PeerJ Preprints: Metabolic Scienceshttps://peerj.com/preprints/index.atom?journal=peerj&subject=5270Metabolic Sciences articles published in PeerJ PreprintsAge-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of ratshttps://peerj.com/preprints/276472019-04-112019-04-11Shangfu XuAnling HuLu XieJiajia LiuQin WuJie J Liu
Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1-4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by Western-blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, 5 nuclear receptors, and 4 phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.
Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1-4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by Western-blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, 5 nuclear receptors, and 4 phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.Hydration, arginine vasopressin, and gluco-regulatory health in humans: A critical perspectivehttps://peerj.com/preprints/276252019-04-012019-04-01Harriet A CarrollLewis J James
Gluco-regulatory diseases, such as type 2 diabetes are currently a key public health priority. Public health messages have started to include the addition of water in their dietary guidelines. Such guidelines however are not based on causal evidence pertaining to the health effects of increased water intake, but rather more heavily based upon non-causal or mechanistic data. One line of thinking linking fluid intake and health is that hypohydration induces elevated blood concentrations of arginine vasopressin (AVP). Research in the 1970s and 1980s implicated AVP in gluco-regulation, supported by observational evidence. This important area of research subsequently appeared to stop until this century during which interest in hypertonic saline infusion studies, animal AVP receptor knockout models, dietary and genetic associations, and human interventions manipulating hydration status have resurged. This narrative review briefly describes and critically evaluates the usefulness of the current AVP-gluco-regulatory research. We offer suggestions on how to test the independent gluco-regulatory effects of body mass reductions versus elevated circulating AVP concentrations, such as investigating hydration manipulations using 3,4-Methylenedioxymethamphetamine. Whilst much research is still needed before making firm conclusions, the current evidence suggests that although AVP may only be partially implicated in gluco-regulation; more ecologically valid models using human participants suggests this effect is independent of hydration status. The key implication of this hypothesis if confirmed in future research is that manipulating hydration status to reduce circulating AVP concentrations may not be an effective method to improve gluco-regulatory health.
Gluco-regulatory diseases, such as type 2 diabetes are currently a key public health priority. Public health messages have started to include the addition of water in their dietary guidelines. Such guidelines however are not based on causal evidence pertaining to the health effects of increased water intake, but rather more heavily based upon non-causal or mechanistic data. One line of thinking linking fluid intake and health is that hypohydration induces elevated blood concentrations of arginine vasopressin (AVP). Research in the 1970s and 1980s implicated AVP in gluco-regulation, supported by observational evidence. This important area of research subsequently appeared to stop until this century during which interest in hypertonic saline infusion studies, animal AVP receptor knockout models, dietary and genetic associations, and human interventions manipulating hydration status have resurged. This narrative review briefly describes and critically evaluates the usefulness of the current AVP-gluco-regulatory research. We offer suggestions on how to test the independent gluco-regulatory effects of body mass reductions versus elevated circulating AVP concentrations, such as investigating hydration manipulations using 3,4-Methylenedioxymethamphetamine. Whilst much research is still needed before making firm conclusions, the current evidence suggests that although AVP may only be partially implicated in gluco-regulation; more ecologically valid models using human participants suggests this effect is independent of hydration status. The key implication of this hypothesis if confirmed in future research is that manipulating hydration status to reduce circulating AVP concentrations may not be an effective method to improve gluco-regulatory health.Multiple propane gas flow rates procedure to determine accuracy and linearity of indirect calorimetry systems : An experimental assessment of a method.https://peerj.com/preprints/275502019-02-232019-02-23Mohammad IsmailAlsubheen A Sana'aAngela Loucks-AtlinsonMatthew AtkinsonLiam P KellyTim AlkananiFabien Basset
Objective: Indirect calorimetry (IC) systems measure the fractions of expired carbon dioxide (FECO2) and oxygen (FEO2) recorded at the mouth in order to estimate whole body energy production (EP). The fundamental principal of IC relates to oxidative mechanisms, expressed as rate of oxygen uptake (V̇O2) and carbon dioxide production (V̇CO2). From these volumes we calculate energy production and respiratory exchange ratio which is used to estimate substrate utilization rates. The accuracy of IC systems is critical to detect small changes in respiratory gas exchanges. The aim of this technical report was to assess the accuracy and linearity of IC systems using multiple propane gas flow rates procedure. Approach: A series of propane gas with different flow rates and ventilation rates were run on three different IC systems. The actual experimental V̇O2 and V̇CO2 were calculated and compared to stoichiometry theoretical values. Results: showed a linear relationship between gas volumes (V̇O2 and V̇CO2) and propane gas flows (99.6%, 99.2%, 94.8% for the Sable, Moxus, and Jaeger metabolic carts, respectively). In terms of system error, Jaeger system had significantly (p < 0.001) greater V̇O2 (M = -0.057, SE = 0.004), and V̇CO2 (M = -0.048, SE = 0.002) error compared to either the Sable (V̇O2, M = 0.044, SE = 0.004; V̇CO2, M = 0.024, SE = 0.002) or the Moxus (V̇O2, M = 0.046, SE = 0.004; V̇CO2, M = 0.025, SE = 0.002) metabolic carts. There were no significant differences between the Sable or Moxus metabolic carts. Conclusion: The multiple flow rates approach permitted the assessment of linearity of IC systems in addition to determining the accuracy of fractions of expired gases.
Objective: Indirect calorimetry (IC) systems measure the fractions of expired carbon dioxide (FECO2) and oxygen (FEO2) recorded at the mouth in order to estimate whole body energy production (EP). The fundamental principal of IC relates to oxidative mechanisms, expressed as rate of oxygen uptake (V̇O2) and carbon dioxide production (V̇CO2). From these volumes we calculate energy production and respiratory exchange ratio which is used to estimate substrate utilization rates. The accuracy of IC systems is critical to detect small changes in respiratory gas exchanges. The aim of this technical report was to assess the accuracy and linearity of IC systems using multiple propane gas flow rates procedure. Approach: A series of propane gas with different flow rates and ventilation rates were run on three different IC systems. The actual experimental V̇O2 and V̇CO2 were calculated and compared to stoichiometry theoretical values. Results: showed a linear relationship between gas volumes (V̇O2 and V̇CO2) and propane gas flows (99.6%, 99.2%, 94.8% for the Sable, Moxus, and Jaeger metabolic carts, respectively). In terms of system error, Jaeger system had significantly (p < 0.001) greater V̇O2 (M = -0.057, SE = 0.004), and V̇CO2 (M = -0.048, SE = 0.002)error compared to either the Sable (V̇O2, M = 0.044, SE = 0.004; V̇CO2, M = 0.024, SE = 0.002) or the Moxus (V̇O2, M = 0.046, SE = 0.004; V̇CO2, M = 0.025, SE = 0.002) metabolic carts. There were no significant differences between the Sable or Moxus metabolic carts. Conclusion: The multiple flow rates approach permitted the assessment of linearity of IC systems in addition to determining the accuracy of fractions of expired gases.Hibernation, puberty and chronic kidney disease in troglodytes from Spain half a million years agohttps://peerj.com/preprints/273702018-11-202018-11-20Antonis BartsiokasJuan Luis Arsuaga
Both animal hibernation (heterothermy) and human renal osteodystrophy are characterized by high levels of serum parathyroid hormone. To test the hypothesis of hibernation in an extinct human species, we examined the hominin skeletal collection from Sima de los Huesos, Cave Mayor, Atapuerca, Spain, for evidence of hyperparathyroidism. We studied the morphology of the fossilized bones by using macrophotography, microscopy, histology and CT scanning. We found trabecular tunneling and osteitis fibrosa, subperiosteal resorption,‘rotten fence post’ signs,brown tumours, subperiosteal new bone, chondrocalcinosis, rachitic osteoplaques and empty gaps between them, craniotabes, and beading in ribs mostly in the adolescent population of these hominins. Since many of the above lesions are pathognomonic, these extinct hominins suffered annually from renal rickets, secondary hyperparathyroidism, and renal osteodystrophy associated with Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). We suggest these diseases were caused by non-tolerated hibernation in dark cavernous hibernacula. This is evidenced by the rachitic osteoplaques and the gaps between them mainly in the adolescent individuals along with the evidence of healing mainly in the adults. The sublayers in the rachitic osteoplaques point to bouts of arousal from hibernation. The strong projection of the external lip of the femoral trochlea, the rachitic osteoplaques with the empty gaps between them,the “rotten fence post sign”, and the evidence of annual healing caused by non-tolerated hibernation in adolescent individuals, also point to the presence of annually intermittent puberty in this population. The hypothesis of hibernation is consistent with the genetic evidence and the fact that the SH hominins lived during a glacial period. The present work will provide a new insight into the physiological mechanism of early human metabolism which could help in determining the life histories and physiologies of extinct human species.
Both animal hibernation (heterothermy) and human renal osteodystrophy are characterized by high levels of serum parathyroid hormone. To test the hypothesis of hibernation in an extinct human species, we examined the hominin skeletal collection from Sima de los Huesos, Cave Mayor, Atapuerca, Spain, for evidence of hyperparathyroidism. We studied the morphology of the fossilized bones by using macrophotography, microscopy, histology and CT scanning. We found trabecular tunneling and osteitis fibrosa, subperiosteal resorption,‘rotten fence post’ signs,brown tumours, subperiosteal new bone, chondrocalcinosis, rachitic osteoplaques and empty gaps between them, craniotabes, and beading in ribs mostly in the adolescent population of these hominins. Since many of the above lesions are pathognomonic, these extinct hominins suffered annually from renal rickets, secondary hyperparathyroidism, and renal osteodystrophy associated with Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). We suggest these diseases were caused by non-tolerated hibernation in dark cavernous hibernacula. This is evidenced by the rachitic osteoplaques and the gaps between them mainly in the adolescent individuals along with the evidence of healing mainly in the adults. The sublayers in the rachitic osteoplaques point to bouts of arousal from hibernation. The strong projection of the external lip of the femoral trochlea, the rachitic osteoplaques with the empty gaps between them,the “rotten fence post sign”, and the evidence of annual healing caused by non-tolerated hibernation in adolescent individuals, also point to the presence of annually intermittent puberty in this population. The hypothesis of hibernation is consistent with the genetic evidence and the fact that the SH hominins lived during a glacial period. The present work will provide a new insight into the physiological mechanism of early human metabolism which could help in determining the life histories and physiologies of extinct human species.Integration of proteomics and metabolomics data in a novel cellular knock out model of methylmalonic acidemiahttps://peerj.com/preprints/273352018-11-092018-11-09Michele CostanzoMarianna CaterinoArmando CeveniniVincent JungIda C GuerreraMargherita Ruoppolo
Background. Methylmalonic acidemia is a rare inborn error of metabolism caused by mutations in methylmalonyl−CoA mutase (MUT) gene. As intermediate of propionate metabolism, MUT converts methylmalonyl−CoA into succinyl−CoA, which enters the Krebs cycle. Downstream MUT deficiency, methylmalonic acid accumulates in body fluids as biomarker of disease. The long-term complications of the disease can include cognitive and neurological impairment, chronic kidney disease, liver failure, and death.
Methods. In order to create a valid cellular model to study the disease, MUT gene was knocked out (KO) in HEK293 cell line by using CRISPR-CAS9 technology. Methylmalonic acid was measured in MUT-KO and wild type (WT) cells by multiple reaction monitoring. A quantitative proteomics analysis was carried out using a label-free mass spectrometry-based approach. Data were processed using MaxQuant software. Moreover, a targeted metabolomics analysis was performed in order to measure an entire panel of amino acids and acylcarnitines.
Results. Methylmalonic acid resulted increased in KO cells if compared with WT ones. The proteomic dataset showed a number of 69 differentially expressed proteins, of which 39 down-regulated and 30 up-regulated in the MUT-KO condition. Gene Ontology analysis revealed an enrichment in energy and lipid metabolism categories. The variations in the metabolomic profile are indicative of alterations in fatty acid oxidation processes and lipid metabolism.
Background. Methylmalonic acidemia is a rare inborn error of metabolism caused by mutations in methylmalonyl−CoA mutase (MUT) gene. As intermediate of propionate metabolism, MUT converts methylmalonyl−CoA into succinyl−CoA, which enters the Krebs cycle. Downstream MUT deficiency, methylmalonic acid accumulates in body fluids as biomarker of disease. The long-term complications of the disease can include cognitive and neurological impairment, chronic kidney disease, liver failure, and death.Methods. In order to create a valid cellular model to study the disease, MUT gene was knocked out (KO) in HEK293 cell line by using CRISPR-CAS9 technology. Methylmalonic acid was measured in MUT-KO and wild type (WT) cells by multiple reaction monitoring. A quantitative proteomics analysis was carried out using a label-free mass spectrometry-based approach. Data were processed using MaxQuant software. Moreover, a targeted metabolomics analysis was performed in order to measure an entire panel of amino acids and acylcarnitines.Results. Methylmalonic acid resulted increased in KO cells if compared with WT ones. The proteomic dataset showed a number of 69 differentially expressed proteins, of which 39 down-regulated and 30 up-regulated in the MUT-KO condition. Gene Ontology analysis revealed an enrichment in energy and lipid metabolism categories. The variations in the metabolomic profile are indicative of alterations in fatty acid oxidation processes and lipid metabolism.Type II diabetes may affect stem cell niche resulting in down regulation of glucose transporters and insulin receptors in cellshttps://peerj.com/preprints/270242018-07-062018-07-06Wenfa Ng
Characterized by high blood glucose concentration, resistance of cells to glucose uptake and reduced insulin sensitivity, Type II diabetes is a major health problem afflicting both developing and developed countries in increasing extent as populations around the world increasing adopt high energy diets. Given that, in Type II diabetes, successive generations of various cell types in the body ranging from muscles, tissues, blood, and organs are resistant to glucose uptake and exhibited reduced sensitivity to insulin, the underlying aetiology of Type II diabetes might involve the altered gene expression of stem cells in stem cell niches that adapted to a high glucose diet through an evolutionary conserved mechanism that aimed at homeostasis. Specifically, faced with a high energy and high sugar diet, stem cells in stem cell niches around the body possibly activated an evolutionary conserved mechanism aimed at reducing glucose uptake by cells for reducing weight gain by the body. Thus, successive generations of cells generated from the stem cell niche would exhibit an epigenetically controlled programme of gene expression that exhibited down regulation of genes for glucose transporters and insulin receptors. Such cells would display a phenotype of reduced glucose uptake together with reduced sensitivity to insulin; thereby, resulting in a high blood glucose concentration characteristic of Type II diabetes. The above hypothesis helped explain why high sugar intake by the body could result in impaired sensitivity to insulin and reduced glucose uptake by cells, and more importantly, the widespread nature in which many cell types (principally muscle cells) are affected by a possible epigenetically controlled gene expression programme which hitherto appeared clinically irreversible. Specifically, the most important clinical question for diabetes treatment and care remains the reasons underlying the clinically observed irreversible nature of the disease that progressively, with age and poor glucose control, worsens with complications to many organs of the body such as the eyes, kidneys, cardiovascular system and brain (stroke). Interested readers are invited to expand on the ideas presented in this abstract preprint.
Characterized by high blood glucose concentration, resistance of cells to glucose uptake and reduced insulin sensitivity, Type II diabetes is a major health problem afflicting both developing and developed countries in increasing extent as populations around the world increasing adopt high energy diets. Given that, in Type II diabetes, successive generations of various cell types in the body ranging from muscles, tissues, blood, and organs are resistant to glucose uptake and exhibited reduced sensitivity to insulin, the underlying aetiology of Type II diabetes might involve the altered gene expression of stem cells in stem cell niches that adapted to a high glucose diet through an evolutionary conserved mechanism that aimed at homeostasis. Specifically, faced with a high energy and high sugar diet, stem cells in stem cell niches around the body possibly activated an evolutionary conserved mechanism aimed at reducing glucose uptake by cells for reducing weight gain by the body. Thus, successive generations of cells generated from the stem cell niche would exhibit an epigenetically controlled programme of gene expression that exhibited down regulation of genes for glucose transporters and insulin receptors. Such cells would display a phenotype of reduced glucose uptake together with reduced sensitivity to insulin; thereby, resulting in a high blood glucose concentration characteristic of Type II diabetes. The above hypothesis helped explain why high sugar intake by the body could result in impaired sensitivity to insulin and reduced glucose uptake by cells, and more importantly, the widespread nature in which many cell types (principally muscle cells) are affected by a possible epigenetically controlled gene expression programme which hitherto appeared clinically irreversible. Specifically, the most important clinical question for diabetes treatment and care remains the reasons underlying the clinically observed irreversible nature of the disease that progressively, with age and poor glucose control, worsens with complications to many organs of the body such as the eyes, kidneys, cardiovascular system and brain (stroke). Interested readers are invited to expand on the ideas presented in this abstract preprint.Short-term starvation at low temperature prior to harvest does not impact the health and acute stress response of adult Atlantic salmonhttps://peerj.com/preprints/28372017-03-012017-03-01Rune WaagbøSven Martin JørgensenGerrit TimmerhausOlav BreckPål A Olsvik
Period of starvation is regarded as a sound practice in aquaculture prior to handling, transportation and harvest, to minimise impacts on welfare and ensure proper hygiene after harvest. However, documentation of welfare issues such as stress following starvation and handling in adult Atlantic salmon are lacking. This study aimed to examine gut emptying and potential stress during a two weeks starvation period, and whether this starvation period changes the tolerance for physical stress. The study confirmed slower emptying of the gut segments at low temperature. Plasma and bile cortisol, and selected clinical analyses were used to characterize potential stress, as well as the response to acute physical crowding stress during the starvation period. Neither the general stress level nor the ability to cope with handling stress was affected by a 14 days starvation period. Down-regulation of selected nutritional related gene markers in liver indicated classical starvation responses, with reduced metabolism and oxidative pressure, and sparing of nutrients. The response to acute handling stress was not affected by two weeks of starvation. There were minor effects of starvation on stress and health markers, as evaluated by plasma lysozyme activity and gene expression of selected inflammation marker proteins in heart and skin tissues.
Period of starvation is regarded as a sound practice in aquaculture prior to handling, transportation and harvest, to minimise impacts on welfare and ensure proper hygiene after harvest. However, documentation of welfare issues such as stress following starvation and handling in adult Atlantic salmon are lacking. This study aimed to examine gut emptying and potential stress during a two weeks starvation period, and whether this starvation period changes the tolerance for physical stress. The study confirmed slower emptying of the gut segments at low temperature. Plasma and bile cortisol, and selected clinical analyses were used to characterize potential stress, as well as the response to acute physical crowding stress during the starvation period. Neither the general stress level nor the ability to cope with handling stress was affected by a 14 days starvation period. Down-regulation of selected nutritional related gene markers in liver indicated classical starvation responses, with reduced metabolism and oxidative pressure, and sparing of nutrients. The response to acute handling stress was not affected by two weeks of starvation. There were minor effects of starvation on stress and health markers, as evaluated by plasma lysozyme activity and gene expression of selected inflammation marker proteins in heart and skin tissues.Seizures and Amyloid-β induce similar changes in neuronal network metabolic parameters in mouse hippocampal sliceshttps://peerj.com/preprints/25212016-10-122016-10-12Anton IvanovAnton E MalkovSvetlna BuldakovaMisha ZilberterYuri Zilberter
Major risk factors for neurodegenerative diseases share brain hypometabolism as one common outcome. In turn, many neurodegenerative pathologies result in brain hypometabolism; both epilepsy and Alzheimer's disease are characterised by disruptions in glucose metabolism. However, the causative link between energy shortage and neuronal pathologies in these disease has remained elusive. Using real-time brain slice recordings of energy metabolism parameter (NAD(P)H, FAD, pO2 and extracellular glucose) transients in response to network activation, we found that induced epileptic seizures and amyloid-beta peptide both result in similar and long-lasting disruptions of neuronal energy metabolism, suggesting a common path of action. In addition, we found that in both cases, subsequent addition of pyruvate, the principal mitochondrial fuel possessing multiple neuroprotective properties, completely normalised the disputed energy state. Our data suggests that energy metabolism disruptions underlie the initiation and progression of neurodegenerative diseases.
Major risk factors for neurodegenerative diseases share brain hypometabolism as one common outcome. In turn, many neurodegenerative pathologies result in brain hypometabolism; both epilepsy and Alzheimer's disease are characterised by disruptions in glucose metabolism. However, the causative link between energy shortage and neuronal pathologies in these disease has remained elusive. Using real-time brain slice recordings of energy metabolism parameter (NAD(P)H, FAD, pO2 and extracellular glucose) transients in response to network activation, we found that induced epileptic seizures and amyloid-beta peptide both result in similar and long-lasting disruptions of neuronal energy metabolism, suggesting a common path of action. In addition, we found that in both cases, subsequent addition of pyruvate, the principal mitochondrial fuel possessing multiple neuroprotective properties, completely normalised the disputed energy state. Our data suggests that energy metabolism disruptions underlie the initiation and progression of neurodegenerative diseases.Dynamics of resource allocation in biological systemshttps://peerj.com/preprints/25032016-10-062016-10-06Imadol V Jeff-Eke
Here we present a single working model that attempts at reconciliation of biological systems. To do this we recognize and emphasize a universal theme of all biological systems: a need for resources. That is, we consider the dynamics of resource allocation as a requirement for actuation of responses to stimuli. In addition, all contemplations are founded on four postulates that are motivated by the homeostatic principle as conceived of by Claude Bernard and Walter Cannon: biological systems exhaust attempts to prevent from reaching the absolute maximum failure potential; biological systems tend in the direction toward the absolute minimum failure potential; biological systems attempt to assume the failure potential of an ideal regulator system; and all biological systems attempt to be in agreement with all four postulates. Finally, we attempt to determine biological manifestations of the stated model.
Here we present a single working model that attempts at reconciliation of biological systems. To do this we recognize and emphasize a universal theme of all biological systems: a need for resources. That is, we consider the dynamics of resource allocation as a requirement for actuation of responses to stimuli. In addition, all contemplations are founded on four postulates that are motivated by the homeostatic principle as conceived of by Claude Bernard and Walter Cannon: biological systems exhaust attempts to prevent from reaching the absolute maximum failure potential; biological systems tend in the direction toward the absolute minimum failure potential; biological systems attempt to assume the failure potential of an ideal regulator system; and all biological systems attempt to be in agreement with all four postulates. Finally, we attempt to determine biological manifestations of the stated model.tmod: an R package for general and multivariate enrichment analysishttps://peerj.com/preprints/24202016-09-042016-09-04January Weiner 3rdTeresa Domaszewska
“Omics” studies generate long lists of genes, proteins, metabolites or other features which can be difficult to decipher. Feature set enrichment analysis utilizing annotated groups/classes of features (such as pathways, gene ontology terms or gene/metabolic modules) can provide a powerful gateway to associate data to phenotypes such as disease process or treatment progression. At the same time, the increasing use of technologies to generate multidimensional omics data sets based on specific cell types or responses to stimuli increases the number and breadth of annotated feature sets available for enrichment analysis, facilitating the ability to draw biologically relevant conclusions. However, existing tools and applications for enrichment analysis are adapted specifically to gene set enrichment and lack functionalities to analyze rapidly growing amounts of metabolomics and other data. Moreover, such tools often provide only a limited range of statistical methods, rely on permutation tests, lack suitable visualization tools to facilitate result interpretation in complex experimental setups, and lack standalone versions usable in semi-automatized workflows. Here, we present tmod, an R package which implements powerful statistical methods for enrichment analysis. Tmod includes definitions of widely used feature sets for transcriptomic and metabolomic profiling and also allows use of custom user-provided feature sets. Moreover, it provides novel and intuitive visualiza- tion methods which facilitate interpretation of complex data sets. The implemented statistical tests allow the significance of enrichment within sorted feature lists to be calculated without randomization tests and thus are suitable for combining functional analysis with multivariate techniques.
“Omics” studies generate long lists of genes, proteins, metabolites or other features which can be difficult to decipher. Feature set enrichment analysis utilizing annotated groups/classes of features (such as pathways, gene ontology terms or gene/metabolic modules) can provide a powerful gateway to associate data to phenotypes such as disease process or treatment progression. At the same time, the increasing use of technologies to generate multidimensional omics data sets based on specific cell types or responses to stimuli increases the number and breadth of annotated feature sets available for enrichment analysis, facilitating the ability to draw biologically relevant conclusions. However, existing tools and applications for enrichment analysis are adapted specifically to gene set enrichment and lack functionalities to analyze rapidly growing amounts of metabolomics and other data. Moreover, such tools often provide only a limited range of statistical methods, rely on permutation tests, lack suitable visualization tools to facilitate result interpretation in complex experimental setups, and lack standalone versions usable in semi-automatized workflows. Here, we present tmod, an R package which implements powerful statistical methods for enrichment analysis. Tmod includes definitions of widely used feature sets for transcriptomic and metabolomic profiling and also allows use of custom user-provided feature sets. Moreover, it provides novel and intuitive visualiza- tion methods which facilitate interpretation of complex data sets. The implemented statistical tests allow the significance of enrichment within sorted feature lists to be calculated without randomization tests and thus are suitable for combining functional analysis with multivariate techniques.