Dysregulation of lipid metabolism is a commonly observed feature associated with metabolic syndrome and leads to the development of negative health outcomes such as obesity, diabetes mellitus, non‐alcoholic fatty liver disease, or atherosclerosis. Time‐restricted feeding/eating (TRF/TRE), an emerging dietary intervention, has been shown to promote pleiotropic health benefits including the alteration of diurnal expression of genes associated with lipid metabolism, as well as levels of lipid species. Although TRF likely induces a response in multiple organs leading to the modulation (...) of lipid metabolism, a majority of the studies related to TRF effects on lipids have focused only on individual tissues, and furthermore there is a lack of insight into potential underlying mechanisms. In this review, we summarize the current insights regarding TRF effects on lipid metabolism and the potential mechanisms in adipose tissue, liver, skeletal muscle, and heart, and conclude by outlining possible avenues for future exploration. (shrink)

In the flowering of Red-Green Thought over the past two decades, metabolic rift thinking is surely one of its most colorful varieties. The metabolic rift has captured the imagination of critical environmental scholars, becoming a shorthand for capitalism’s troubled relations in the web of life. This article pursues an entwined critique and reconstruction: of metabolic rift thinking and the possibilities for a post-Cartesian perspective on historical change, the world-ecology conversation. Far from dismissing metabolic rift thinking, my (...) intention is to affirm its dialectical core. At stake is not merely the mode of explanation within environmental sociology. The impasse of metabolic rift thinking is suggestive of wider problems across the environmental social sciences, now confronted by a double challenge. One of course is the widespread—and reasonable—sense of urgency to evolve modes of thought appropriate to an era of deepening biospheric instability. The second is the widely recognized—but inadequately internalized—understanding that humans are part of nature. (shrink)

I consider the case of the “simplest” living beings—bacteria—and examine how their embodied activity constitutes an organism/environment interaction, out of which emerges the possibility of learning from an environment. I suggest that this mutual co-emergence of organism and environment implies a panbiotic educational interaction that is at once the condition for, and achievement of, all living beings. Learning and being learned from are entangled in varied ways throughout the biosphere. Education is not an exclusively human project, it is part of (...) the ancient evolutionary process of elaborating and diversifying the relational possibilities inherent in metabolism that has brought forth our diverse and flourishing world.ed from context, “education” appears as a set of ways in which humans actively engage and take responsibility for the learning outcomes of relationships with each other. Insofar as we consider this distinction absolute rather than a performed construct to be assessed by its consequences, we blind ourselves to the educative dimension of other species as well as our many miseducative engagements with them. If learning processes are inherent and constitutive of ecological communities, education theorists should devote their pedagogical sensitivities and insights to the crucial challenge of developing educative sustainable human–nature relations. (shrink)

Several metabolites serve as substrates for histone modifications and communicate changes in the metabolic environment to the epigenome. Technologies such as metabolomics and proteomics have allowed us to reconstruct the interactions between metabolic pathways and histones. These technologies have shed light on how nutrient availability can have a dramatic effect on various histone modifications. This metabolism–epigenome cross talk plays a fundamental role in development, immune function, and diseases like cancer. Yet, major challenges remain in understanding the interactions (...) between cellular metabolism and the epigenome. How the levels and fluxes of various metabolites impact epigenetic marks is still unclear. Discussed herein are recent applications and the potential of systems biology methods such as flux tracing and metabolic modeling to address these challenges and to uncover new metabolic–epigenetic interactions. These systems approaches can ultimately help elucidate how nutrients shape the epigenome of microbes and mammalian cells. (shrink)

Immune cells are highly dynamic in their response to the tissue environment. Most immune cells rapidly change their metabolic profile to obtain sufficient energy to engage in defensive or homeostatic processes. Such “immunometabolism” is governed through intermediate metabolites, and has a vital role in regulating immune‐cell function. The underlying metabolic reactions are shaped by the abundance and accessibility of specific nutrients, as well as the overall metabolic status of the host. Here, we discuss how different immune‐cell types (...) gain a sufficient energy supply. We then explain how immune cells perform various functions under challenged conditions and expend energy to sustain homeostasis. Finally, we speculate on how the immune‐cell metabolic profile might be modulated in health and disease, by manipulating nutrient availability. By such intervention, the recovery of patient with dysregulated immune system responses might be sped up and the fitness of an individual efficiently restored. (shrink)

A major challenge for The Cancer Genome Atlas (TCGA) Project is solving the high level of genetic and epigenetic heterogeneity of cancer. For the majority of solid tumors, evolution patterns are stochastic and the end products are unpredictable, in contrast to the relatively predictable stepwise patterns classically described in many hematological cancers. Further, it is genome aberrations, rather than gene mutations, that are the dominant factor in generating abnormal levels of system heterogeneity in cancers. These features of cancer could significantly (...) reduce the impact of the sequencing approach, as it is only when mutated genes are the main cause of cancer that directly sequencing them is justified. Many biological factors (genetic and epigenetic variations, metabolic processes) and environmental influences can increase the probability of cancer formation, depending on the given circumstances. The common link between these factors is the stochastic genome variations that provide the driving force behind the cancer evolutionary process within multiple levels of a biological system. This analysis suggests that cancer is a disease of probability and the most‐challenging issue to the TCGA project, as well as the development of general strategies for fighting cancer, lie at the conceptual level. BioEssays 29:783–794, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In this short contribution we explore the historical roots of recent synthetic approaches in biology and try to assess their real potential, as well as identify future hurdles or the reasons behind some of the main difficulties they currently face. We suggest that part of these difficulties might not be just the result of our present lack of adequate technical skills or understanding, but could spring directly from the nature of the biological phenomenon itself. In particular, if life is conceived (...) as autonomy in open-ended evolution, which would help to explain the highly complex and dynamic organization of the simplest known organisms (i.e., genetically-instructed cellular metabolisms), external synthetic implementations of such systems, or interventions on them, are bound to interfere with some of their characteristic transformation processes, both at the ontogenetic and phylogenetic scales. In any case, this will prove very revealing and productive, technologically and scientifically speaking, since the knowledge gathered from those implementations/interventions will be extremely valuable in establishing our capacities and limitations to fully comprehend, utilize, and expand the living domain as we know it today. (shrink)

This paper addresses theoretical challenges, still relevant today, that arose in the first decades of the twentieth century related to the concept of the organism. During this period, new insights into the plasticity and robustness of organisms as well as their complex interactions fueled calls, especially in the UK and in the German-speaking world, for grounding biological theory on the concept of the organism. This new organism-centered biology understood organisms as the most important explanatory and methodological unit in biological (...) investigations. At least three theoretical strands can be distinguished in this movement: Organicism, dialectical materialism, and holistic biology. This paper shows that a major challenge of OCB was to describe the individual organism as a causally autonomous and discrete unit with consistent boundaries and, at the same time, as inextricably interwoven with its environment. In other words, OCB had to conciliate individualistic with anti-individualistic perspectives. This challenge was addressed by developing a concept of life that included functionalist and metabolic elements, as well as biochemical and physical ones. It allowed for specifying organisms as life forms that actively delimit themselves from the environment. Finally, this paper shows that the recent return to the concept of the organism, especially in the so-called “Extended Evolutionary Synthesis,” is challenged by similar anti-individualistic tendencies. However, in contrast to its early-twentieth-century forerunner, today’s organism-centered approaches have not yet offered a solution to this problem. (shrink)

Reconstructing the genetic traits of the Last Common Ancestor and the Tree of Life are two examples of the reaches of contemporary molecular phylogenetics. Nevertheless, the whole enterprise has led to paradoxical results. The presence of Lateral Gene Transfer poses epistemic and empirical challenges to meet these goals; the discussion around this subject has been enriched by arguments from philosophers and historians of science. At the same time, a few but influential research groups have aimed to reconstruct the LCA (...) with rich-in-detail hypotheses and high-resolution gene catalogs and metabolic traits. We argue that LGT poses insurmountable challenges for detailed and rich in details reconstructions and propose, instead, a middle-ground position with the reconstruction of a slim LCA based on traits under strong pressures of Negative Natural Selection, and for the need of consilience with evidence from organismal biology and geochemistry. We defend a cautionary perspective that goes beyond the statistical analysis of gene similarities and assumes the broader consequences of evolving empirical data and epistemic pluralism in the reconstruction of early life. (shrink)

Originally published in 1928, this book examines the growth and decay of the view of Christianity as a revealed religion, as opposed to a 'religion of nature', and the development of the concept of 'revelation'. Challenger demonstrates how Christian thinkers over time conceived Christianity's relationship to prophecy and philosophy, and the various syntheses between faith and reason. This book will be of value to anyone with an interest in the history of Christianity and Christian philosophy.

In recent years, the established paradigm of the three Rs of animal research—refinement, replacement, and reduction—has come under scrutiny. A crucial weakness in use of the three Rs is uncertainty about how they should be prioritized. Events like pandemics have the power to alter the research landscape, fast‐tracking innovation and setting new precedents. Existential threats can raise perceptions of social benefit and can lower animal‐welfare thresholds. The rush to develop new research models may also undermine progress in reducing or replacing (...) animal models. By circumventing the barrier posed by animal models that are poorly matched to human conditions, new technologies like CRISPR can enhance the refinement component while undermining reduction and replacement. This pandemic has exposed the need for an urgent review of the efficacy of the three Rs, with the potential to establish a new set of protocols for animal research, both inside and beyond the context of an emergency. (shrink)

A 1998 Cincinnati Enquirer investigation into the Central American labor practices of Chiquita Brands International was substantiated by the taped words of company officials themselves. Yet, soon after publication, the Enquirer ran a stunning front-page retraction and disavowed the report without challenging its claims. The Gannett Corporation, the paper's owner, paid Chiquita $14 million to avoid a suit. The resultant outcry by journalists was directed not at Gannett, but at lead reporter Michael Gallagher, who had surreptitiously accessed Chiquita voice mail (...) to support his allegations. Rather than being lauded as a tough investigative reporter serving a greater good, Gallagher was fired, convicted, sued by Chiquita, and vilified in the media. Was the backlash driven simply by higher ethical standards or also by anxieties about intrusive technology? A reexamination of the case suggests the latter explanation and helps frame an evolving debate about electronic eavesdropping by the media. (shrink)

It is hypothesized that repeated, non‐invasive stimulation of the vestibular (balance) system, via a small electrical current to the skin behind the ears, will cause the brain centers that control energy homeostasis to shift the body toward a leaner physique. This is because these centers integrate multiple inputs to, in effect, fix a set‐point for body fat, which though difficult to alter is not immutable. They will interpret repeated stimulation of the parts of the vestibular system that detect acceleration as (...) a state of chronic activity. During such a physiologically challenging time it is preferable, from an energy homeostasis viewpoint, to both utilize fat reserves, and reduce the volume of these reserves and thus the energy cost of carrying them around. Hence, this type of vestibular stimulation could potentially be a therapeutic option for metabolic syndrome disorders such as obesity. This hypothesis is eminently testable via a clinical trial. (shrink)

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)

The aim of this paper is to provide a theoretical framework to understand how multicellular systems realize functionally integrated physiological entities by organizing their intercellular space. From a perspective centered on physiology and integration, biological systems are often characterized as organized in such a way that they realize metabolic self-production and self-maintenance. The existence and activity of their components rely on the network they realize and on the continuous management of the exchange of matter and energy with their environment. (...) One of the virtues of the organismic approach focused on organization is that it can provide an understanding of how biological systems are functionally integrated into coherent wholes. Organismic frameworks have been primarily developed by focusing on unicellular life. Multicellularity, however, presents additional challenges to our understanding of biological systems, related to how cells are capable to live together in higher-order entities, in such a way that some of their features and behaviors are constrained and controlled by the system they realize. Whereas most accounts of multicellularity focus on cell differentiation and increase in size as the main elements to understand biological systems at this level of organization, we argue that these factors are insufficient to provide an understanding of how cells are physically and functionally integrated in a coherent system. In this paper, we provide a new theoretical framework to understand multicellularity, capable to overcome these issues. Our thesis is that one of the fundamental theoretical principles to understand multicellularity, which is missing or underdeveloped in current accounts, is the functional organization of the intercellular space. In our view, the capability to be organized in space plays a central role in this context, as it enables (and allows to exploit all the implications of) cell differentiation and increase in size, and even specialized functions such as immunity. We argue that the extracellular matrix plays a crucial active role in this respect, as an evolutionary ancient and specific (non-cellular) control subsystem that contributes as a key actor to the functional specification of the multicellular space and to modulate cell fate and behavior. We also analyze how multicellular systems exert control upon internal movement and communication. Finally, we show how the organization of space is involved in some of the failures of multicellular organization, such as aging and cancer. (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)

Pleiotropically acting eukaryotic corepressors such as retinoblastoma and SIN3 have been found to physically interact with many widely expressed “housekeeping” genes. Evidence suggests that their roles at these loci are not to provide binary on/off switches, as is observed at many highly cell‐type specific genes, but rather to serve as governors, directly modulating expression within certain bounds, while not shutting down gene expression. This sort of regulation is challenging to study, as the differential expression levels can be small. We hypothesize (...) that depending on context, corepressors mediate “soft repression,” attenuating expression in a less dramatic but physiologically appropriate manner. Emerging data indicate that such regulation is a pervasive characteristic of most eukaryotic systems, and may reflect the mechanistic differences between repressor action at promoter and enhancer locations. Soft repression may represent an essential component of the cybernetic systems underlying metabolic adaptations, enabling modest but critical adjustments on a continual basis. (shrink)

Intentional weight loss can increase health risk in the long‐term, despite short‐term benefits, because human adipose tissue is widely contaminated with various lipophilic environmental contaminants, especially persistent organic pollutants (POPs). Recently, chronic exposure to low POPs has emerged as a new risk factor for common metabolic diseases and cardiovascular diseases. The amount of POPs released from adipocytes to the circulation increases during weight loss, thereby increasing POPs exposure of other critical organs. Possible harmful effects due to release of POPs (...) during weight loss are opposite to those usually expected from losing weight. It is speculated that this tradeoff can explain recent puzzling findings on intensive weight loss. The presence of POPs in adipose tissue adds a challenge to weight management and an optimal strategy of weight management needs to consider both fat mass and dynamics of POPs. (shrink)

Parents, providers, policy makers, and the public need to talk about the implications of advances in genomic technologies for state run newborn metabolic screening programs. Technologies, such as highly multiplex testing and whole genome sequencing, are raising old issues with new urgency and are posing new challenges that threaten to overwhelm newborn screening programs.Newborn screening programs in their current form were born in the late 1960s. Robert Guthrie developed a screening test for phenylketonuria that could be performed on (...) blood spots collected on filter cards that Guthrie also developed. States rapidly established newborn screening programs, which were almost always mandatory, in response to advocacy by geneticists and parents. Although the programs initially varied in form and experienced significant pushback from the medical community, by the early 1970s, all states had established programs with centralized laboratories, and the medical community had come on board. (shrink)

Parents, providers, policy makers, and the public need to talk about the implications of advances in genomic technologies for state run newborn metabolic screening programs. Technologies, such as highly multiplex testing and whole genome sequencing, are raising old issues with new urgency and are posing new challenges that threaten to overwhelm newborn screening programs.Newborn screening programs in their current form were born in the late 1960s. Robert Guthrie developed a screening test for phenylketonuria that could be performed on (...) blood spots collected on filter cards that Guthrie also developed. States rapidly established newborn screening programs, which were almost always mandatory, in response to advocacy by geneticists and parents. Although the programs initially varied in form and experienced significant pushback from the medical community, by the early 1970s, all states had established programs with centralized laboratories, and the medical community had come on board. (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)

As we know, Merleau-Ponty was struggling with a dynamic shift in his thinking at the premature end of his life. In those last notes he raises the question of how to elaborate a phenomenology of “’the other world’, as the limit of a phenomenology of the imaginary and the ‘hidden’”—a phenomenology that would open onto an invisible life, community, other and culture (VI, Jan. 1960). In her essay on “Eye and Mind”, “To Paint the Invisible”, Luce Irigaray shows why Merleau-Ponty (...) was not yet ready to address this question, why he was not yet ready to engage the limits of his vision posed by the presence of an other. Against Merleau-Ponty’s assertion that the artist has no other task than to bring to appearance the world in the way he corporeally encounters it employing no “other technique than what his eyes and hands discover in seeing and painting”, Irigaray argues that the painter as phenomenologist then appropriates what is other to his vision without reflecting upon a limit to vision, as well as the limit provided by the invisible of an other, an other world. This is not to say that there are no intertwinings with this other, for there are other metabolisms with which we engage the world. Moreover, the sharing of vision with an other can alter the ways I see, challenging cultural complicity, rather than providing evidence that we share the same world. Irigaray is of course not the first to challenge a phenomenological approach to art and to vision—and here I turn specifically to Gilles Deleuze—who is critical of the phenomenological tendency to take on a world given to us by others. His artist, Francis Bacon, focuses on the sensation, which remains unmediated by narration or the feelings of others. Finally, the artworks of abstract expressionist artist Joan Mitchell are considered in the ways that they open up a different time-space; they suggest an other world with which we intertwine without appropriation. Her works, I argue, defy reduction to essences, but also do not rely merely on sensation—for this reason they point in the direction of how to think phenomenology anew. For I do think Merleau-Ponty would be open to these conversations, to these other worlds and other visions. (shrink)

Starting dialysis at an advanced age is a clinical challenge and an ethical dilemma. The advantages of starting dialysis at “extreme” ages are questionable as high dialysis-related morbidity induces a reflection on the cost- benefit ratio of this demanding and expensive treatment in a person that has a short life expectancy. Where clinical advantages are doubtful, ethical analysis can help us reach decisions and find adapted solutions. Mr. H is a ninety-year-old patient with end-stage kidney disease that is no longer (...) manageable with conservative care, in spite of optimal nutritional management, good blood pressure control and strict clinical and metabolic evaluations; dialysis is the next step, but its morbidity is challenging. The case is analysed according to principlism (beneficence, non-maleficence, justice and respect for autonomy). In the setting of care, dialysis is available without restriction; therefore the principle of justice only partially applied, in the absence of restraints on health-care expenditure. The final decision on whether or not to start dialysis rested with Mr. H (respect for autonomy). However, his choice depended on the balance between beneficence and non-maleficence. The advantages of dialysis in restoring metabolic equilibrium were clear, and the expected negative effects of dialysis were therefore decisive. Mr. H has a contraindication to peritoneal dialysis (severe arthritis impairing self-performance) and felt performing it with nursing help would be intrusive. Post dialysis fatigue, poor tolerance, hypotension and intrusiveness in daily life of haemodialysis patients are closely linked to the classic thrice-weekly, four-hour schedule. A personalized incremental dialysis approach, starting with one session per week, adapting the timing to the patient’s daily life, can limit side effects and “dialysis shock”. An individualized approach to complex decisions such as dialysis start can alter the delicate benefit/side-effect balance, ultimately affecting the patient’s choice, and points to a narrative, tailor-made approach as an alternative to therapeutic nihilism, in very old and fragile patients. (shrink)

This article examines Aristotle’s theory of ‘factional conflict’ (stasis) in Book 5 of the Politics and claims that it is mainly directed against the a-historical account of constitutional change Plato develops in the Republic. Aristotle’s investigation of the causes of stasis is oriented towards the normative political goal of stabilizing political orders and preventing their ‘change’ (metabolê) into different ones. This article argues that the constitution Aristotle calls ‘polity’ (politeia) constitutes his solution to the challenge of stabilizing democracies and oligarchies. (...) The paper also aims at elucidating Aristotle’s conception of an empirical political science, his political realism, and the method he applies in conjunction with it in the ‘empirical’ Books of the Politics (Book 4 through 6). (shrink)

It seems that in interpreting others we sometimes simulate, sometimes apply theory. Josef Perner has suggested that a fruitful line of inquiry in folk psychology would seek "criteria for problems where we have to use simulation from those where we do without or where it is even impossible to use." In this paper I follow Perner with a suggestion that our understanding of our interpretive processes may benefit from considering their physiological bases. In particular, I claim that it may be (...) useful to consider the role emotion plays in the respective interpretive processes. I give reasons for believing that affective processes are more heavily involved in simulation (especially in situations of practical judgment and practical reasoning) than in theory-application. But affective processes have distinctive neurological and metabolic properties. These distinctive features of emotion may not only enrich our understanding of the simulation process, but also afford us a step towards responding to Perner's challenge. (shrink)

Ageing causes progressive decline in metabolic, behavioural, and physiological functions, leading to a reduced health span. The extracellular matrix (ECM) is the three‐dimensional network of macromolecules that provides our tissues with structure and biomechanical resilience. Imbalance between damage and repair/regeneration causes the ECM to undergo structural deterioration with age, contributing to age‐associated pathology. The ECM ‘Ageing Across the Life Course’ interdisciplinary research network (ECMage) was established to bring together researchers in the United Kingdom, and internationally, working on the emerging (...) field of ECM ageing. Here we report on a consultation at a joint meeting of ECMage and the Medical Research Council / Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, held in January 2023, in which delegates analysed the key questions and research opportunities in the field of ECM ageing. We examine fundamental biological questions, enabling technologies, systems of study and emerging in vitro and in silico models, alongside consideration of the broader challenges facing the field. (shrink)

Specificities of enzymes involved in plant specialized metabolism, including flavonoid biosynthesis, are generally promiscuous. This enzyme promiscuity has served as an evolutionary basis for new enzyme functions and metabolic pathways in land plants adapting to environmental challenges. This phenomenon may lead, however, to inefficiency in specialized metabolism and adversely affect metabolite‐mediated plant survival. How plants manage enzyme promiscuity for efficient specialized metabolism is, thus, an open question. Recent studies of flavonoid biosynthesis addressing this issue have revealed a conserved (...) strategy, namely, a homolog of chalcone isomerase with no catalytic activity binds to chalcone synthase, a key flavonoid pathway enzyme, to narrow (or rectify) the enzyme's highly promiscuous product specificity. Reducing promiscuity via specific protein–protein interactions among metabolic enzymes and proteins may be a solution adopted by land plants to achieve efficient operation of specialized metabolism, while the intrinsic promiscuity of enzymes has likely been retained incidentally. (shrink)

Graphical AbstractThe variable photoperiods of Northern latitudes challenge the entrainment capacity of the circadian pacemaker, which evolved under constant photoperiods in Equatorial regions. Entrainment to the erratic photoperiods facilitated by artificial light presents an additional challenge. Metabolic dysfunction and obesity are potential consequences of such desynchronization of circadian and environmental rhythms.

Chronic back pain (CBP) is a leading cause of disability and results in considerable socio-economic burdens worldwide. Although CBP patients are commonly diagnosed and treated with a focus on the ‘end organ dysfunction’ (i.e., peripheral nerve injuries or diseases), the evaluation of CBP remains flawed and problematic with great challenges. Given that the peripheral nerve injuries or diseases are insufficient to define the etiology of CBP in some cases, the evaluation of alterations in the central nervous system becomes particularly (...) necessary and important. With the development of advanced neuroimaging techniques, extensive studies have been carried out to identify the cortical abnormalities in CBP patients. Here, we provide a comprehensive overview on a series of novel findings from these neuroimaging studies to improve our understanding of the cortical abnormalities originated in the disease. First, CBP patients normally exhibit central sensitization to external painful stimuli, which is indexed by increased pain sensitivity and brain activations in pain-related brain regions. Second, long-term suffering from chronic pain leads to emotional disorders, cognitive impairments, and the abnormalities of the relevant brain networks among CBP patients. Third, CBP is associated with massive cortical reorganization, including structural, functional, and metabolic brain changes. Overall, a deep insight into the neural mechanisms underlying the development and outcome of CBP through more sophisticated neuroimaging investigations could not only improve our current understanding of the etiology of CBP but also facilitate the diagnosis and treatment of CBP based on precision medicine. (shrink)

BackgroundIntegrating a sex and gender lens is increasingly recognized as important in health research studies. Past failures to adequately consider sex in drug development, for example, led to medications that were metabolized differently, proved harmful, or ineffective, for females. Including both males and females in study populations is important but not sufficient; health, access to healthcare, and treatment provided are also influenced by gender, the socially mediated roles, responsibilities, and behaviors of boys, girls, women and men. Despite understanding the relevance (...) of sex and gender to health research, integrating this lens into study designs can still be challenging. Identified here, are nine opportunities to address sex and gender and thereby strengthen research proposals.MethodsOntario investigators were invited to submit a draft of their health research proposal to the Sex and Gender Research Support Service at Women’s College Hospital in Toronto, Ontario. The service works to build capacity on the integration of sex, gender, and other identity factors, in health research. Using the SAGER Guidelines and the METRICS for the Study of Sex and Gender in Human Participants as guides, proposals were reviewed to enhance their sex and gender considerations. Content analysis of the feedback provided these investigators was subsequently completed.ResultsNearly 100 hundred study proposals were reviewed and investigators provided with suggestions on how to enhance their proposal. Analyzing the feedback provided across the reviewed studies revealed commonly overlooked opportunities to elevate consideration of sex and gender. These were organized into nine suggestions to mirror the sections of a research proposal.ConclusionHealth researchers are often challenged on how to integrate a sex and gender lens into their work. Reviews completed across a range of health research studies show there are several commonly overlooked opportunities to do better in this regard. Nine ways to improve the integration of a sex and gender lens in health research proposals have been identified. (shrink)

Introduction of O2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy-yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O2 also presented major challenges as O2 and many of its derived reactive oxygen species are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to play (...) a major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. The importance of Earth's oxygen cycle and reactive oxygen species produced on the evolution of complex life. The ability to detoxify oxygen species is not a trait that emerged as a response to increased O2 levels but rather crucial adaptation to the early Earth's weakly oxic microenvironments. (shrink)

Four aspects of Mazur & Booth's target article are discussed from a comparative perspective using teleost fish as a reference: (a) the relationship between aggression, dominance, and androgens; (b) the interpretation of the data in light of the challenge hypothesis; (c) the potential role of testosterone as a physiological mediator between social status and the expression of male characters; and (d) the fact that metabolic conversions of testosterone may be important in its effect on aggression/ dominance.

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)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of production, (...) plant developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

Jaegwon Kim’s exclusion argument is a general ontological argument, applicable to any properties deemed supervenient on a microproperty basis, including biological properties. It implies that the causal power of any higher-level property must be reducible to the subset of the causal powers of its lower-level properties. Moreover, as Kim’s recent version of the argument indicates, a higher-level property can be causally efficient only to the extent of the efficiency of its micro-basis. In response, I argue that the ontology that aims (...) to capture experimentally based explanations of metabolic control systems and morphogenetic systems must involve causally relevant contextual properties. Such an ontology challenges the exclusiveness of micro-based causal efficiency that grounds Kim’s reductionism, since configurations themselves are inherently causally efficient constituents. I anticipate and respond to the reductionist’s objection that the nonreductionist ontology’s account of causes and inter-level causal relations is incoherent. I also argue that such an ontology is not open to Kim’s overdetermination objection. (shrink)

Functionally distinct anatomic subdivisions of the brain can often be only a few millimeters in one or more dimensions. The study of metabolic differences in such structures by means of localized in vivo MR spectroscopy is therefore challenging, if not impossible. In fact, the spatial resolution of chemical shift imaging (CSI) in humans is typically in the range of centimeters. The aim of the present study was to optimize 1H CSI in monkeys and demonstrate the feasibility of high spatial (...) resolutions up to 1.4 ؋ 2 ؋ 1.4 mm3. The obtained spatial resolution permitted the segregation of gray and white matter in the visual cortex based on the concentration of different metabolites and neurotrans- mitters like N-acetylaspartate, glutamate, and creatine. Con- centration ratios of white matter versus gray matter tissue as well as between metabolites matched those reported in the literature from healthy human brain, demonstrating the consis- tency and reliability of the procedure. Magn Reson Med 54: 1541–1546, 2005. © 2005 Wiley-Liss, Inc. Key words: in vivo 1H NMR spectroscopy; spectroscopic imag- ing; chemical shift imaging; spatial resolution; monkey visual cortex.. (shrink)

Objectives: Recent fMRI studies have shown that it is possible to reliably identify the defaultmode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. Experimental design: A spatial independent component analysis-based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation-corrected connectivity with (...) or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain-damaged patients [locked-in syndrome (n ¼ 2), minimally conscious (n ¼ 1), and vegetative state (n ¼ 8)]. Principal observations: All vegetative patients showed fewer connections in the default-mode areas, when compared with controls, contrary to locked-in patients who showed nearnormal connectivity. In the minimally conscious-state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. Conclusions: When assess-. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell (...) division are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen species, improved mitochondrial (...) efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

The gut microbiota is an important component of the human body and its immune‐modulating and metabolic activities are critical to maintain good health. Gut microbes, however, are sensitive to changes in diet, exposure to antibiotics, or infections, all of which cause transient disruptions in the microbial composition, a phenomenon known as dysbiosis. It is now recognized that microbial dysbiosis is at the root of many gastrointestinal disorders. However, the mechanisms through which bacterial dysbiosis initiates disease are not fully understood. (...) Microbially‐derived metabolites and their role in disease have also attracted significant attention. Identification of cancer‐associated bacteria and understanding the contributions of microbial metabolism in health and disease are exciting but challenging areas that will allow defining microbial biomarkers for predicting gastrointestinal disorders. Understanding the complex interactions between gut microbiota, diet, host immune system and host genetics will be critical to developing more personalized therapies and approaches to treat disease. (shrink)

To ensure their survival in natural habitats, plants must recognize and respond to a wide variety of insect herbivores. Aphids and other Hemiptera pose a particular challenge, because they cause relatively little direct tissue damage when inserting their slender stylets intercellularly to feed from the phloem sieve elements. Plant responses to this unusual feeding strategy almost certainly include recognition of aphid salivary components and the induction of phloem‐specific defenses. Due to the excellent genetic and genomic resources that are available for (...) Arabidopsis thaliana (Arabidopsis), this plant was chosen as a model system to study the metabolic and transcriptional responses to infestation by two aphids, Myzus persicae (green peach aphid, a broad generalist) and Brevicoryne brassicae (cabbage aphid, a crucifer‐feeding specialist). Future research on Arabidopsis–aphid interactions will lead to the identification of aphid‐specific elicitors, components of the defense‐signaling pathway, and additional metabolic responses that are induced by aphid infestation. BioEssays 29:871–883, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

While genomic and proteomic information describe the overall cellular machinery available to an organism, the metabolic profile of an individual at a given time provides a canvas as to the current physiological state. Concentration levels of relevant metabolites vary under different conditions, in particular, in the presence or absence of different disorders. Metabolite concentrations thus mediate an important link between chemistry and biology, contributing to a systems-wide understanding of biological processes and pathways. However, there are a number of (...) class='Hi'>challenges in the ontological representation of such information. Firstly, concentration information is numeric and ranges over continuous values, while ontologies consist of discrete classes. Secondly, ontologies usually model only what is certain, and their logical formalisms are adapted to reasoning from certain axioms to logical deductions, however, the link between chemicals and diseases via concentration levels, like many threshold phenomena, is both uncertain and vague. In this paper we evaluate the representation of this knowledge using a combination of concrete domains and probabilistic reasoning. We parse concentration values from HMDB and create an ontology able to distinguish normal from abnormal concentrations and able to evaluate a probabilistic risk category for the presence of an associated disorder. (shrink)