Publications
348 results found
Smith HE, Mackenzie AM, Seddon C, et al., 2024, The use of NADH anisotropy to investigate mitochondrial cristae alignment., Sci Rep, Vol: 14
Life may be expressed as the flow of electrons, protons, and other ions, resulting in large potential difference. It is also highly photo-sensitive, as a large proportion of the redox capable molecules it relies on are chromophoric. It is thus suggestive that a key organelle in eukaryotes, the mitochondrion, constantly adapt their morphology as part of the homeostatic process. Studying unstained in vivo nano-scale structure in live cells is technically very challenging. One option is to study a central electron carrier in metabolism, reduced nicotinamide adenine dinucleotide (NADH), which is fluorescent and mostly located within mitochondria. Using one and two-photon absorption (340-360 nm and 730 nm, respectively), fluorescence lifetime imaging and anisotropy spectroscopy of NADH in solution and in live cells, we show that mitochondria do indeed appear to be aligned and exhibit high anisotropy (asymmetric directionality). Aqueous solution of NADH showed an anisotropy of ~ 0.20 compared to fluorescein or coumarin of < 0.1 and 0.04 in water respectively and as expected for small organic molecules. The anisotropy of NADH also increased further to 0.30 in the presence of proteins and 0.42 in glycerol (restricted environment) following two-photon excitation, suggesting more ordered structures. Two-photon NADH fluorescence imaging of Michigan Cancer Foundation-7 (MCF7) also showed strong anisotropy of 0.25 to 0.45. NADH has a quantum yield of fluorescence of 2% compared to more than 40% for photoionisation (electron generation), when exposed to light at 360 nm and below. The consequence of such highly ordered and directional NADH patterns with respect to electron ejection upon ultra-violet (UV) excitation could be very informative-especially in relation to ascertaining the extent of quantum effects in biology, including electron and photonic cascade, communication and modulation of effects such as spin and tunnelling.
Mackenzie AM, Smith HE, Mould RR, et al., 2024, Rooting out ultraweak photon emission a-mung bean sprouts, Journal of Photochemistry and Photobiology, Vol: 19, Pages: 100224-100224, ISSN: 2666-4690
Heymsfield S, Bell JD, Heber D, 2024, Phenotyping, Body Composition, and Precision Nutrition, Precision Nutrition, Publisher: Elsevier, Pages: 143-152, ISBN: 9780443153150
Mould RR, Mackenzie AM, Kalampouka I, et al., 2024, Ultra weak photon emission-a brief review., Front Physiol, Vol: 15, ISSN: 1664-042X
Cells emit light at ultra-low intensities: photons which are produced as by-products of cellular metabolism, distinct from other light emission processes such as delayed luminescence, bioluminescence, and chemiluminescence. The phenomenon is known by a large range of names, including, but not limited to, biophotons, biological autoluminescence, metabolic photon emission and ultraweak photon emission (UPE), the latter of which shall be used for the purposes of this review. It is worth noting that the photons when produced are neither 'weak' nor specifically biological in characteristics. Research of UPE has a long yet tattered past, historically hamstrung by a lack of technology sensitive enough to detect it. Today, as technology progresses rapidly, it is becoming easier to detect and image these photons, as well as to describe their function. In this brief review we will examine the history of UPE research, their proposed mechanism, possible biological role, the detection of the phenomenon, and the potential medical applications.
Aguida B, Chabi M-M, Baouz S, et al., 2023, Near-Infrared Light Exposure Triggers ROS to Downregulate Inflammatory Cytokines Induced by SARS-CoV-2 Spike Protein in Human Cell Culture., Antioxidants (Basel), Vol: 12, ISSN: 2076-3921
The leading cause of mortality from SARS-CoV-2 is an exaggerated host immune response, triggering cytokine storms, multiple organ failure and death. Current drug- and vaccine-based therapies are of limited efficacy against novel viral variants. Infrared therapy is a non-invasive and safe method that has proven effective against inflammatory conditions for over 100 years. However, its mechanism of action is poorly understood and has not received widespread acceptance. We herein investigate whether near-infrared (NIR) light exposure in human primary alveolar and macrophage cells could downregulate inflammatory cytokines triggered by the SARS-CoV-2 spike (S) protein or lipopolysaccharide (LPS), and via what underlying mechanism. Our results showed a dramatic reduction in pro-inflammatory cytokines within days of NIR light treatment, while anti-inflammatory cytokines were upregulated. Mechanistically, NIR light stimulated mitochondrial metabolism, induced transient bursts in reactive oxygen species (ROS) and activated antioxidant gene transcription. These, in turn, downregulated ROS and inflammatory cytokines. A causal relationship was shown between the induction of cellular ROS by NIR light exposure and the downregulation of inflammatory cytokines triggered by SARS-CoV-2 S. If confirmed by clinical trials, this method would provide an immediate defense against novel SARS-CoV-2 variants and other inflammatory infectious diseases.
Rundle M, Fiamoncini J, Thomas EL, et al., 2023, Diet-induced Weight Loss and Phenotypic Flexibility Among Healthy Overweight Adults: A Randomized Trial, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 118, Pages: 591-604, ISSN: 0002-9165
Nunn AVW, Guy GW, Bell JD, 2023, Informing the Cannabis Conjecture: From Life's Beginnings to Mitochondria, Membranes and the Electrome-A Review, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24, ISSN: 1661-6596
Brown AA, Fernandez-Tajes JJ, Hong M-G, et al., 2023, Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits, NATURE COMMUNICATIONS, Vol: 14
Basty ND, Sorokin E, Thanaj M, et al., 2023, Abdominal imaging associates body composition with COVID-19 severity, PLOS ONE, Vol: 18, ISSN: 1932-6203
Mould RR, Kalampouka I, Thomas EL, et al., 2023, Non-chemical signalling between mitochondria., Front Physiol, Vol: 14, ISSN: 1664-042X
A wide variety of studies have reported some form of non-chemical or non-aqueous communication between physically isolated organisms, eliciting changes in cellular proliferation, morphology, and/or metabolism. The sources and mechanisms of such signalling pathways are still unknown, but have been postulated to involve vibration, volatile transmission, or light through the phenomenon of ultraweak photon emission. Here, we report non-chemical communication between isolated mitochondria from MCF7 (cancer) and MCF10A (non-cancer) cell lines. We found that mitochondria in one cuvette stressed by an electron transport chain inhibitor, antimycin, alters the respiration of mitochondria in an adjacent, but chemically and physically separate cuvette, significantly decreasing the rate of oxygen consumption compared to a control (p = <0.0001 in MCF7 and MCF10A mitochondria). Moreover, the changes in O2-consumption were dependent on the origin of mitochondria (cancer vs. non-cancer) as well as the presence of "ambient" light. Our results support the existence of non-chemical signalling between isolated mitochondria. The experimental design suggests that the non-chemical communication is light-based, although further work is needed to fully elucidate its nature.
Nunn AVW, Guy GW, Bell JD, 2022, Bioelectric fields at the beginnings of life, Bioelectricity, Vol: 4, Pages: 237-247, ISSN: 2576-3105
The consensus on the origins of life is that it involved organization of prebiotic chemicals according to the underlying principles of thermodynamics to dissipate energy derived from photochemical and/or geochemical sources. Leading theories tend to be chemistry-centric, revolving around either metabolism or information-containing polymers first. However, experimental data also suggest that bioelectricity and quantum effects play an important role in biology, which might suggest that a further factor is required to explain how life began. Intriguingly, in the early part of 20th century, the concept of the “morphogenetic field” was proposed by Gurwitsch to explain how the shape of an organism was determined, while a role for quantum mechanics in biology was suggested by Bohr and Schrödinger, among others. This raises the question as to the potential of these phenomena, especially bioelectric fields, to have been involved in the origin of life. It points to the possibility that as bioelectricity is universally prevalent in biological systems today, it represents a more complex echo of an electromagnetic skeleton which helped shape life into being. It could be argued that as a flow of ions creates an electric field, this could have been pivotal in the formation of an energy dissipating structure, for instance, in deep sea thermal vents. Moreover, a field theory might also hint at the potential involvement of nontrivial quantum effects in life. Not only might this perspective help indicate the origins of morphogenetic fields, but also perhaps suggest where life may have started, and whether metabolism or information came first. It might also help to provide an insight into aging, cancer, consciousness, and, perhaps, how we might identify life beyond our planet. In short, when thinking about life, not only do we have to consider the accepted chemistry, but also the fields that must also shape it. In effect, to fully understand life, as well as the yin of
Woodley S, Butt J, Mould R, et al., 2022, Licorice Root Ameliorates Drug Induced Mitochondrial Stress in MCF7 and MCF10A Cells, Publisher: GEORG THIEME VERLAG KG, Pages: 1513-1513, ISSN: 0032-0943
Nunn AVW, Guy GW, Brysch W, et al., 2022, Understanding Long COVID; Mitochondrial Health and Adaptation-Old Pathways, New Problems, BIOMEDICINES, Vol: 10
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- Citations: 8
O'Donovan SD, Erdos B, Jacobs DM, et al., 2022, Quantifying the contribution of triglycerides to metabolic resilience through the mixed meal model, ISCIENCE, Vol: 25
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- Citations: 2
Asaturyan HA, Basty N, Thanaj M, et al., 2022, Improving the accuracy of fatty liver index to reflect liver fat content with predictive regression modelling, PLOS ONE, Vol: 17, ISSN: 1932-6203
Thanaj M, Basty N, Cule M, et al., 2022, Liver Shape Analysis using Statistical Parametric Maps at Population Scale
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Morphometric image analysis enables the quantification of differences in the shape and size of organs between individuals.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Here we have applied morphometric methods to the study of the liver by constructing surface meshes from liver segmentations from abdominal MRI images in 33,434 participants in the UK Biobank. Based on these three dimensional mesh vertices, we evaluated local shape variations and modelled their association with anthropometric, phenotypic and clinical conditions, including liver disease and type-2 diabetes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found that age, body mass index, hepatic fat and iron content, as well as, health traits were significantly associated with regional liver shape and size. Interaction models in groups with specific clinical conditions showed that the presence of type-2 diabetes accelerates age-related changes in the liver, while presence of liver fat further increased shape variations in both type-2 diabetes and liver disease.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The results suggest that this novel approach may greatly benefit studies aiming at better categorisation of pathologies associated with acute and chronic clinical conditions.</jats:p></jats:sec>
Basty N, Sorokin EP, Thanaj M, et al., 2022, Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture
<jats:title>Abstract</jats:title><jats:p>Features extracted from cardiac MRI (CMR) are correlated with cardiovascular disease outcomes such as aneurysm, and have a substantial heritable component. To determine whether disease-relevant measurements are feasible in non-cardiac specific MRI, and to explore their associations with disease outcomes, and genetic and environmental risk factors. We segmented the heart, aorta, and vena cava from abdominal MRI scans using deep learning, and generated six image-derived phenotypes (IDP): heart volume, four aortic and one vena cava cross-sectional areas (CSA), from 44,541 UK Biobank participants. We performed genome- and phenome-wide association studies, and constructed a polygenic risk score for each phenotype. We demonstrated concordance between our IDPs and related IDPs from CMR, the current gold standard. We replicated previous findings related to sex differences and age-related changes in heart and vessel dimensions. We identified a significant association between infrarenal descending aorta CSA and incident abdominal aortic aneurysm, and between heart volume and several cardiovascular disorders. In a GWAS, we identified 72 associations at 59 loci (15 novel). We derived a polygenic risk score for each trait and demonstrated an association with TAA diagnosis, pointing to a potential screening method for individuals at high-risk of this condition. We demonstrated substantial genetic correlation with cardiovascular traits including aneurysms, varicose veins, dysrhythmia, and cardiac failure. Finally, heritability enrichment analysis implicated vascular tissue in the heritability of these traits. Our work highlights the value of non-specific MRI for exploring cardiovascular disease risk in cohort studies.</jats:p>
Fiamoncini J, Donado-Pestana CM, Duarte GBS, et al., 2022, Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test, FRONTIERS IN NUTRITION, Vol: 9, ISSN: 2296-861X
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- Citations: 4
Sorokin E, Basty N, Whitcher B, et al., 2022, Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology, American Journal of Human Genetics, Vol: 109, Pages: 1092-1104, ISSN: 0002-9297
The spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging, and provide the first reference range for spleen iron in an unselected population. Through genome-wide association study, we identify associations between spleen iron and regulatory variation at two hereditary spherocytosis genes, ANK1 and SPTA1 . Spherocytosis-causing coding mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while these novel common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes that have been observed clinically. Our genetic study also identifies a signal which co-localizes with a splicing quantitative trait locus for MS4A7 , and we show this gene is abundantly expressed in the spleen and in macrophages. The combination of deep learning and efficient image processing enables non-invasive measurement of spleen iron and, in turn, characterization of genetic factors related to iron recycling and erythrocyte morphology.
Martin S, Tyrrell J, Thomas EL, et al., 2022, Correction: Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation., Elife, Vol: 11
Whitcher B, Thanaj M, Cule M, et al., 2022, Precision MRI phenotyping enables detection of small changes in body composition for longitudinal cohorts, Scientific Reports, Vol: 12, ISSN: 2045-2322
Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom.
Basty N, Sorokin EP, Thanaj M, et al., 2022, Abdominal Imaging Associates Body Composition with COVID-19 Severity
<jats:title>Abstract</jats:title><jats:p>The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n=967) and matched controls (n=913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.</jats:p>
Nunn AVW, Guy GW, Bell JD, 2022, Thermodynamics and inflammation: insights into quantum biology and ageing, Quantum Reports, Vol: 4, Pages: 47-74, ISSN: 2624-960X
Inflammation as a biological concept has been around a long time and derives from the Latin “to set on fire” and refers to the redness and heat, and usually swelling, which accompanies injury and infection. Chronic inflammation is also associated with ageing and is described by the term “inflammaging”. Likewise, the biological concept of hormesis, in the guise of what “does not kill you, makes you stronger”, has long been recognized, but in contrast, seems to have anti-inflammatory and age-slowing characteristics. As both phenomena act to restore homeostasis, they may share some common underlying principles. Thermodynamics describes the relationship between heat and energy, but is also intimately related to quantum mechanics. Life can be viewed as a series of self-renewing dissipative structures existing far from equilibrium as vortexes of “negentropy” that ages and dies; but, through reproduction and speciation, new robust structures are created, enabling life to adapt and continue in response to ever changing environments. In short, life can be viewed as a natural consequence of thermodynamics to dissipate energy to restore equilibrium; each component of this system is replaceable. However, at the molecular level, there is perhaps a deeper question: is life dependent on, or has it enhanced, quantum effects in space and time beyond those normally expected at the atomistic scale and temperatures that life operates at? There is some evidence it has. Certainly, the dissipative adaptive mechanism described by thermodynamics is now being extended into the quantum realm. Fascinating though this topic is, does exploring the relationship between quantum mechanics, thermodynamics, and biology give us a greater insight into ageing and, thus, medicine? It could be said that hormesis and inflammation are expressions of thermodynamic and quantum principles that control ageing via natural selection that could operate at all scales
Martin S, Tyrrell J, Thomas EL, et al., 2022, Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation, ELIFE, Vol: 11, ISSN: 2050-084X
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- Citations: 12
Wesolowska-Andersen A, Brorsson CA, Bizzotto R, et al., 2022, Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study, CELL REPORTS MEDICINE, Vol: 3, ISSN: 2666-3791
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- Citations: 26
Mould RR, Thomas EL, Guy G, et al., 2022, Cell-cell death communication by signals passing through non-aqueous environments: A reply, RESULTS IN CHEMISTRY, Vol: 4, ISSN: 2211-7156
Whitcher B, Thanaj M, Cule M, et al., 2021, Precision MRI Phenotyping Enables Detection of Small Changes in Body Composition for Longitudinal Cohorts
<jats:title>ABSTRACT</jats:title><jats:p>Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3,088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom.</jats:p>
Liu Y, Basty N, Whitcher B, et al., 2021, Genetic architecture of 11 organ traits derived from abdominal MRI using deep learning, eLife, Vol: 10, ISSN: 2050-084X
Cardiometabolic diseases are an increasing global health burden. While socioeconomic, environmental, behavioural, and genetic risk factors have been identified, a better understanding of the underlying mechanisms is required to develop more effective interventions. Magnetic resonance imaging (MRI) has been used to assess organ health, but biobank-scale studies are still in their infancy. Using over 38,000 abdominal MRI scans in the UK Biobank, we used deep learning to quantify volume, fat, and iron in seven organs and tissues, and demonstrate that imaging-derived phenotypes reflect health status. We show that these traits have a substantial heritable component (8–44%) and identify 93 independent genome-wide significant associations, including four associations with liver traits that have not previously been reported. Our work demonstrates the tractability of deep learning to systematically quantify health parameters from high-throughput MRI across a range of organs and tissues, and use the largest-ever study of its kind to generate new insights into the genetic architecture of these traits.
MARTIN S, TYRRELL J, THOMAS EL, et al., 2021, 190-LB: Using Genetics to Uncouple Higher Adiposity from Its Adverse Metabolic Effects, Diabetes, Vol: 70, ISSN: 0012-1797
<jats:p>Type 2 diabetes is linked to higher risk of many non-metabolic conditions (e.g. cancers, neuropsychiatric and musculoskeletal disease) which all share a common risk factor: obesity. The causal pathways from excess weight to disease are unknown. We aimed to use specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects. Using metabolic biomarkers from 442,278 UK Biobank individuals, we identified two clusters of body fat % increasing alleles: a) 36 “favourable adiposity” (FA) alleles associated with a favourable metabolic profile (higher HDL and SHBG and lower triglyceride and liver enzymes); b) 38 “unfavourable adiposity” (UFA) alleles associated with an unfavourable profile (lower HDL and SHBG and higher triglyceride and liver enzymes). We used two-sample Mendelian randomization with 43 diseases from non-UK Biobank GWASs. We identified two sets of diseases. 1) Those where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here the FA and UFA clusters had an opposing effect on the risk of disease: type 2 diabetes (FA: 0.11 OR per 1 standard deviation higher body fat % [95%CI: 0.08, 0.16] vs. UFA: 5.50 [4.29, 7.05]), stroke (0.65 [0.52, 0.83] vs. 1.43 [1.23, 1.67]), gout (0.44 [0.29, 0.68] vs. 2.49 [1.88, 3.29]), breast cancer (1.12 [0.64, 1.94] vs. 0.52 [0.39, 0.68]) and colorectal cancer (0.67 [0.52, 0.85] vs. 1.20 [1, 1.50]). 2) Those where the mechanical excess weight (or other non-metabolic effects) is likely a cause of the disease. Here the FA cluster, despite having lower metabolic risk, and the UFA cluster were both associated with higher disease risk: venous thromboembolism (2.52 [1.82, 3.47] vs. 1.63 [1.25, 2.13]), osteoarthritis (1.45 [1.19, 1.76] vs. 2.20 [1.64, 2.95]), depression (2.85 [1.38, 5.89] vs. 2.59 [1.60, 4.21]). Our results assist in understanding the consequences of higher adiposity uncoupled from its ad
Woodley SB, Mould RR, Sahuri-Arisoylu M, et al., 2021, Mitochondrial Function as a Potential Tool for Assessing Function, Quality and Adulteration in Medicinal Herbal Teas, FRONTIERS IN PHARMACOLOGY, Vol: 12
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