Reproduction places severe demands on the energy metabolism in human females. When physical work entails higher energy expenditure, not enough energy will be left for the support of the reproductive processes and temporal suppression of the reproductive function is expected. While energy needed for reproduction may be obtained by increases in energy intake, utilization of fat reserves, or reallocation of energy from basal metabolism, several environmental or physiological constraints render such solutions unlikely. (...) For human ancestors increases in energy intake were limited by availability of food, by labor of food preparation and by metabolic ceilings to energy assimilation. Energy stored as fat may support only a fraction of the requirements for reproduction (especially lactation). Effects of intense physical activity on basal metabolism may also interfere with fat accumulation during pregnancy. Finally, the female physiology may experience demands on increasing the basal metabolism as a consequence of physical activity and, at the same time, on decreasing the basal metabolism, when energy to support the ongoing pregnancy or lactation is inadequate. The resulting metabolic dilemmas could constitute a plausible cause for the occurrence of reproductive suppression in response to physical activity. It is, therefore, likely that allocating enough energy to the reproductive processes during periods when energy expenditure rises may be difficult due to physiological and bioenergetic constraints. Females attempting pregnancy in such conditions may compromise their lifetime reproductive output. A reproductive suppression occurring in low energy availability situations may thus represent an adaptive rather then a pathological response. (shrink)

In this paper, we aim at rethinking the concept of obesity in a way that better captures the connection between underlying medical aspects, on the one hand, and an individual’s developmental history, on the other. Our proposal rests on the idea that obesity is not to be understood as a phenotypic trait or character; rather, obesity represents one of the many possible states of a more complex phenotypic trait that we call ‘energy metabolism.’ We argue that this apparently (...) simple conceptual shift can help solve important theoretical misconceptions regarding the genetics, epigenetics, and development of obesity. In addition, we show that our proposal can be fruitfully paired with the concept of developmental channeling of a trait, which connects to the study of the plasticity and canalization of complex traits. Finally, we discuss the potential impact of our approach on the assessment, treatment, and social narratives of obesity. (shrink)

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long‐lived C. elegans vhl‐1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. (...) elegans by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy‐intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt (...) a previously developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in (...) various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders. (shrink)

Metabolism is a criterion of life. Three senses are distinguished. The weakest allows strong A-Life: virtual creatures having physical existence in computer electronics, but not bodies, are classes as 'alive'. The second excludes strong A-Life but allows that some non-biochemical A-Life robots could be classed as alive. The third, which stresses the body's self-production by energy budgeting and self-equilibrating energy exchanges of some (necessary) complexity, excludes both strong A-Life and living non-biochemical robots.

Metabolomics, including lipidomics, is emerging as a quantitative biology approach for the assessment of energy flow through metabolism and information flow through metabolic signaling; thus, providing novel insights into metabolism and its regulation, in health, healthy ageing and disease. In this forward‐looking review we provide an overview on the origins of metabolomics, on its role in this postgenomic era of biochemistry and its application to investigate metabolite role and (bio)activity, from model systems to human population studies. We (...) present the challenges inherent to this analytical science, and approaches and modes of analysis that are used to resolve, characterize and measure the infinite chemical diversity contained in the metabolome (including lipidome) of complex biological matrices. In the current outbreak of metabolic diseases such as cardiometabolic disorders, cancer and neurodegenerative diseases, metabolomics appears to be ideally situated for the investigation of disease pathophysiology from a metabolite perspective. (shrink)

We provide a mathematical study of a model of energy metabolism and hemodynamics of glioma allowing a better understanding of metabolic modifications leading to anaplastic transformation from low grade glioma.This mathematical analysis allows ultimately to unveil the solution to a viability problem which seems quite pertinent for applications to medecine.

Use of symbols, the key to the biosemiotics field as to many others, required bigger brains which implied a promissory note for greater energy consumption; symbols are obviously expensive. A score years before the current estimate of 18–20% for the human brain’s metabolic demand on the organism, it was known that neural tissue is metabolically dear. This paper first discusses two evolutionary responses to this demand, on both of which there is some consensus. The first, assigning care of altricial (...) infants with burgeoning brains (and in human infants the metabolic demand peaks at 65% of the total) to “allomothers” is not unique to humans. The second, using relatively small neurons as primates do, risks misfires past a certain minimal value. Moreover, in apparent paradox, there is an increasing consensus that large “Von Economo” neurons are critical for communication. This paper’s main contribution is the discussion of two further evolutionary tricks. The first is the use of self-similarity in the cortex, both in structure and process, to allow the cortex readily—and in energetic terms, parsimoniously—to shift between states in a high-dimensional space. This leads to discussion of the kind of formalism appropriate to model these shifts, a formalism which—it is tentatively suggested—may do double duty for the modeling of symbolic thought. The second trick is the superimposition on the background “white noise” of neural firing of EEG-detected waves like gamma. The paper describes a method, using the Hilbert transform, of calculating the dips in energy consumption as the brain is transitioned by gamma waves. It is hypothesized that consciousness may be a spandrel, the incidental result of a neurodynamic imperative that the brain enter a maximally sensitive (in sensory terms) “zero power” state a few times a second. If that is the case, then there are obvious benefits for health in meditation, which can be viewed as a state of consciousness extended over time by limiting afferent stimuli. (shrink)

Metagenomics bears upon all aspects of microbiology, including our understanding of mitochondrial and eukaryote origin. Recently, ribosomal protein phylogenies show the eukaryote host lineage – the archaeal lineage that acquired the mitochondrion – to branch within the archaea. Metagenomic studies are now uncovering new archaeal lineages that branch more closely to the host than any cultivated archaea do. But how do they grow? Carbon and energy metabolism as pieced together from metagenome assemblies of these new archaeal lineages, such (...) as the Deep Sea Archaeal Group (including Lokiarchaeota) and Bathyarchaeota, do not match the physiology of any cultivated microbes. Understanding how these new lineages live in their environment is important, and might hold clues about how mitochondria arose and how the eukaryotic lineage got started. Here we look at these exciting new metagenomic studies, what they say about archaeal physiology in modern environments, how they impact views on host‐mitochondrion physiological interactions at eukaryote origin. (shrink)

Non‐invasive microanalytical methods have been devised to study the energy metabolism of single human preimplantation embryos. Psyruvate, which is added routinely to all media used to culture human embryos, is consumed throughout the preimplantation period, with glucose assuming an increasing role at embryo compaction and blastocyst formation. All of the glucose consumed may be accounted for by the appearance of lactate in the incubation medium. The enzyme hexokinase my be involved in regulating this aerobic glycolysis. There is cosiderable (...) indirect evidence for the utilisation of endogenous as opposed to exogenous energy substrates, the most likely candidate being protein. Information on early human embryo metabolismis likely to find application in a number of areas: these include the improvement of techniques for assisted human conception, notably in the selection of embryos for transfer following In Vitro Fertilisation; the diagnosis of gentic defects at the preimplantation stage; increased undersding of the causes of implantation failure and miscarriage, and the development of novel post‐coital contraceptives. (shrink)

The brain's reliance on glucose as a primary fuel source is well established, but psychological models of cognitive processing that take energy supply into account remain uncommon. One exception is research on self-control depletion, where debate continues over a limited-resource model of self-control depletion. This model argues that transient reduction in self-control after exertion of prior self-control is caused by the depletion of brain glucose, and that self-control processes are special, perhaps unique, in this regard. This model has been (...) argued to be physiologically implausible in several recent reviews. This paper attempts to correct some inaccuracies that have occurred during debate over the physiological plausibility of this model. We contend that not only is such limitation of cognition by constraints on glucose supply plausible, it is well established in the neuroscience literature across several cognitive domains. Conversely, we argue that there is no evidence that self-control is special in regard to its metabolic cost. Mental processes require physical energy, and the body is limited in its ability to supply the brain with sufficient energy to fuel mental processes. This article reviews current findings in brain metabolism and seeks to resolve the current conflict in the field regarding the physiological plausibility of the self-control glucose-depletion hypothesis. (shrink)

Several recently discovered small proteins of less than 100 amino acids control important, but sometimes surprising, steps in the metabolism of cyanobacteria. There is mounting evidence that a large number of small protein genes have also been overlooked in the genome annotation of many other microorganisms. Although too short for enzymatic activity, their functional characterization has frequently revealed the involvement in processes such as signaling and sensing, interspecies communication, stress responses, metabolism, regulation of transcription and translation, and in (...) the formation of multisubunit protein complexes. Cyanobacteria are the only prokaryotes that perform oxygenic photosynthesis. They thrive under a wide variety of conditions as long as there is light and must cope with dynamic changes in the environment. To acclimate to these fluctuations, frequently small regulatory proteins become expressed that target key enzymes and metabolic processes. The consequences of their actions are profound and can even impact the surrounding microbiome. This review highlights the diverse functions of recently discovered small proteins that control cyanobacterial metabolism. It also addresses why many of these proteins have been overlooked so far and explores the potential for implementing metabolic engineering strategies to improve the use of cyanobacteria in biotechnological applications. (shrink)

In biological electron transport the spin, and thus the magnetic property of electrons, is neglected. Furthermore, no attention is paid to the fact that the great majority of biologically important molecules are chiral, and during excitation a magnetic moment is induced in them. It is shown, both theoretically and experimentally, that the magnetic moment of the electron and the magnetic transition moment of the optically active molecules may interact. The main consequences of such an interaction are a higher probability of (...) the occurrence of optically active molecules in triplet states, and the polarization of transported electrons. (shrink)

The widespread adoption of radioisotopes as tools in biomedical research and therapy became one of the major consequences of the "physicists' war" for postwar life science. Scientists in the Manhattan Project, as part of their efforts to advocate for civilian uses of atomic energy after the war, proposed using infrastructure from the wartime bomb project to develop a government-run radioisotope distribution program. After the Atomic Energy Bill was passed and before the Atomic Energy Commission was formally established, (...) the Manhattan Project began shipping isotopes from Oak Ridge. Scientists and physicians put these reactor-produced isotopes to many of the same uses that had been pioneered with cyclotron-generated radioisotopes in the 1930s and early 1940s. The majority of early AEC shipments were radioiodine and radiophosphorus, employed to evaluate thyroid function, diagnose medical disorders, and irradiate tumors. Both researchers and politicians lauded radioisotopes publicly for their potential in curing diseases, particularly cancer. However, isotopes proved less successful than anticipated in treating cancer and more successful in medical diagnostics. On the research side, reactor-generated radioisotopes equipped biologists with new tools to trace molecular transformations from metabolic pathways to ecosystems. The U.S. government's production and promotion of isotopes stimulated their consumption by scientists and physicians, such that in the postwar period isotopes became routine elements of laboratory and clinical use. In the early postwar years, radioisotopes signified the government's commitment to harness the atom for peace, particularly through contributions to biology, medicine, and agriculture. (shrink)

In order to make an attempt at grouping the various aspects of brain functional imaging (fMRI, MRS, EEG-MEG, ...) within a coherent frame, we implemented a model consisting of a system of differential equations, that includes: (1) sodium membrane transport, (2) Na/K ATPase, (3) neuronal energy metabolism (i.e. glycolysis, buffering effect of phosphocreatine, and mitochondrial respiration), (4) blood-brain barrier exchanges and (5) brain hemodynamics, all the processes which are involved in the activation of brain areas. We assumed that (...) the correlation between brain activation and metabolism could be due to either changes in the concentrations of ATP and ADP following activation of Na/K ATPase that result from the changes in ion concentrations, or the involvement, in different phases of metabolism, of a second messenger such as calcium. In this article, we show how this type of model enables interpretation of MRS and fMRI published data that were obtained during prolonged stimulations. (shrink)

Citrate, an organic trivalent anion, is a major substrate for generation of energy in most cells. It is produced in mitochondria and used either in the Krebs' cycle or released into cytoplasm through a specific mitochondrial carriers. Citrate can also be taken up from blood through different plasma membrane transporters. In the cytoplasm, citrate can be used ultimately for fatty acid synthesis, which is increased in cancer cells. Here, we review the ways in which citrate can be transported and (...) discuss the changes in transport and metabolism that occur in cancer cells. The primary focus is on the prostate gland, which is known to produce and release large amounts of citrate during its normal secretory function. The significant changes that occur in citrate‐related metabolism and transport in prostate cancer are the second focus. This review strives to relate these mechanisms to molecular biology on the one hand and to clinical applications on the other. (shrink)

In this article, we discuss a hypothesis to explain the preferential synthesis of the superoxide sensitive form of aconitase in mitochondria and the phenotype observed in manganese superoxide dismutase mutant mice, which show a gross over accumulation of stored fat in liver. The model proposes that intermediary metabolism is redox regulated by mitochondrial superoxide generated during mitochondrial respiration. This regulates the level of reducing equivalents (NADH) entering the electron transport chain (ETC) through the reversible inactivation of mitochondrial aconitase. This (...) control mechanism has a dual function; firstly, it regulates levels of superoxide generated by the ETC and, secondly, it fine‐tunes metabolism by channeling citrate either for the production of NADH for energy metabolism or diverting it for the synthesis of fats. In this setting, the mitochondrial redox state influences metabolic decisions via a superoxide–aconitase rheostat. BioEssays 26:894–900, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The hypothalamus is a specialized area in the brain that integrates the control of energy homeostasis. More than 70 years ago, it was proposed that the central nervous system sensed circulating levels of metabolites such as glucose, lipids and amino acids and modified feeding according to the levels of those molecules. This led to the formulation of the Glucostatic, Lipostatic and Aminostatic Hypotheses. It has taken almost that much time to demonstrate that circulating long‐chain fatty acids act as signals (...) of nutrient surplus in the hypothalamus. Moreover, pharmacological and/or genetic inhibition of fatty acid synthase, AMP‐activated protein kinase and carnitine palmitoyltransferase 1 results in profound decrease in feeding and body weight in rodents. The molecular mechanism behind these actions depends on changes in the cellular pool of malonyl‐CoA and fatty acyl‐CoAs. Current evidence also suggests that this pathway may play a major role in the physiological regulation of feeding, by integrating hormonal and nutrient‐derived signals in the hypothalamus. Here, we summarize what is known about hypothalamic fatty acid metabolism and feeding control and provide future directions for research. Understanding these molecular mechanisms could provide new targets for the treatment of obesity and related disorders. BioEssays 29: 248–261, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In recent years, there has been a growing interest in the relation between Marxism and the Soviet productivist economy. While historical scholarship rarely explores the intellectual context in which the Soviet experiment unfolded, ecomarxists tend to describe the Soviet Union’s mistaken path as a result of the loss of ‘metabolic’ thinkers following the rise of Stalin. This article challenges the neat, purported divide between a ‘metabolic’ and ‘productivist’ Marxism by analysing the energy-economic thinking of Gleb M. Krzhizhanovskii, a Bolshevik (...) engineer and old friend of Lenin. As chairman of both the electrification commission (GOELRO) and the State Planning Commission (Gosplan), Krzhizhanovskii conceptualised the energy economy as something embedded in the metabolism of nature and society and as the technical-economic basis of the socialist economy. This argument drew its strength from his idea that production is part of the general, ongoing life-process, and the hope that large-scale electrification and electro-chemistry could help govern the metabolism between nature and society more rationally – both arguments commonly found among contemporary natural scientists. Any ecomarxist attempt to recover the concept of metabolism today has to come to terms with its productivist and technocratic history. (shrink)

To explain consciousness as a physical process we must acknowledge the role of energy in the brain. Energetic activity is fundamental to all physical processes and causally drives biological behavior. Recent neuroscientific evidence can be interpreted in a way that suggests consciousness is a product of the organization of energetic activity in the brain. The nature of energy itself, though, remains largely mysterious, and we do not fully understand how it contributes to brain function or consciousness. According to (...) the principle outlined here, energy, along with forces and work, can be described as actualized differences of motion and tension. By observing physical systems, we can infer there is something it is like to undergo actualized difference from the intrinsic perspective of the system. Consciousness occurs because there is something it is like, intrinsically, to undergo a certain organization of actualized differences in the brain. (shrink)

Control of DNA supercoiling by the free-energy of hydrolysis of ATP that involves gene expression is analyzed in terms of three levels of unconnected metabolic pathways. These are synthesis and breakdown of topoisomerase mRNAs, synthesis and breakdown of topoisomerase proteins and supercoiling and relaxation of DNA. The so-called square-matrix method previously developed for the control of metabolic pathways, is extended to deal with this hierarchical control system. It turns out that also in this case, the matrix of control coefficients (...) is equal to the inverse of the so-called elasticity matrix, which contains all relevant elasticity coefficients as well as information about the structure and connectedness of the pathways involved. For a simpler case of a hierarchy of two systems, we demonstrate that the explicit matrix inversion method may be replaced by an implicit method in which the regulatory effects that run through the other level are described by an additional elasticy coefficient which may then be treated as if local. (shrink)

The present trend of resource depletion and environmental destruction is related to a lack of morals in society. Available tools like exergy, ecology and democracy are ignored. This not only makes us unaware of reality but also of the possibilities of avoiding a catastrophe. Instead, economics and politics are often based on myths. The most dangerous threat to humankind is new, unknown diseases, fostered by environmental pollution. This knowledge is suppressed. The author concludes that too much attention has been given (...) to the body of society, that is, its metabolism. Therefore, the focus should now be directed to the soul of society, especially morals and love. (shrink)

Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography, brain imaging, genetics, and biochemistry are reviewed: Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. Studies of the absolute level of regional cerebral (...) blood flow show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index. High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory. (shrink)

The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of (...) neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. (shrink)

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin‐releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. (...) Highly conserved, both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the “teneurin C‐terminal associated peptide” (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons. (shrink)

The Transforming growth factor beta (TGF‐β) family of secreted proteins regulates a variety of key events in normal development and physiology. In mammals, this family, represented by 33 ligands, including TGF‐β, activins, nodal, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), regulate biological processes as diverse as cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine functions. In Drosophila, only 7 members of this family are present, with 4 TGF‐β/BMP and 3 TGF‐β/activin ligands. Studies (...) in the fly have illustrated the role of TGF‐β/BMP ligands during embryogenesis and organ patterning, while the TGF‐β/activin ligands have been implicated in the control of wing growth and neuronal functions. In this review, we focus on the emerging roles of Drosophila TGF‐β/activins in inter‐organ communication via long‐distance regulation, especially in systemic lipid and carbohydrate homeostasis, and discuss findings relevant to metabolic diseases in humans. -/- . (shrink)

In the cytoplasm of practically all living cells, potassium is the major cation while sodium dominates in the media (seawater, extracellular fluids). Both prokaryotes and eukaryotes have elaborate mechanisms and spend significant energy to maintain this asymmetric K+/Na+ distribution. This essay proposes an original line of evidence to explain how bacteria selected potassium at the very beginning of the evolutionary process and why it remains essential for eukaryotes.

The course of biological evolution is regarded by many authors as an ascending path toward higher levels of variety, complexity and integration. There are similar but partly conflicting accounts of the nature and causes of this ascending course. With the aim of reaching a unified conception I start by summarily reviewing three notable examples. These are, in their latest presentations, those of Hoffmeyer and Stjernfelt 2015, Szathmáry 2015, and Lane 2015a. Comparison of their commonalities and divergences, combined with further reflections, (...) leads to the following views: 1) cooperation between preexistent traits and processes is the primary determinant in the emergence of evolutionary novelty; 2) cooperation is a triadic relation similar to semiosis ; 3) regulation, the key element of both metabolism and replication, results from the cooperation of energetic and semiotic causation; 4) conceptual generalization and concrete generalization are fruits of cooperation. Conceptual generalizations spring from the cooperation of ideas. I believe these realizations supply essential elements for a unified view of the ascent of biological evolution towards higher levels of organization. Some of these conceptions are also applicable to similar ascending trajectories through the stages of cultural and technological evolution. (shrink)

DNA helicases catalyze the disruption of the hydrogen bonds that hold the two strands of double‐stranded DNA together. This energy‐requiring unwinding reaction results in the formation of the single‐stranded DNA required as a template or reaction intermediate in DNA replication, repair and recombination. A combination of biochemical and genetic studies have been used to probe and define the roles of the multiple DNA helicases found in E. coli. This work and similar efforts in eukaryotic cells, although far from complete, (...) have established that DNA helicases are essential components of the machinery that interacts with the DNA molecule. (shrink)

Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging‐related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding (...) of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear‐encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism. (shrink)

Carbon monoxide intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. 1 H magnetic resonance spectroscopy may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven patients with CO (...) poisoning assessed by gray and white matter MRS, magnetic resonance imaging and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline and decreased N -acetyl aspartate ratios to creatine, predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by 1 H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed. (shrink)

l‐Lactate is emerging as a crucial regulatory nexus for energy metabolism in the brain and signaling transduction in synaptic plasticity, memory processes, and drug addiction instead of being merely a waste by‐product of anaerobic glycolysis. In this review, the role of lactate in various memory processes, synapse plasticity and drug addiction on the basis of recent studies is summarized and discussed. To this end, three main parts are presented: first, lactate as an energy substrate in energy (...) metabolism of the brain is described; second, lactate as a novel signaling molecule in synaptic plasticity, neural circuits, memory, and drug addiction is described; and third, in light of the above descriptions, it is plausible to speculate that lactate is predominantly a signaling molecule in specific memory processes and partly acts as an energy substrate. The future perspective in lactate signaling involving microglia and associated precise signaling pathways in the brain is highlighted. (shrink)

Many solar systems in the universe may be expected to contain rocky planets that have accreted organic compounds. These compounds are likely to be universally found. In addition, the chemistry of sulfur, phosphorus, and iron is likely to dominate energy transductions and monomer activation, leading to the eventual emergence of polymers. Proteins and polynucleotides provide living matter with function, structure, and information. The conceptual puzzle regarding their emergence is discussed. The fitness of various elements to serve various roles is (...) analyzed from the viewpoint of electron orbitals. Elements with d orbitals are of central importance. (shrink)

After more than a century of research on glycolysis, we have detailed descriptions of its molecular organization, but despite this wealth of knowledge, linking the enzyme properties to metabolic pathway behavior remains challenging. These challenges arise from multi‐layered regulation and the context and time dependence of component functions. However, when viewed as a system that functions according to the principles of supply and demand, a simplifying theoretical framework can be applied to study its regulation logic and to assess the coherence (...) of experimental interpretations. These principles are universally applicable, as they emphasize the common metabolic tasks of glycolysis: the provision of free‐energy carriers, and precursors for biosynthesis and stress‐related compounds. Here we will review the regulation of multi‐tasking by glycolysis and consider how an understanding of this central metabolic pathway can be pursued using general principles, rather than focusing on the biochemical details of constituent components. (shrink)

Despite thermodynamic, bioenergetic and phylogenetic failings, the 81‐year‐old concept of primordial soup remains central to mainstream thinking on the origin of life. But soup is homogeneous in pH and redox potential, and so has no capacity for energy coupling by chemiosmosis. Thermodynamic constraints make chemiosmosis strictly necessary for carbon and energy metabolism in all free‐living chemotrophs, and presumably the first free‐living cells too. Proton gradients form naturally at alkaline hydrothermal vents and are viewed as central to the (...) origin of life. Here we consider how the earliest cells might have harnessed a geochemically created proton‐motive force and then learned to make their own, a transition that was necessary for their escape from the vents. Synthesis of ATP by chemiosmosis today involves generation of an ion gradient by means of vectorial electron transfer from a donor to an acceptor. We argue that the first donor was hydrogen and the first acceptor CO2. (shrink)

MicroRNAs are non-coding parts of nuclear and mitochondrial genomes, preventing the weakest part of the genetic regulatory networks from being expressed and preventing the appearance of a too many attractors in these networks. They have also a great influence on the chromatin clock, which ensures the updating of the genetic regulatory networks. The post-transcriptional inhibitory activity by the microRNAs, which is partly unspecific, is due firstly to their possibly direct negative action during translation by hybridizing tRNAs, especially those inside the (...) mitochondrion, hence slowing mitochondrial respiration, and secondly to their action on a large number of putative m-RNA targets like those involved in immunetworks; We show that the circuits in the core of the interaction graphs are responsible for the small number of dedicated attractors that correspond to genetically controlled functions, partly due to a general filtering by the microRNAs. We analyze this influence as well as their impact on important functions like the control by the p53 network over the apoptosis/proliferation system and the homeostasis of the energy metabolism. In this last case, we show the role of two kinds of microRNAs, both involved in the control of the mitochondrial genome: (1) nuclear microRNAs, called mitoMirs, inhibiting mitochondrial genes and (2) putative mitochondrial microRNAs inhibiting the tRNAs functioning. (shrink)

The origin and early evolution of animals marks an important event in life's history. This event is historically associated with an important variable in Earth history – oxygen. One view has it that an increase in oceanic oxygen levels at the end of the Neoproterozoic Era (roughly 600 million years ago) allowed animals to become large and leave fossils. How important was oxygen for the process of early animal evolution? New data show that some modern sponges can survive for several (...) weeks at low oxygen levels. Many groups of animals have mechanisms to cope with low oxygen or anoxia, and very often, mitochondria – organelles usually associated with oxygen – are involved in anaerobic energy metabolism in animals. It is a good time to refresh our memory about the anaerobic capacities of mitochondria in modern animals and how that might relate to the ecology of early metazoans. (shrink)

Type 2 diabetes mellitus is associated with cognitive impairment in many domains. There are several pieces of evidence that changes in neuronal neuropathies and metabolism have been observed in T2DM. Structural and functional MRI shows that abnormal connections and synchronization occur in T2DM brain circuits and related networks. Neuroplasticity and energy metabolism appear to be principal effector systems, which may be related to amyloid beta deposition, although there is no unified explanation that includes the complex etiology of (...) T2DM with cognitive impairment. Herein, we assume that cognitive impairment in diabetes may lead to abnormalities in neuroplasticity and energy metabolism in the brain, and those reflected to MRI structural connectivity and functional connectivity, respectively. (shrink)

Glycerol is a small and simple molecule produced in the breakdown of glucose, proteins, pyruvate, triacylglycerols and other glycerolipid, as well as release from dietary fats. An increasing number of observations show that glycerol is probably involved in a surprising variety of physiopathologic mechanisms. Glycerol has long been known to play fundamental roles in several vital physiological processes, in prokaryotes and eukaryotes, and is an important intermediate of energy metabolism. Despite some differences in the details of their operation, (...) many of these mechanisms have been preserved throughout evolution, demonstrating their fundamental importance. In particular, glycerol can control osmotic activity and crystal formation and then act as a cryoprotective agent. Furthermore, its properties make it useful in numerous industrial, therapeutic and diagnostic applications. Few studies have focussed directly on glycerol, however, and while its metabolism is increasingly well documented, much of the details remain unknown. Considering the importance of glycerol in multiple vital physiological processes, its study could help unlock important physiopathological mechanisms. BioEssays 23:534–542, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Metabolic pathways underlying brain function remain largely unexplored during neurodevelopment, predominantly due to the lack of feasible techniques for use with awake infants. Broadband near-infrared spectroscopy provides the opportunity to explore the relationship between cerebral energy metabolism and blood oxygenation/haemodynamics through the measurement of changes in the oxidation state of mitochondrial respiratory chain enzyme cytochrome-c-oxidase alongside haemodynamic changes. We used a bNIRS system to measure ΔoxCCO and haemodynamics during functional activation in a group of 42 typically developing infants (...) aged between 4 and 7 months. bNIRS measurements were made over the right hemisphere over temporal, parietal and central cortical regions, in response to social and non-social visual and auditory stimuli. Both ΔoxCCO and Δ[HbO2] displayed larger activation for the social condition in comparison to the non-social condition. Integration of haemodynamic and metabolic signals revealed networks of stimulus-selective cortical regions that were not apparent from analysis of the individual bNIRS signals. These results provide the first spatially resolved measures of cerebral metabolic activity alongside haemodynamics during functional activation in infants. Measuring synchronised changes in metabolism and haemodynamics have the potential for uncovering the development of cortical specialisation in early infancy. (shrink)

The Holy Quran and the Sunnah provide the Islamic approach to a complete food system, regulating the consumption of food and drinks, clarifying permissibility and prohibition, to protect human health. This analytical study aimed to explore various categories and benefits of food in Islam derived from plants and animals, focusing specifically on how Islamic Shariah advocates halal food consumption, and what permissions or prohibitions are granted, highlighting the underlying religious evidence and reasoning. The data was collected through both inductive and (...) deductive approaches; the inductive method gathered literature on the topic from the Quran, Sunnah, and Hadith commentaries, while the deductive approach classified plant-based and animal-based foods and elaborated on the benefits of halal items versus the harms of prohibited ones. The study found the plant foods endorsed in Islam include fruits, vegetables, grains, and nuts like dates, beans, olives, and ziziphus, while the permissible animal foods comprise seafood, fish, beef, dairy products, and honey. These foods assist in the growth and repair of body tissues, digestion, energy, metabolism, and overall wellbeing. Meanwhile, prohibited foods contained toxins, germs, and substances that lead to obesity, cancer, blood issues, and more. The implications of this study lie in showcasing how Islam forbids monopoly control of commodities and encourages activities like land rehabilitation for farming and public cultivation. Islam also advises only consuming foods from permitted animals while emphasizing sustenance provisions for milk-producing animals to avoid wastage, as commanded by Allah. (shrink)

Tackling impaired bioenergetics in multiple sclerosis has been recently recognized as an innovative approach with therapeutic potential. Guanidinoacetic acid is an experimental nutrient that plays a significant role in high-energy phosphate metabolism. The preliminary trials suggest beneficial effects of supplemental GAA in MS, with GAA augments biomarkers of brain energy metabolism and improves patient-reported features of the disease. GAA can also impact other metabolic footprints of MS, including demyelination, oxidative stress, and GABA-glutamate imbalance. In this mini-review (...) article, we summarize studies evaluating GAA effectiveness in MS, explore mechanisms of GAA action, and discuss the challenges of using dietary GAA as an element of MS therapy. (shrink)

Thirty years ago, a number of human inborn errors in carbohydrate metabolism were explored with specific enzymatic tests on blood samples (hemolysates). Hereditary galactosemia was the first example. When the inoperative step in galactose metabolism was specified, the basis for the diet therapy used on the galactosemic infants, namely galactose‐free diet, could be shown to be securely founded.As far as galactose metabolism is concerned, the cells of the infant are faced with two problems: (i) the conversion of (...) dietary lactose (galactosyl glucose) to glucose and its catabolites involved in energy metabolism, and (ii) the conversion of dietary glucose or lactose to galactosyl units of glycolipids and glycoprotein cell structures.Subsequent studies on microorganisms revealed several types of hereditary defect in galactose metabolism. One type which permits the bacteria to develop a normal carbohydrate pattern in their cell walls includes an enzyme defect, like that described in the cells of the galactosemic infant. Two other types, with the inability to synthesize UDPGlc or UDPGal from glucose, do not permit the bacteria to build the fabric of the normal bacterial cell wall. This is the subject for discussion. (shrink)

A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate (...) the neural effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1–2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging measures from the ID infants were compared with monkeys who remained continuously iron sufficient. A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID. (shrink)