanoparticles in the composite materials also provides for improved reusability of the adsorbent. Generally, the formation of these composites tends to make adsorption a more viable alternative to conventional water treatment options for heavy metal pollutants in water.
- Published
- 2021
23. Commentary: GPR160 De-Orphanization Reveals Critical Roles in Neuropathic Pain in Rodents (Finally, a Receptor for CART Peptide)
- Author
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Michael J. Kuhar and Martin O. Job
- Subjects
Cart ,Orphan receptor ,chemistry.chemical_compound ,chemistry ,Neuropathic pain ,Biology ,Neurotransmitter ,Receptor ,Neuroscience ,CART peptide ,Cocaine and amphetamine regulated transcript ,G protein-coupled receptor - Abstract
1. Abstract The discovery of the CART transcript and peptides implicated CART peptide (CARTp) as a neurotransmitter involved in the action of psychostimulants and several other physiological processes, buttressing the importance of the CARTp system. While there is evidence that a receptor(s) for CARTp exists, the receptor(s) has/have not been cloned. To understand how CARTp functions, it is important to identify its receptor(s). Given the evidence that CARTp receptor is a GPCR, a reasonable approach to searching for a CARTp receptor is to closely examine GPCR orphan receptors, receptors for which there are no known neurotransmitters. One of such GPCR orphan receptors that may be linked directly to CARTp function is GPR160. While studying neuropathic pain, Yosten et al (2020) identified CARTp effects were related to GPR160 expression. While studying food and water intake, Haddock et al (2021) also determined that the effects of CARTp were blocked by immuno-neutralization of GPR160. These findings suggest that the orphan receptor GPR160 may be the elusive CARTp receptor, a welcome observation after so many years of searching. This important discovery will advance the understanding of the CARTp system, including facilitating drug screening for small molecule agonists and antagonists and the identification of therapeutic compounds.
- Published
- 2021
24. Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice
- Author
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Rui Zhong, David A. Bennett, Shaowu Cheng, Angela Jeong, Ling Li, and Martin O. Bergo
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Male ,Farnesyltransferase ,Farnesyl pyrophosphate ,Plaque, Amyloid ,Small GTPases ,chemistry.chemical_compound ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Extracellular Signal-Regulated MAP Kinases ,Aged, 80 and over ,Mice, Knockout ,Neurons ,biology ,Behavior, Animal ,Brain ,Isoprenoids ,Cell biology ,Cholesterol ,Protein farnesylation ,lipids (amino acids, peptides, and proteins) ,Female ,Alzheimer’s disease ,Signal Transduction ,Amyloid ,Transgene ,Protein Prenylation ,Mice, Transgenic ,Mechanistic Target of Rapamycin Complex 1 ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Prenylation ,Downregulation and upregulation ,Alzheimer Disease ,Presenilin-1 ,Animals ,Farnesyltranstransferase ,Humans ,Cognitive Dysfunction ,RC346-429 ,organic chemicals ,Research ,Disease Models, Animal ,030104 developmental biology ,chemistry ,biology.protein ,Protein prenylation ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,030217 neurology & neurosurgery - Abstract
The pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.
- Published
- 2021
25. Reversal of Insulin Resistance in Overweight and Obese Subjects by trans-Resveratrol and Hesperetin Combination—Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation
- Author
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Mingzhan Xue, Paul J. Thornalley, Naila Rabbani, and Martin O. Weickert
- Subjects
0301 basic medicine ,Male ,obesity ,Glycosylation ,glyoxalase ,Blood Pressure ,Body Mass Index ,chemistry.chemical_compound ,0302 clinical medicine ,insulin resistance ,methylglyoxal ,low-grade inflammation ,TX341-641 ,Correlation of Data ,Nutrition and Dietetics ,Cross-Over Studies ,Methylglyoxal ,Hesperetin ,Pyruvaldehyde ,Drug Therapy, Combination ,Female ,medicine.symptom ,Inflammation Mediators ,TXNIP ,Adult ,medicine.medical_specialty ,Thioredoxin-Interacting Protein ,030209 endocrinology & metabolism ,Inflammation ,Peripheral blood mononuclear cell ,Article ,03 medical and health sciences ,Insulin resistance ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Dyslipidemias ,Glucose Metabolism Disorders ,Nutrition. Foods and food supply ,business.industry ,Tumor Necrosis Factor-alpha ,Hesperidin ,nutritional and metabolic diseases ,Overweight ,medicine.disease ,polyphenol ,030104 developmental biology ,Endocrinology ,chemistry ,Resveratrol ,Dietary Supplements ,Leukocytes, Mononuclear ,business ,Carrier Proteins ,Dyslipidemia ,Food Science - Abstract
The dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP), induces expression of glyoxalase 1, countering the accumulation of reactive dicarbonyl glycating agent, methylglyoxal (MG), in overweight and obese subjects. tRES-HESP produced reversal of insulin resistance, improving dysglycemia and low-grade inflammation in a randomized, double-blind, placebo-controlled crossover study. Herein, we report further analysis of study variables. MG metabolism-related variables correlated with BMI, dysglycemia, vascular inflammation, blood pressure, and dyslipidemia. With tRES-HESP treatment, plasma MG correlated negatively with endothelial independent arterial dilatation (r = −0.48, p <, 0.05) and negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity (r = −0.68, p <, 0.05)—a marker of the activation status of transcription factor Nrf2. For change from baseline of PBMC gene expression with tRES-HESP treatment, Glo1 expression correlated negatively with change in the oral glucose tolerance test area-under-the-curve plasma glucose (ΔAUGg) (r = −0.56, p <, 0.05) and thioredoxin interacting protein (TXNIP) correlated positively with ΔAUGg (r = 0.59, p <, 0.05). Tumor necrosis factor-α (TNFα) correlated positively with change in fasting plasma glucose (r = 0.70, p <, 0.001) and negatively with change in insulin sensitivity (r = −0.68, p <, 0.01). These correlations were not present with placebo. tRES-HESP decreased low-grade inflammation, characterized by decreased expression of CCL2, COX-2, IL-8, and RAGE. Changes in CCL2, IL-8, and RAGE were intercorrelated and all correlated positively with changes in MLXIP, MAFF, MAFG, NCF1, and FTH1, and negatively with changes in HMOX1 and TKT, changes in IL-8 also correlated positively with change in COX-2. Total urinary excretion of tRES and HESP metabolites were strongly correlated. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for further evaluation for treatment of insulin resistance and related disorders.
- Published
- 2021
26. Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs
- Author
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Martin O Schmiady, Thomas F. Lüscher, Peter Libby, Giovanni G. Camici, Alexander Akhmedov, Michael Reinehr, Simon Kraler, and Paul C. Evans
- Subjects
medicine.medical_specialty ,Vascular smooth muscle ,Endothelium ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Vascular Remodeling ,Risk Assessment ,Article ,Nitric oxide ,Coronary artery disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Coronary Artery Bypass ,Mammary Arteries ,Stroke ,Vascular Patency ,Health Services Needs and Demand ,biology ,business.industry ,medicine.disease ,Atherosclerosis ,Plaque, Atherosclerotic ,Nitric oxide synthase ,medicine.anatomical_structure ,Treatment Outcome ,chemistry ,Cardiology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Artery - Abstract
Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.
- Published
- 2021
27. 338-OR: Reversal of Insulin Resistance by Resveratrol and Hesperetin Combination in Overweight and Obese Subjects Correlates with Decrease in Expression of Thioredoxin Interacting Protein
- Author
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Naila Rabbani, Mingzhan Xue, Martin O. Weickert, and Paul J. Thornalley
- Subjects
medicine.medical_specialty ,Thioredoxin-Interacting Protein ,Endocrinology, Diabetes and Metabolism ,Methylglyoxal ,Hesperetin ,Resveratrol ,medicine.disease ,Peripheral blood mononuclear cell ,Crossover study ,chemistry.chemical_compound ,Endocrinology ,Insulin resistance ,chemistry ,Internal medicine ,Internal Medicine ,medicine ,Unfolded protein response - Abstract
Trans-Resveratrol and hesperetin combination (tRES-HESP) in randomized, double-blind, placebo-controlled crossover study in overweight and obese subjects corrected insulin resistance; healthy aging through functional food study (HATFF, Clinicaltrials.gov identifier NCT02095873). tRES-HESP is an optimized supplement for induction of expression of glyoxalase 1 (Glo1) via activation of transcription factor Nrf2. Increased Glo1 expression decreases reactive metabolite, methylglyoxal (MG), contributing to insulin resistance through glycation-linked unfolded protein formation and activation of the unfolded protein response (UPR). Herein, we report further analysis of study variables and follow-up reverse translational studies. With tRES-HESP treatment, plasma MG correlated negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity - a marker of Nrf2 activation (r = - 0.68, P Disclosure M. Xue: None. M. Weickert: None. N. Rabbani: None. P. Thornalley: None. Funding Qatar Foundation; Qatar University
- Published
- 2021
28. Analysis of vibrational modes from alpha-synuclein: a theoretical model using density functional theory and Raman spectroscopy
- Author
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Miguel G. Ramírez-Elías, Martin O. Mendez, Ricardo A. Guirado-López, Alfonso Alba, Ildelfonso Rodríguez-Leyva, and Fabiola León-Bejarano
- Subjects
Alpha-synuclein ,Physics ,Biomedical Engineering ,A protein ,Bioengineering ,Applied Microbiology and Biotechnology ,nervous system diseases ,chemistry.chemical_compound ,symbols.namesake ,Nuclear magnetic resonance ,nervous system ,chemistry ,Molecular vibration ,Synuclein ,symbols ,Density functional theory ,Raman spectroscopy ,Biotechnology - Abstract
Parkinson’s disease is a neurodegenerative pathology difficult to diagnose. Researches have confirmed the presences of death cells in the brain produced by the modification of a protein called alpha-synuclein synuclein in people with Parkinson disease. Currently, a great amount of research is conducted to identify its biomarkers for early diagnostics. Recently, a studio found differences between the alpha- synuclein of the skin from Parkinson’s disease and normal patients. In this paper, we use Raman spectroscopy through a numerical model to simulate the vibrational modes of well-defined finite clusters of alpha-synuclein in normal and pathological state, using the Gaussian09 software. The results of the model in the range of x − y cm−1 are in good agreement with the experimental Raman spectra acquired from human skin with alpha-synuclein in the normal and pathological state.
- Published
- 2019
29. De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy
- Author
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Anne Christine Lf Wong Te Fong, James Mui, Roland A. Fleck, Lesley-Ann Martin, Gigin Lin, Louise Howell, Elham Shamsaei, Yuen-Li Chung, Gabriela Andrejeva, Florence I. Raynaud, Joanna Nikitorowicz-Buniak, Sharon Gowan, Yasmin Asad, Harry G. Parkes, Melanie Valenti, Vladimir Kirkin, Gema Vizcay-Barrena, and Martin O. Leach
- Subjects
0301 basic medicine ,Autophagosome ,autophagy ,Bioenergetics ,CTP:phosphocholine cytidylyltransferase ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Phosphatidylcholine ,Molecular Biology ,phosphatidylcholine ,030102 biochemistry & molecular biology ,Vesicle ,fungi ,Autophagy ,food and beverages ,Cell Biology ,Cell biology ,030104 developmental biology ,chemistry ,choline phospholipids ,propargylcholine ,Cancer cell ,Autophagosome membrane ,Homeostasis ,Research Article ,Research Paper - Abstract
Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. Abbreviations AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5ʹ-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type
- Published
- 2019
30. Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions
- Author
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Donghai Wang, Malin C. Erlandsson, Mohamed X. Ibrahim, Israiel T. Kumar, Christin Karlsson, Cord Brakebusch, Xiufeng Xu, Volkan I. Sayin, Maria Bokarewa, Omar M. Khan, Emil G. Ivarsson, Martin O. Bergo, Murali K. Akula, and Mikael Brisslert
- Subjects
rac1 GTP-Binding Protein ,0301 basic medicine ,Mice, 129 Strain ,RHOA ,Science ,Protein Prenylation ,General Physics and Astronomy ,Mice, Transgenic ,RAC1 ,02 engineering and technology ,Signal transduction ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,Prenylation ,Animals ,lcsh:Science ,Innate immunity ,Inflammation ,Mice, Knockout ,Alkyl and Aryl Transferases ,Multidisciplinary ,Innate immune system ,biology ,Chemistry ,Effector ,Macrophages ,Signal transducing adaptor protein ,General Chemistry ,021001 nanoscience & nanotechnology ,Immunity, Innate ,Cell biology ,Mice, Inbred C57BL ,RAW 264.7 Cells ,030104 developmental biology ,ras GTPase-Activating Proteins ,biology.protein ,Cytokines ,Protein prenylation ,lcsh:Q ,0210 nano-technology ,Protein Binding - Abstract
Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-I in mouse macrophages increases GTP-loading of Rho proteins, leading to enhanced inflammatory responses and severe rheumatoid arthritis. Here we show that heterozygous deletion of the Rho family gene Rac1, but not Rhoa and Cdc42, reverses inflammation and arthritis in GGTase-I-deficient mice. Non-prenylated Rac1 has a high affinity for the adaptor protein Ras GTPase-activating-like protein 1 (Iqgap1), which facilitates both GTP exchange and ubiquitination-mediated degradation of Rac1. Consistently, inactivating Iqgap1 normalizes Rac1 GTP-loading, and reduces inflammation and arthritis in GGTase-I-deficient mice, as well as prevents statins from increasing Rac1 GTP-loading and cytokine production in macrophages. We conclude that blocking prenylation stimulates Rac1 effector interactions and unleashes proinflammatory signaling. Our results thus suggest that prenylation normally restrains innate immune responses by preventing Rac1 effector interactions., Macrophage specific deletion of GGTase-I, a prenylation enzyme, in mice induces inflammatory response and rheumatoid arthritis. Here the authors show that GGTase-I deficiency and the resulting reduction of RAC1 prenylation increase RAC1 interaction with the adaptor protein IQGAP1, leading to GTP-loading of RAC1 and enhanced proinflammatory cytokine production.
- Published
- 2019
31. A behavioral economic analysis of the effects of rimcazole on reinforcing effects of cocaine injection and food presentation in rats
- Author
-
Martin O. Job and Jonathan L. Katz
- Subjects
Male ,Reinforcement Schedule ,Rimcazole ,Carbazoles ,Self Administration ,Pharmacology ,Article ,Rats, Sprague-Dawley ,Eating ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cocaine ,medicine ,Animals ,Economic analysis ,Dopamine transporter ,Dose-Response Relationship, Drug ,biology ,Economic demand ,Methylphenidate ,business.industry ,Economics, Behavioral ,Antagonist ,Rats ,030227 psychiatry ,Blockade ,Neuroprotective Agents ,chemistry ,biology.protein ,Self-administration ,business ,Reinforcement, Psychology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
RATIONALE AND OBJECTIVES: Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects. METHODS: Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q(0)) and sensitivity to price (essential value, EV), derived. RESULTS: Rimcazole dose-dependently decreased Q(0) and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q(0) at the lower cocaine dose/injection, but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. CONCLUSIONS: Though the drug combinations only replicated rimcazole’s effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.
- Published
- 2019
32. Structural and optical properties of novel CdSe nanoparticles produced via a facile synthetic route: Studies on the effects of cadmium sources
- Author
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Francis B. Dejene, Sharon Kiprotich, and Martin O. Onani
- Subjects
Cadmium ,Cdse nanoparticles ,Materials science ,Photoluminescence ,Morphology (linguistics) ,chemistry.chemical_element ,Surfaces and Interfaces ,General Chemistry ,Condensed Matter Physics ,Surfaces, Coatings and Films ,chemistry ,Chemical engineering ,Materials Chemistry ,Particle size - Published
- 2019
33. Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women
- Author
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John H. Hipwell, Jeffrey M P Holly, Rachel Denholm, Elizabeth Folkerd, Isabel dos-Santos-Silva, Bianca De Stavola, Simon J. Doran, Martin O. Leach, David J. Hawkes, and Mitch Dowsett
- Subjects
Adult ,Adolescent ,Epidemiology ,Physiology ,Dehydroepiandrosterone ,Estrone ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Sex hormone-binding globulin ,Sex Hormone-Binding Globulin ,medicine ,Humans ,Breast ,030212 general & internal medicine ,Androstenedione ,biology ,business.industry ,medicine.disease ,Prolactin ,Parity ,Cross-Sectional Studies ,Oncology ,chemistry ,Growth Hormone ,030220 oncology & carcinogenesis ,biology.protein ,Female ,business ,Body mass index ,Hormone - Abstract
Background: Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women. Methods: A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception (n = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone–binding globulin, prolactin). Testosterone (n = 330) and sex hormone–binding globulin (n = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels. Results: Estradiol at age 21.5 and sex hormone–binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%–7%) and 3% (1%–5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%–4%) and 4% (1%–7%), respectively]. Conclusions: The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women. Impact: The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.
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- 2018
34. Effects of intake of breakfast or caffeine-containing beverages on measurement of circulating chromogranin A in plasma
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Harpal Randeva, Helen L. Robbins, Dimitri Grammatopoulos, Gregory Kaltsas, Catherine Darby, Ana Penedo, Barbara Mosterman, Clara Ferreira, Martin O. Weickert, Megan Symington, Louise Davies, and Fiona Tranter
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medicine.medical_specialty ,Food intake ,biology ,business.industry ,Chromogranin A ,030209 endocrinology & metabolism ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,chemistry ,Internal medicine ,biology.protein ,Medicine ,030211 gastroenterology & hepatology ,business ,Caffeine - Published
- 2018
35. Tomographic Reservoir Imaging with DNA-Labeled Silica Nanotracers: The First Field Validation
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Anniina Kittilä, Márk Somogyvári, Claudia A. Deuber, Martin O. Saar, Gediminas Mikutis, Peter Bayer, Xiang-Zhao Kong, and Wendelin J. Stark
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Dye tracer ,Materials science ,Silicon dioxide ,0208 environmental biotechnology ,Mineralogy ,02 engineering and technology ,010501 environmental sciences ,01 natural sciences ,chemistry.chemical_compound ,Hydraulic head ,Contact surfaces ,Hydraulic conductivity ,TRACER ,Water Movements ,Environmental Chemistry ,Tomography ,0105 earth and related environmental sciences ,Hydrogeology ,Institut für Mathematik ,DNA ,General Chemistry ,Models, Theoretical ,Silicon Dioxide ,020801 environmental engineering ,chemistry ,ddc:500 ,Switzerland - Abstract
This study presents the first field validation of using DNA-labeled silica nanoparticles as tracers to image subsurface reservoirs by travel time based tomography. During a field campaign in Switzerland, we performed short-pulse tracer tests under a forced hydraulic head gradient to conduct a multisource-multireceiver tracer test and tomographic inversion, determining the two-dimensional hydraulic conductivity field between two vertical wells. Together with three traditional solute dye tracers, we injected spherical silica nanotracers, encoded with synthetic DNA molecules, which are protected by a silica layer against damage due to chemicals, microorganisms, and enzymes. Temporal moment analyses of the recorded tracer concentration breakthrough curves (BTCs) indicate higher mass recovery, less mean residence time, and smaller dispersion of the DNA-labeled nanotracers, compared to solute dye tracers. Importantly, travel time based tomography, using nanotracer BTCs, yields a satisfactory hydraulic conductivity tomogram, validated by the dye tracer results and previous field investigations. These advantages of DNA-labeled nanotracers, in comparison to traditional solute dye tracers, make them well-suited for tomographic reservoir characterizations in fields such as hydrogeology, petroleum engineering, and geothermal energy, particularly with respect to resolving preferential flow paths or the heterogeneity of contact surfaces or by enabling source zone characterizations of dense nonaqueous phase liquids.
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- 2018
36. Endothelial dysfunction in diabetes and hypertension: Role of microRNAs and long non-coding RNAs
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Abhimanyu Thakur, Hai-na Zhang, Xuben Yu, Arunima Ghosh, Qiao-qiao Xu, Manas Chakraborty, and Martin O. Alfred
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0301 basic medicine ,Nitric Oxide Synthase Type III ,Endothelium ,Angiogenesis ,Inflammation ,030204 cardiovascular system & hematology ,Nitric Oxide ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Diabetes mellitus ,microRNA ,Diabetes Mellitus ,Animals ,Humans ,Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Endothelial dysfunction ,business.industry ,Endothelial Cells ,General Medicine ,Atherosclerosis ,medicine.disease ,Non-coding RNA ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Cardiovascular Diseases ,Hyperglycemia ,Hypertension ,Angiogenesis Inducing Agents ,RNA, Long Noncoding ,Endothelium, Vascular ,medicine.symptom ,business - Abstract
The vascular endothelium acts as a barrier between the blood flow and the inner lining of the vessel wall, and it functions as a filtering machinery to filter out any unwanted transfer of materials from both sides (i.e. the blood and the surrounding tissues). It is evident that diseases such as diabetes, obesity, and hypertension disturb the normal endothelial functions in humans and lead to endothelial dysfunction, which may further precede to the development of atherosclerosis. Long non-coding RNAs and micro RNAs both are types of non-coding RNAs which, in the recent years, have increasingly been studied in the pathophysiology of many diseases including diabetes, obesity, cardiovascular diseases, neurological diseases, and others. Recent findings have pointed out important aspects on their relevance to endothelial function as well as dysfunction of the system which may arise from presence of diseases such as diabetes and hypertension. Diabetes or hypertension-mediated endothelial dysfunction show characteristics such as reduced nitric oxide synthesis through suppression of endothelial nitric oxide synthase activity in endothelial cells, reduced sensitivity of nitric oxide in smooth muscle cells, and inflammation - all of which have been either shown to be directly caused by gene regulatory mechanisms of non-coding RNAs or shown to be having a correlation with them. In this review, we aim to discuss such findings on the role of these non-coding RNAs in diabetes or hypertension-associated endothelial dysfunction and the related mechanisms that may pave the way for alleviating endothelial dysfunction and its related complications such as atherosclerosis.
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- 2018
37. COVID-19 and Cancer Therapy: Interrelationships and Management of Cancer Cases in the Era of COVID-19
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Martin O. Onani, Lydia W. Njenga, Simon N. Mbugua, Ruth A. Odhiambo, and Shem O. Wandiga
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Chemistry ,Download ,Public health ,Warranty ,Cancer ,Context (language use) ,General Chemistry ,medicine.disease ,Pandemic ,medicine ,Adverse effect ,Intensive care medicine ,QD1-999 - Abstract
The COVID-19 global epidemic poses this generation's biggest worldwide public health challenge probably since the 1918 influenza epidemic. Recent reports on two new variants have triggered a dramatic upsurge in research to understand the pandemic, primarily focussing on the virology, triggers, clinical characteristics, and diagnostic tests including the prevention and management of the novel coronavirus. Whilst such studies are important in managing the present medical emergency, there is a need for further work to include interdependencies between the epidemic and other illnesses. This will help in developing effective approaches to treat and manage associated diseases in both the short and the long term. In this regard, people living with cancer are a subgroup that is highly vulnerable to respiratory infections and acute pneumonitis similar to the one caused by the COVID-19 virus. This is because the state of their immunity is compromised due to malignancy and the adverse effects of anticancer treatments. With annual cancer projections rising globally and an estimated 70 percent of all cancer-related deaths occurring in low- and middle-income countries, the patient population with impaired immune systems that could be adversely impacted by COVID-19 is only anticipated to rise. In this review, we delve into the challenges and health risks facing cancer patients and cancer treatment in the COVID-19 context, with suggestions into viable measures which can be taken to minimize exposure to the risk of contracting COVID-19 for this vulnerable subgroup. New mutations and the prospects offered by vaccines development and how they relate to this class of patients are also discussed. [ABSTRACT FROM AUTHOR] Copyright of Journal of Chemistry is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2021
38. 2021 roadmap for sodium-ion batteries
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John T. S. Irvine, Emma Kendrick, Valerie R. Seymour, Aamod V. Desai, Edmund J. Cussen, Peter Gross, Andrew J. Naylor, Maria-Magdalena Titirici, Jake M. Brittain, Rebecca Boston, Ruth Sayers, Stewart A. M. Dickson, Sudeshna Sen, Sara I. R. Costa, Zhuangnan Li, Ashish Rudola, Heather Au, Dominic S. Wright, Nuria Tapia-Ruiz, Yongseok Choi, Hande Alptekin, John M. Griffin, Martin O. Jones, Marco Amores, Shahin Nikman, Eun Jeong Kim, A. Robert Armstrong, Reza Younesi, Maria Crespo Ribadeneyra, Laure Monconduit, William I. F. David, Christopher I Thomas, Patrik Johansson, Serena A. Cussen, Grant S. Stone, Jincheng Tong, Russell E. Morris, Clare P. Grey, Alexandre Ponrouch, Oleg Kolosov, Emmanuel I. Eweka, Darren M. C. Ould, Robert G. Palgrave, Thomas J. Wood, Yue Chen, Jerry Barker, Ronnie Mogensen, Stijn F. L. Mertens, Philippe Poizot, Juan Forero-Saboya, David O. Scanlon, Manish Chhowalla, Lorenzo Stievano, Emily M. Reynolds, Xiao Hua, Moulay Tahar Sougrati, William R. Brant, Martin Karlsmo, Stéven Renault, Christopher A. O’Keefe, Begoña Silván, Lancaster University, Harwell Science and Innovation Campus, Imperial College London, University of Sheffield [Sheffield], Faradion Limited, University of Virginia [Charlottesville], University of Oxford [Oxford], University of Cambridge [UK] (CAM), University College of London [London] (UCL), University of St Andrews [Scotland], AUTRES, Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Chalmers University of Technology [Gothenburg, Sweden], Science and Technology Facilities Council (STFC), University of Birmingham [Birmingham], Uppsala University, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Réseau sur le stockage électrochimique de l'énergie (RS2E), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Aix Marseille Université (AMU)-Université de Pau et des Pays de l'Adour (UPPA)-Université de Nantes (UN)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Collège de France (CdF (institution))-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Université Grenoble Alpes (UGA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institut des Matériaux Jean Rouxel (IMN), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN), Alistore, European Commission, Swedish Research Council, Swedish Energy Agency, Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, Ministerio de Economía, Industria y Competitividad (España), Faraday Institution, Austrian Science Fund, Innovate UK, Tapia-Ruiz, Nuria [0000-0002-5005-7043], Armstrong, A Robert [0000-0003-1937-0936], Alptekin, Hande [0000-0001-6065-0513], Au, Heather [0000-0002-1652-2204], Barker, Jerry [0000-0002-8791-1119], Brant, William R [0000-0002-8658-8938], Choi, Yong-Seok [0000-0002-3737-2989], Costa, Sara I R [0000-0001-8105-207X], Crespo Ribadeneyra, Maria [0000-0001-6455-4430], Cussen, Serena A [0000-0002-9303-4220], Desai, Aamod V [0000-0001-7219-3428], Forero-Saboya, Juan D [0000-0002-3403-6066], Griffin, John M [0000-0002-8943-3835], Irvine, John T S [0000-0002-8394-3359], Johansson, Patrik [0000-0002-9907-117X], Karlsmo, Martin [0000-0002-0437-6860], Kendrick, Emma [0000-0002-4219-964X], Kolosov, Oleg V [0000-0003-3278-9643], Mertens, Stijn F L [0000-0002-5715-0486], Monconduit, Laure [0000-0003-3698-856X], Naylor, Andrew J [0000-0001-5641-7778], Poizot, Philippe [0000-0003-1865-4902], Renault, Stéven [0000-0002-6500-0015], Rudola, Ashish [0000-0001-9368-0698], Sayers, Ruth [0000-0003-1289-0998], Seymour, Valerie R [0000-0003-3333-5512], Silván, Begoña [0000-0002-1273-3098], Sougrati, Moulay Tahar [0000-0003-3740-2807], Stievano, Lorenzo [0000-0001-8548-0231], Thomas, Chris I [0000-0001-8090-4541], Titirici, Maria-Magdalena [0000-0003-0773-2100], Tong, Jincheng [0000-0001-7762-1460], Wood, Thomas J [0000-0002-5893-5664], Younesi, Reza [0000-0003-2538-8104], Apollo - University of Cambridge Repository, Kim, Eunjeong [0000-0002-2941-068], Kim, Eunjeong [0000-0002-2941-0682], University of Virginia, University of Oxford, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Aix Marseille Université (AMU)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Collège de France (CdF (institution))-Université de Picardie Jules Verne (UPJV)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Pau et des Pays de l'Adour (UPPA)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Université Grenoble Alpes (UGA), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Tapia-Ruiz, N [0000-0002-5005-7043], Armstrong, AR [0000-0003-1937-0936], Alptekin, H [0000-0001-6065-0513], Au, H [0000-0002-1652-2204], Barker, J [0000-0002-8791-1119], Brant, WR [0000-0002-8658-8938], Choi, YS [0000-0002-3737-2989], Costa, SIR [0000-0001-8105-207X], Ribadeneyra, MC [0000-0001-6455-4430], Cussen, SA [0000-0002-9303-4220], Desai, AV [0000-0001-7219-3428], Forero-Saboya, JD [0000-0002-3403-6066], Griffin, JM [0000-0002-8943-3835], Irvine, JTS [0000-0002-8394-3359], Johansson, P [0000-0002-9907-117X], Karlsmo, M [0000-0002-0437-6860], Kendrick, E [0000-0002-4219-964X], Kolosov, OV [0000-0003-3278-9643], Mertens, SFL [0000-0002-5715-0486], Monconduit, L [0000-0003-3698-856X], Naylor, AJ [0000-0001-5641-7778], Poizot, P [0000-0003-1865-4902], Renault, S [0000-0002-6500-0015], Rudola, A [0000-0001-9368-0698], Sayers, R [0000-0003-1289-0998], Seymour, VR [0000-0003-3333-5512], Silván, B [0000-0002-1273-3098], Sougrati, MT [0000-0003-3740-2807], Stievano, L [0000-0001-8548-0231], Thomas, CI [0000-0001-8090-4541], Titirici, MM [0000-0003-0773-2100], Tong, J [0000-0001-7762-1460], Wood, TJ [0000-0002-5893-5664], Younesi, R [0000-0003-2538-8104], The Faraday Institution, University of St Andrews. School of Chemistry, University of St Andrews. Centre for Energy Ethics, University of St Andrews. Centre for Designer Quantum Materials, and University of St Andrews. EaSTCHEM
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Chemical process ,Technology ,Computer science ,PAIR DISTRIBUTION FUNCTION ,HIGH-ENERGY DENSITY ,ELECTROCHEMICAL PROPERTIES ,Materialkemi ,02 engineering and technology ,01 natural sciences ,7. Clean energy ,Materials Chemistry ,QD ,LITHIUM-ION ,Energy demand ,Scope (project management) ,anodes ,NA2TI3O7 NANOSHEETS ,[CHIM.MATE]Chemical Sciences/Material chemistry ,sodium ion ,021001 nanoscience & nanotechnology ,Variety (cybernetics) ,General Energy ,Roadmap ,T-DAS ,Lithium ,0210 nano-technology ,Battery (electricity) ,energy materials ,Energy & Fuels ,HIGH-CAPACITY ANODE ,batteries ,Materials Science (miscellaneous) ,Materials Science ,chemistry.chemical_element ,Materials Science, Multidisciplinary ,electrolytes ,010402 general chemistry ,Energy storage ,MECHANISTIC INSIGHTS ,SDG 7 - Affordable and Clean Energy ,STRUCTURAL EVOLUTION ,SOLID-ELECTROLYTE INTERPHASE ,Science & Technology ,QD Chemistry ,0104 chemical sciences ,chemistry ,13. Climate action ,Sustainability ,HIGH-PERFORMANCE CATHODE ,Biochemical engineering ,cathodes - Abstract
Tapia-Ruiz, Nuria et al., Increasing concerns regarding the sustainability of lithium sources, due to their limited availability and consequent expected price increase, have raised awareness of the importance of developing alternative energy-storage candidates that can sustain the ever-growing energy demand. Furthermore, limitations on the availability of the transition metals used in the manufacturing of cathode materials, together with questionable mining practices, are driving development towards more sustainable elements. Given the uniformly high abundance and cost-effectiveness of sodium, as well as its very suitable redox potential (close to that of lithium), sodium-ion battery technology offers tremendous potential to be a counterpart to lithium-ion batteries (LIBs) in different application scenarios, such as stationary energy storage and low-cost vehicles. This potential is reflected by the major investments that are being made by industry in a wide variety of markets and in diverse material combinations. Despite the associated advantages of being a drop-in replacement for LIBs, there are remarkable differences in the physicochemical properties between sodium and lithium that give rise to different behaviours, for example, different coordination preferences in compounds, desolvation energies, or solubility of the solid–electrolyte interphase inorganic salt components. This demands a more detailed study of the underlying physical and chemical processes occurring in sodium-ion batteries and allows great scope for groundbreaking advances in the field, from lab-scale to scale-up. This roadmap provides an extensive review by experts in academia and industry of the current state of the art in 2021 and the different research directions and strategies currently underway to improve the performance of sodium-ion batteries. The aim is to provide an opinion with respect to the current challenges and opportunities, from the fundamental properties to the practical applications of this technology., The authors gratefully acknowledge RS2E and Alistore-ERI for funding their research into Na-ion batteries. The funding received from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 646433 (NAIADES), the Swedish Research Council, the Swedish Energy Agency (#37671-1), and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), are all gratefully acknowledged. The many fruitful discussions within ALISTORE-ERI, and especially with M Rosa Palacín, have been most valuable. P J is also grateful for the continuous support from several of the Chalmers Areas of Advance: Materials Science and Energy. Funding from the European Union’s innovation program H2020 is acknowledged: H2020-MSCA-COFUND-2016 (DOC-FAM, Grant Agreement No. 754397). A Ponrouch is grateful to the Spanish Ministry for Economy, Industry and Competitiveness Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2015-0496).
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- 2021
39. AMY1 gene copy number correlates with glucose absorption and visceral fat volume, but not with insulin resistance
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Ronan Calvez, Patrick J D Elder, Thomas M. Barber, David B. Ramsden, David Burnett, Sarah Ball, Daniel J. Cuthbertson, Andreas Pfeiffer, Martin O. Weickert, and Ahsan A Bhatti
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Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Gene Dosage ,Administration, Oral ,Urine ,Intra-Abdominal Fat ,Biochemistry ,Body Mass Index ,Cohort Studies ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,Humans ,Insulin ,Amylase ,Adiposity ,Glycemic ,Adiponectin ,biology ,Chemistry ,Biochemistry (medical) ,Starch ,Glucose Tolerance Test ,medicine.disease ,Magnetic Resonance Imaging ,Obesity ,QP ,Healthy Volunteers ,Cross-Sectional Studies ,Liver ,Gastrointestinal Absorption ,Salivary alpha-Amylases ,Cohort ,biology.protein ,Female ,Insulin Resistance ,Homeostasis ,RC - Abstract
Background The human amylase gene (AMY1) has a broad copy number (CN) variation that may associate with body mass index. Methods Deoxyribonucleic acid was extracted from urine (n = 74) and serum (n = 6) samples (Protein, Fiber and Metabolic Syndrome [ProFiMet] cohort), and buccal (n = 17) samples (Oral Starch Challenge [OSC] cohort), and assessed for AMY1 CN by droplet digital polymerase chain reaction. The association of AMY1 CN with comprehensive markers of metabolic status (ProFiMet cohort) were analyzed with Pearson’s correlation coefficient (CC). For the healthy, euglycemic OSC cohort, glycemic response to OSC was analyzed with independent sample t-tests (subgroups: high AMY1 CN 9–12, n = 10; low AMY1 CN 4–6, n = 7). Results There were significant inverse correlations of AMY1 CN with total visceral fat volume (CC -0.33; P = 0.004) and positive correlations of AMY1 CN with oral glucose insulin sensitivity score (derived from an oral glucose tolerance test, CC 0.26; P = 0.02), serum HDL-cholesterol (CC 0.325; P = 0.003), and serum adiponectin (CC 0.249; P = 0.026). Linear regression multivariate analysis (adiponectin as dependent variable), showed independent association of adiponectin with AMY1 CN (Beta = 0.29; P = 0.03). There were no significant associations between AMY1 CN and clamp-derived M-value, homeostasis model assessment of insulin resistance (IR), hepatic endogenous glucose production, fecal floral signature, or macronutrient dietary preference. Delta (mean) change in blood glucose concentration (fasting to 30-minutes post-OSC) was significantly greater in the high versus low AMY1 CN subgroups (mean 1.7 mmol/l [SEM 0.6] vs 0.9 mmol/l [SEM 0.9], respectively; P = 0.016). Conclusions High AMY1 CN associates with a favorable metabolic profile (lower visceral fat volume, higher serum adiponectin, enhanced glucose absorption following oral glucose, and OSC), but not with whole-body or hepatic IR.
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- 2020
40. Targeting RAS-converting enzyme 1 overcomes senescence and improves progeria-like phenotypes of ZMPSTE24 deficiency
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Ting Wang, Clotilde Wiel, Muhammad Kashif, Maria Eriksson, Mohamed X. Ibrahim, Haidong Yao, Gwladys Revêchon, Xue Chen, Martin O. Bergo, and Elin Tüksammel
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0301 basic medicine ,Senescence ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Biology ,Cleavage (embryo) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Progeria ,Prenylation ,medicine ,Animals ,Humans ,mouse models ,Protein kinase B ,chemistry.chemical_classification ,Mice, Knockout ,prelamin A ,integumentary system ,ZMPSTE24 ,nutritional and metabolic diseases ,Membrane Proteins ,Metalloendopeptidases ,Short Take ,Cell Biology ,medicine.disease ,Phenotype ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Enzyme ,Genes, ras ,chemistry ,RCE1 ,030217 neurology & neurosurgery ,Lamin - Abstract
Several progeroid disorders are caused by deficiency in the endoprotease ZMPSTE24 which leads to accumulation of prelamin A at the nuclear envelope. ZMPSTE24 cleaves prelamin A twice: at the third carboxyl‐terminal amino acid following farnesylation of a –CSIM motif; and 15 residues upstream to produce mature lamin A. The carboxyl‐terminal cleavage can also be performed by RAS‐converting enzyme 1 (RCE1) but little is known about the importance of this cleavage for the ability of prelamin A to cause disease. Here, we found that knockout of RCE1 delayed senescence and increased proliferation of ZMPSTE24‐deficient fibroblasts from a patient with non‐classical Hutchinson‐Gilford progeria syndrome (HGPS), but did not influence proliferation of classical LMNA‐mutant HGPS cells. Knockout of Rce1 in Zmpste24‐deficient mice at postnatal week 4–5 increased body weight and doubled the median survival time. The absence of Rce1 in Zmpste24‐deficient fibroblasts did not influence nuclear shape but reduced an interaction between prelamin A and AKT which activated AKT‐mTOR signaling and was required for the increased proliferation. Prelamin A levels increased in Rce1‐deficient cells due to a slower turnover rate but its localization at the nuclear rim was unaffected. These results strengthen the idea that the presence of misshapen nuclei does not prevent phenotype improvement and suggest that targeting RCE1 might be useful for treating the rare progeroid disorders associated with ZMPSTE24 deficiency., A deficiency in the protease ZMPSTE24 causes rare forms of accelerated aging. Here, we show that knockout of a related protease, RCE1, prevents carboxyl‐terminal processing of their shared substrate prelamin A, which disrupts an interaction with AKT and thereby stimulates AKT‐mTOR signaling. Knockout of RCE1 thus overcame senescence of cultured ZMPSTE24‐deficient cells and improved survival of Zmpste24‐deficient mice.
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- 2020
41. Lack of RAC1 in macrophages protects against atherosclerosis
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Murali K. Akula, Chandu Ala, Matias Ekstrand, Levent M. Akyürek, Göran Bergström, Xi Liu, Liliana Håversen, Matteo Pedrelli, Jan Borén, Sashidar Bandaru, and Martin O. Bergo
- Subjects
rac1 GTP-Binding Protein ,0301 basic medicine ,030204 cardiovascular system & hematology ,Filamin ,Vascular Medicine ,Biochemistry ,White Blood Cells ,Mice ,Contractile Proteins ,0302 clinical medicine ,Animal Cells ,Immunofluorescence Staining ,Medicine and Health Sciences ,Macrophage ,Cells, Cultured ,Foam cell ,Staining ,Multidisciplinary ,Chemistry ,Animal Models ,Lipids ,Cholesterol ,medicine.anatomical_structure ,Experimental Organism Systems ,Kexin ,Medicine ,Cellular Types ,Research Article ,Immune Cells ,Lipoproteins ,Science ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Mouse Models ,RAC1 ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Antigens, CD ,In vivo ,Lysosome ,medicine ,Animals ,Humans ,Blood Cells ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Macrophages ,Neuropeptides ,Biology and Life Sciences ,Proteins ,Cell Biology ,Atherosclerosis ,Lipid Metabolism ,Proprotein convertase ,Molecular biology ,Actins ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,030104 developmental biology ,Specimen Preparation and Treatment ,Animal Studies - Abstract
The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed RAC1 expression in human carotid atherosclerotic plaques using immunofluorescence and found higher macrophage RAC1 expression in advanced plaques compared with intermediate human atherosclerotic plaques. We then produced mice with Rac1-deficient macrophages by breeding conditional floxed Rac1 mice (Rac1fl/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis was studied in vivo by infecting Rac1fl/fl and Rac1fl/fl/LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Rac1fl/fl/LC macrophages secreted lower levels of IL-6 and TNF-α and exhibited reduced foam cell formation and lipid uptake. The deficiency of Rac1 in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infected Rac1fl/fl/LC mice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced in Rac1-deficient mice. Moreover, we found that RAC1 interacts with actin-binding filamin A. Macrophages expressed increased RAC1 levels in advanced human atherosclerosis. Genetic inactivation of RAC1 impaired macrophage function and reduced atherosclerosis in mice, suggesting that drugs targeting RAC1 may be useful in the treatment of atherosclerosis.
- Published
- 2020
42. Single molecule light field microscopy
- Author
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Sarah I. Benaissa, Ruth Sims, Martin O. Lenz, Edward W. Sanders, Ezra Bruggeman, Leila Muresan, Sohaib Abdul Rehman, Adam Clark, Aleks Ponjavic, Steven F. Lee, Kevin O'Holleran, Lenz, Martin [0000-0002-1658-4368], Sanders, Edward [0000-0002-8972-7702], Muresan, Leila [0000-0002-7602-0249], Lee, Steven [0000-0003-4492-5139], and Apollo - University of Cambridge Repository
- Subjects
Materials science ,Fluorophore ,business.industry ,super-resolution ,Fluorescence ,computational imaging ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,Cardinal point ,Optics ,chemistry ,Microscopy ,microscopy ,Depth of field ,bioimaging ,Parallax ,Phase retrieval ,business ,Light field - Abstract
We introduce single molecule light field microscopy (SMLFM), a new class of three-dimensional (3D) single molecule localization microscopy. By segmenting the back focal plane of a microscope objective with an array of microlenses to generate multiple 2D perspective views, the same single fluorophore can be imaged from different angles. These views, in combination with a bespoke fitting algorithm, enable the 3D positions of single fluorophores to be determined from parallax. SMLFM achieves up to 20 nm localization precision throughout an extended 6 µ m depth of field. The capabilities of SMLFM are showcased by imaging membranes of fixed eukaryotic cells and DNA nanostructures below the optical diffraction limit.
- Published
- 2020
43. Metabolic biomarkers of response to the AKT inhibitor MK-2206 in pre-clinical models of human colorectal and prostate carcinoma
- Author
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Helen Troy, Suzanne A. Eccles, Timothy A. Yap, Anne Christine Wong Te Fong, Jessica K.R. Boult, L. Elizabeth Jackson, Roberta Paravati, Yuen-Li Chung, Nada M.S. Al-Saffar, Simon P. Robinson, Sharon Gowan, and Martin O. Leach
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Magnetic Resonance Spectroscopy ,Antineoplastic Agents ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Choline ,Animals ,Humans ,Enzyme Inhibitors ,Protein kinase B ,Phosphocholine ,Cancer ,Prostatic Neoplasms ,medicine.disease ,Glutamine ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,MK-2206 ,Cancer research ,Heterografts ,Colorectal Neoplasms ,Heterocyclic Compounds, 3-Ring ,Proto-Oncogene Proteins c-akt - Abstract
Background AKT is commonly overexpressed in tumours and plays an important role in the metabolic reprogramming of cancer. We have used magnetic resonance spectroscopy (MRS) to assess whether inhibition of AKT signalling would result in metabolic changes that could potentially be used as biomarkers to monitor response to AKT inhibition. Methods Cellular and metabolic effects of the allosteric AKT inhibitor MK-2206 were investigated in HT29 colon and PC3 prostate cancer cells and xenografts using flow cytometry, immunoblotting, immunohistology and MRS. Results In vitro treatment with MK-2206 inhibited AKT signalling and resulted in time-dependent alterations in glucose, glutamine and phospholipid metabolism. In vivo, MK-2206 resulted in inhibition of AKT signalling and tumour growth compared with vehicle-treated controls. In vivo MRS analysis of HT29 subcutaneous xenografts showed similar metabolic changes to those seen in vitro including decreases in the tCho/water ratio, tumour bioenergetic metabolites and changes in glutamine and glutathione metabolism. Similar phosphocholine changes compared to in vitro were confirmed in the clinically relevant orthotopic PC3 model. Conclusion This MRS study suggests that choline metabolites detected in response to AKT inhibition are time and microenvironment-dependent, and may have potential as non-invasive biomarkers for monitoring response to AKT inhibitors in selected cancer types.
- Published
- 2018
44. The small airway epithelium as a target for the adverse pulmonary effects of silver nanoparticle inhalation
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Rachel Smith, Martin O Leonard, Timothy W. Gant, James Warren, Alison Buckley, Tim Marczylo, Isabella Römer, Alan Hodgson, Joanna Seiffert, Kian Fan Chung, and Chang Guo
- Subjects
Male ,0301 basic medicine ,Silver ,Biomedical Engineering ,Metal Nanoparticles ,Inflammation ,Toxicology ,Epithelium ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,In vivo ,microRNA ,Gene expression ,medicine ,Animals ,Humans ,Lung ,Cells, Cultured ,Aerosols ,Inhalation exposure ,Inhalation Exposure ,Inhalation ,Chemistry ,Rats ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Respiratory epithelium ,medicine.symptom - Abstract
Experimental modelling to identify specific inhalation hazards for nanomaterials has in the main focussed on in vivo approaches. However, these models suffer from uncertainties surrounding species specific differences and cellular targets for biological response. In terms of pulmonary exposure, approaches which combine ‘inhalation-like’ nanoparticulate aerosol deposition with relevant human cell and tissue air-liquid interface cultures are considered an important complement to in vivo work. In this study, we utilized such a model system to build on previous results from in vivo exposures, which highlighted the small airway epithelium as a target for silver nanoparticle (AgNP) deposition. RNA-SEQ was used to characterise alterations in mRNA and miRNA within the lung. Organotypic reconstituted 3D human primary small airway epithelial cell cultures (SmallAir) were exposed to the same spark generated AgNP and at the same dose used in vivo, in an aerosol-exposure air-liquid-interface (AE-ALI) system. Adverse effects were characterised using lactate, LDH release and alterations in mRNA and miRNA. Modest toxicological effects were paralleled by significant regulation in gene expression, reflective mainly of specific inflammatory events. Importantly, there was a level of concordance between gene expression changes observed in vitro and in vivo. We also observed a significant correlation between AgNP and mass equivalent silver ion (Ag(+)) induced transcriptional changes in SmallAir cultures. In addition to key mechanistic information relevant for our understanding of the potential health risks associated with AgNP inhalation exposure, this work further highlights the small airway epithelium as an important target for adverse effects.
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- 2018
45. Isolation, characterization and biological activity of organic extractives from Calodendrum capense (L.f.) Thunb.(Rutaceae)
- Author
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Martin O. Onani, O. Amuka, J M Onyancha, R I Okwemba, Alex K. Machocho, A. W. Wanyonyi, Paul K. Tarus, and I. M. Waweru
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Pharmacology ,Traditional medicine ,biology ,010405 organic chemistry ,Limonin ,Alkaloid ,010401 analytical chemistry ,food and beverages ,Pharmaceutical Science ,Biological activity ,Plant Science ,Bacillus subtilis ,biology.organism_classification ,complex mixtures ,01 natural sciences ,Bergapten ,0104 chemical sciences ,chemistry.chemical_compound ,Furanocoumarin ,Rutaceae ,Complementary and alternative medicine ,chemistry ,Drug Discovery ,Calodendrum capense - Abstract
A novel prenylfuroquinoline alkaloid capensenin (1), an alkaloid confusameline (2), two furanocoumarins psolaren (3) and bergapten (4), were isolated from hexane and dichloromethane crude extracts of stem bark, leaves and fruit pericarp of Calodendrum capense. Limonin (5) was also isolated from the stem bark, while limonin diosphenol (6) was isolated from the seeds. Capensenin (1) showed weak antimicrobial activity against Bacillus subtilis, while the leaves, stem bark and fruit pericarp crude extracts exhibited activity against Staphylococcus aureus, B. subtilis and P. citrinum. Hexane pericarp extract showed slight cytotoxicity to Vero cell E199 in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structures of the compounds were elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and infra-red spectroscopy. Key words: Capensenin, 4-hydroxyfuroquinoline, furanocoumarin, Calodendrum capense, alkaloid, Rutaceae.
- Published
- 2018
46. Peptide-functionalized quantum dots for potential applications in the imaging and treatment of obesity
- Author
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Ntevheleni Thovhogi, Nicole Remaliah Samantha Sibuyi, Abram M. Madiehe, Mervin Meyer, and Martin O. Onani
- Subjects
Male ,0301 basic medicine ,Pharmaceutical Science ,Adipose tissue ,02 engineering and technology ,White adipose tissue ,Pharmacology ,Drug Delivery Systems ,International Journal of Nanomedicine ,Drug Discovery ,Tissue Distribution ,Mononuclear Phagocyte System ,adipose homing peptide ,Original Research ,nanotechnology ,Chemistry ,General Medicine ,021001 nanoscience & nanotechnology ,Adipose Tissue ,Drug delivery ,0210 nano-technology ,Cadmium ,Biodistribution ,Biophysics ,prohibitin ,Bioengineering ,CHO Cells ,Diet, High-Fat ,Biomaterials ,03 medical and health sciences ,Cricetulus ,white adipose tissue ,In vivo ,Prohibitins ,Quantum Dots ,Animals ,Humans ,Obesity ,Rats, Wistar ,Organic Chemistry ,technology, industry, and agriculture ,Repressor Proteins ,030104 developmental biology ,Microscopy, Fluorescence ,Targeted drug delivery ,drug delivery ,Anti-Obesity Agents ,Caco-2 Cells ,Nanocarriers ,Molecular imaging ,Peptides - Abstract
Ntevheleni Thovhogi,1 Nicole Remaliah Samantha Sibuyi,1 Martin Opiyo Onani,2 Mervin Meyer,1 Abram Madimabe Madiehe1 1Department of Science and Technology (DST)/Mintek Nanotechnology Innovation Centre, Biolabels Unit, Department of Biotechnology, 2Organometallics and Nanomaterials, Department of Chemistry, University of the Western Cape, Bellville, South Africa Background: Obesity is a worldwide epidemic affecting millions of people. The current pharmacological treatment of obesity remains limited and ineffective due to drugs’ undesirable side effects. Hence, there is a need for novel or improved strategies for long-term therapies that will help prevent the disease progression into other chronic diseases. Nanotechnology holds the future for the treatment of obesity because of its versatility, as shown by improved drug efficiency and safety in cancer clinical trials. Nano-based drug delivery systems could potentially do the same for obesity through targeted drug delivery. This study investigated the use of peptide-functionalized quantum dots (QDs) for the imaging of prohibitin (PHB)-expressing cells in vitro and in diet-induced obese rats, which could potentially be used as nanocarriers of antiobesity drugs. Methods: Cadmium (Cd)-based QDs were functionalized with an adipose homing peptide (AHP) and injected intravenously into lean and obese Wistar rats. Biodistribution of the QDs was analyzed by an IVIS® Lumina XR imaging system and inductively coupled plasma optical emission spectroscopy (ICP-OES). For in vitro studies, PHB-expressing (Caco-2 and MCF-7) and non-PHB-expressing (KMST-6 and CHO) cells were exposed to either unfunctionalized QDs (QD625) or AHP-functionalized QDs (AHP-QD625) and analyzed by fluorescence microscopy. Results: AHP-QD625 accumulated significantly in PHB-expressing cells in vitro when compared with non-PHB-expressing cells. In vivo data indicated that QD625 accumulated mainly in the reticuloendothelial system (RES) organs, while the AHP-QD625 accumulated mostly in the white adipose tissues (WATs). Conclusion: AHP-functionalized QDs were successfully and selectively delivered to the PHB-expressing cells in vitro (Caco-2 and MCF-7 cells) and in the WAT vasculature in vivo. This nanotechnology-based approach could potentially be used for dual targeted drug delivery and molecular imaging of adipose tissues in obese patients in real time. Keywords: adipose homing peptide, drug delivery, nanotechnology, prohibitin, white adipose tissue
- Published
- 2018
47. Changes in Phenolic Acid Content in Maize during Food Product Processing
- Author
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Nicole A. Yana, Kent D. Rausch, Rita H. Mumm, Alexandra Ostezan, Carrie J. Butts-Wilmsmeyer, Mary M Happ, Martin O. Bohn, Matthew Wasmund, and Gurshagan Kandhola
- Subjects
0106 biological sciences ,0301 basic medicine ,Hot Temperature ,Genotype ,Food Handling ,Zea mays ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Nutrient ,Hydroxybenzoates ,Cooking ,Food science ,030109 nutrition & dietetics ,business.industry ,Product processing ,General Chemistry ,Phenolic acid ,Bioavailability ,chemistry ,Food products ,Seeds ,Food processing ,General Agricultural and Biological Sciences ,business ,010606 plant biology & botany - Abstract
The notion that many nutrients and beneficial phytochemicals in maize are lost due to food product processing is common, but this has not been studied in detail for the phenolic acids. Information regarding changes in phenolic acid content throughout processing is highly valuable because some phenolic acids are chemopreventive agents of aging-related diseases. It is unknown when and why these changes in phenolic acid content might occur during processing, whether some maize genotypes might be more resistant to processing induced changes in phenolic acid content than other genotypes, or if processing affects the bioavailability of phenolic acids in maize-based food products. For this study, a laboratory-scale processing protocol was developed and used to process whole maize kernels into toasted cornflakes. High-throughput microscale wet-lab analyses were applied to determine the concentrations of soluble and insoluble-bound phenolic acids in samples of grain, three intermediate processing stages, and toasted cornflakes obtained from 12 ex-PVP maize inbreds and seven hybrids. In the grain, insoluble-bound ferulic acid was the most common phenolic acid, followed by insoluble-bound p-coumaric acid and soluble cinnamic acid, a precursor to the phenolic acids. Notably, the ferulic acid content was approximately 1950 μg/g, more than ten-times the concentration of many fruits and vegetables. Processing reduced the content of the phenolic acids regardless of the genotype. Most changes occurred during dry milling due to the removal of the bran. The concentration of bioavailable soluble ferulic and p-coumaric acid increased negligibly due to thermal stresses. Therefore, the current dry milling based processing techniques used to manufacture many maize-based foods, including breakfast cereals, are not conducive for increasing the content of bioavailable phenolics in processed maize food products. This suggests that while maize is an excellent source of phenolics, alternative or complementary processing methods must be developed before this nutritional resource can be utilized.
- Published
- 2018
48. Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models
- Author
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Karen E Swales, Udai Banerji, Parames Thavasu, Sladjana Gagrica, Martin O. Leach, Yuen-Li Chung, Sabina Cosulich, and Anne-Christine Wong Te Fong
- Subjects
0301 basic medicine ,medicine.medical_treatment ,chemo-resistance ,03 medical and health sciences ,chemistry.chemical_compound ,AZD2014 ,0302 clinical medicine ,In vivo ,medicine ,PI3K/AKT/mTOR pathway ,Phosphocholine ,Cisplatin ,Chemotherapy ,vistusertib ,Cell growth ,mTORC1/2 ,medicine.disease ,ovarian cancer ,030104 developmental biology ,Oncology ,chemistry ,Paclitaxel ,030220 oncology & carcinogenesis ,Cancer research ,Ovarian cancer ,Research Paper ,medicine.drug - Abstract
Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel (n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo. We demonstrated inhibition of mTORC1 and mTORC2 by vistusertib and the combination by showing reduction in p-S6 and p-AKT levels, respectively. In the A2780CisR xenograft model compared to control, there was a significant reduction in tumor volumes (p = 0.03) caused by the combination and not paclitaxel or vistusertib alone. In vivo, we observed a significant increase in apoptosis (cleaved PARP measured by immunohistochemistry; p = 0.0003). Decreases in phospholipid and bioenergetic metabolites were studied using magnetic resonance spectroscopy and significant changes in phosphocholine (p = 0.01), and ATP (p = 0.04) were seen in tumors treated with the combination when compared to vehicle-control. Based on this data, a clinical trial evaluating the combination of paclitaxel and vistusertib has been initiated (NCT02193633). Interestingly, treatment of ovarian cancer patients with paclitaxel caused an increase in p-AKT levels in platelet-rich plasma and it was possible to abrogate this increase with the co-treatment with vistusertib in 4/5 patients: we believe this combination will benefit patients with ovarian cancer.
- Published
- 2017
49. Re-assessing the toxicity of particles from biodiesel combustion: A quantitative analysis of in vitro studies
- Author
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Daniel Southern, Martin O. Leonard, Midhat Talibi, Nicos Ladommatos, and Paul Hellier
- Subjects
Atmospheric Science ,Diesel fuel ,Biodiesel ,Biofuel ,Chemistry ,Environmental chemistry ,Toxicity ,Particulates ,Combustion ,Literature survey ,complex mixtures ,Quantitative analysis (chemistry) ,General Environmental Science - Abstract
Biofuels may reduce road transport carbon intensity; however, it is uncertain whether displacing fossil diesel would alter the engine-derived particulate toxicity. The primary objective of this work was to determine whether there is a fuel effect on the comparative in vitro toxicity of biodiesel exhaust particulates relative to those from fossil diesel. A secondary aim was to determine qualitatively whether the observed outcome is related to the organic phase, namely Polycyclic Aromatic Hydrocarbons (PAHs). In vitro and acellular exposure studies were recovered from a literature survey following the PRISMA framework. Biological responses attributable to biodiesel and paired fossil diesel particles, including particle-extracts were selected. To qualify for inclusion, either of the paired responses must differ statistically significantly (p
- Published
- 2021
50. Enantiocontrolled preparation of indolizidines: synthesis of (-)-2-epilentiginosine and (+)-lentiginosine
- Author
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Rasmussen, Martin O., Delair, Philippe, and Greene, Andrew E.
- Subjects
Chemistry, Organic -- Research ,Ethers -- Physiological aspects ,Ring formation (Chemistry) -- Physiological aspects ,Biological sciences ,Chemistry - Abstract
Research has been conducted on the (-)-2-epilentiginosine and (+)-lentiginosine. The development of the stereoselective approach to these compounds based on the diastereofacially selective cycloaddition of dichloroketene with the chiral dienol ether is described.
- Published
- 2001
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