Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), depressive symptoms (...) (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity. (shrink)

The defense of plants against herbivores and pathogens involves the participation of an enormous range of different metabolites, some of which act directly as defensive weapons against enemies (toxins or deterrents) and some of which act as components of the complex internal signaling network that insures that defense is timed to enemy attack. Recent work reveals a surprising trend: The same compounds may act as both weapons and signals of defense. For example, two groups of well‐studied defensive weapons, glucosinolates and (...) benzoxazinoids, trigger the accumulation of the protective polysaccharide callose as a barrier against aphids and pathogens. In the other direction, several hormones acting in defense signaling (and their precursors and products) exhibit activity as weapons against pathogens. Knowing which compounds are defensive weapons, which are defensive signals and which are both is vital for understanding the functioning of plant defense systems. (shrink)

Early life stress precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social (...) affiliation were taken over a 12-week period followed by the first cerebrospinal fluid sample. Subjects were then either exposed to a 12-week repeated separation paradigm or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine, tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid, and anthranilic acid as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only. Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems. (shrink)

Mammalian AMP‐activated protein kinase is the central component of a protein kinase cascade which inactivates three key enzymes involved in the synthesis or release of free fatty acids and cholesterol inside the cell. The kinase cascade is activated by elevation of AMP, and perhaps also by fatty acid and cholesterol metabolites. The system may fulfil a protective function, preventing damage caused by depletion of ATP or excessive intracellular release of free lipids, a type of stress response. Recent evidence suggests that (...) it may have been in existence for at least a billion years, since a very similar protein kinase cascade is present in higher plants. This system therefore represents an early eukaryotic protein kinase cascade, which is unique in that it is regulated by intracellular metabolites rather than extracellular signals or cell cycle events. (shrink)

Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by‐product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI‐1, (...) and MUC1‐C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid – which affect the balance of formaldehyde in the body – may serve as the basis of future anticancer therapy. (shrink)

Resistance to the drugs used in the treatment of many infectious diseases is increasing, while microbial infections are being found to be responsible for more life‐threatening diseases than previously thought. Despite a large investment in the invention and application of high‐throughput screening techniques involving miniaturization and automation, and a diverse array of strategies for designing and constructing various chemical libraries, relatively few new drugs have resulted. Natural products, however, have been a major source of drugs for centuries. Since some of (...) them are produced by organisms as a result of selection in favour of improved defense against competing deleterious microorganisms, in principle they would be less likely to incur resistance. Furthermore, the production of those defensive secondary metabolites is inducible because their original function is a response to environmental challenges. Moreover, symbioses, co‐habitation associations between two or more different species of organisms, are universal in nature, and the production of secondary metabolites by symbiotic microbes may be an important adaptation allowing microbes to affect their hosts. Therefore, co‐culture strategies, using combinations of plant cell–pathogenic microbes, plant cell–endophytes (or symbionts), and symbiont–pathogenic microbes, based on the principles of chemical defense and the known mechanisms of organism interactions, may be an efficient general approach in the search for new anti‐microbial drugs. BioEssays 26:808–813, 2004. © 2004 Wiley Periodicals, Inc. (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 osmotic activity produced by internal, non‐permeable, anionic nucleic acids and metabolites causes a persistent and life‐threatening cell swelling, or cellular edema, produced by the Gibbs‐Donnan effect. This evolutionary‐critical osmotic challenge must have been resolved by LUCA or its ancestors, but we lack a cell‐physiology look into the biophysical constraints to the solutions. Like mycoplasma, early cells conceivably preserved their volume with Cl−, Na+, and K+‐channels, Na+/H+‐exchangers, and a light‐dependent bacteriorhodopsin‐like H+‐pump. Here, I simulated protocells having these ionic‐permeabilities and (...) inhabiting an oceanic pond before the Great‐Oxygenation‐Event. Protocells showed better volume control and stable resting potentials at lower external pH and higher temperatures, favoring a certain type of extremophile life. Prevention of Na+‐influx at night, with low bacteriorhodopsin activity, required deep shutdown of highly voltage‐sensitive Na+‐channels and extremely selective K+‐channels, two conserved features essential for modern neuronal encoding. The Gibbs‐Donnan effect universality implies that extraterrestrial cells, if they exist, may reveal similar volume‐controlling mechanisms. (shrink)

Niche construction is a concept that captures a wide array of biological phenomena, from the environmental effects of metabolism to the creation of complex structures such as termite mounds and beaver dams. A central point in niche construction theory is that organisms do not just passively undergo developmental, ecological, or evolutionary processes, but are also active participants in them Evolution: From molecules to men, Cambridge University Press, Cambridge, 1983; Laland KN, Odling-Smee J, Feldman MW, In: KN Laland and T Uller (...) Evolutionary causation: Biological and philosophical reflections, MIT Press, Cambridge, MA, 2019). In this paper, we distinguish between two fundamentally different ways in which organisms are active participants: as agents and as contributors. Roughly, organisms act as agents when niche constructing effects are a result of a goal-directed behavior over which the organisms have some degree of control. Organisms act as contributors when the niche constructing effects do not arise from a goal to perform the constructive activity. As illustrative examples we discuss plants altering leaf-morphology to optimize light exposure as reported by Sultan and bacteria creating novel niches through excreting energy-rich metabolites. The difference between agential and contributional niche construction is important for understanding the different ways organisms can actively participate in development, ecology, and evolution. Additionally, this distinction can increase our understanding of how the capacity of agency is distributed across the tree of life and how agency influences developmental and evolutionary processes. (shrink)

Most cells communicate with their immediate neighbors through the exchange of cytosolic molecules such as ions, second messengers and small metabolites. This activity is made possible by clusters of intercellular channels called gap junctions, which connect adjacent cells. In terms of molecular architecture, intercellular channels consist of two channels, called connexons, which interact to span the plasma membranes of two adjacent cells and directly join the cytoplasm of one cell to another. Connexons are made of structural proteins named connexins, (...) which compose a multigene family. Connexin channels participate in the regulation of signaling between developing and differentiated cell types, and recently there have been some unexpected findings. First, unique ionic‐ and size‐selectivities are determined by each connexin; second, the establishment of intercellular communication is defined by the expression of compatible connexins; third, the discovery of connexin mutations associated with human diseases and the study of knockout mice have illustrated the vital role of cell‐cell communication in a diverse array of tissue functions. (shrink)

Although the generation of reactive oxygen species is an activity normally associated with phagocytic leucocytes, mammalian spermatozoa were, in fact, the first cell type in which this activity was described. In recent years it has become apparent that spermatozoa are not the only nonphagocytic cells to exhibit a capacity for reactive oxygen species production, because this activity has been detected in a wide variety of different cells including fibroblasts, mesangial cells, oocytes, Leyding cells endothelial cells, thryroid cells, (...) adipocytes, tumour cell and platelets. Since the capacity to generate reactive oxygen species is apparently so widespread, the risk‐benefit equation for these potentially pernicious molecules becomes a matter of intese interest. In the case of human spermatozoa, the risk of manufacturing reactive oxygen metabolites is considerable because these cells are particularly vulnerable to lipid peroxidation. Indeed, there is now good evidence to indicate that oxygen radicals are involved in the initiation of peroxidative damage to the sperm plasma membrane, seen in many cases of male infertility. This risk is off‐set by recent data suggesting that superoxide anions and hydrogen peroxide also participate in the induction of key biological events such as hyperactiavated motility and the acrosome reaction. Thus, human spermatozoa appear to use reactive oxygen species for a physiological purpose and have the difficult task of ensuring the balanced generation of these potentially harmful, but biologically important, modulators of cellular function. (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)

Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α‐granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet‐derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet‐secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding this early (...) step of muscle regeneration exacerbates inflammation at later stages, compromises neo‐angiogenesis and the growth of newly formed myofibers, and reduces post‐injury muscle force production. Platelets also contribute to the recruitment of pro‐regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease. (shrink)

In this review, we provide an overview of the dynamic changes within the microbiota and its metabolites that are implicated in establishing and maintaining gastrointestinal homeostasis during various stages of microbial colonization. The gradual conversion of the gut microbiota toward a mutualistic microbial community involves replacement of pioneer gut colonizers with bacterial taxa that are characteristic for the adult gut. An important microbial signature of homeostasis in the adult gut is the prevalence and activity of a diverse spectrum of (...) bacterial species that produce beneficial metabolites through metabolic interactions between microbial groups. Deciphering these microbial signatures and their metabolites that govern short and long‐term equilibrium, as well as imbalances in host‐microbial relationships, may provide novel diagnostic tools and/or therapeutic targets for specific disorders associated with intestinal dysbiosis and loss of homeostasis. (shrink)

The mammalian blastocyst exhibits a high capacity for aerobic glycolysis, a metabolic characteristic of tumours. It has been considered that aerobic glycolysis is a means to ensure a high carbon flux to fulfil biosynthetic demands. Here, alternative explanations for this pattern of metabolism are considered. Lactate creates a microenvironment of low pH around the embryo to assist the disaggregation of uterine tissues to facilitate trophoblast invasion. Further it is proposed that lactate acts as a signalling molecule (especially at the reduced (...) oxygen tension present at implantation) to elicit bioactive VEGF recruitment from uterine cells, to promote angiogenesis. Finally it is suggested that the region of high lactate/low pH created by the blastocyst modulates the activity of the local immune response, helping to create immune tolerance. Consequently, the mammalian blastocyst offers a model to study the role of microenvironments, and how metabolites and pH are used in signalling. (shrink)

New concepts may prove necessary to profit from the avalanche of sequence data on the genome, transcriptome, proteome and interactome and to relate this information to cell physiology. Here, we focus on the concept of large activity-based structures, or hyperstructures, in which a variety of types of molecules are brought together to perform a function. We review the evidence for the existence of hyperstructures responsible for the initiation of DNA replication, the sequestration of newly replicated origins of replication, cell (...) division and for metabolism. The processes responsible for hyperstructure formation include changes in enzyme affinities due to metabolite-induction, lipid-protein affinities, elevated local concentrations of proteins and their binding sites on DNA and RNA, and transertion. Experimental techniques exist that can be used to study hyperstructures and we review some of the ones less familiar to biologists. Finally, we speculate on how a variety of in silico approaches involving cellular automata and multi-agent systems could be combined to develop new concepts in the form of an Integrated cell (I-cell) which would undergo selection for growth and survival in a world of artificial microbiology. (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)

In addition to their function in transport of water, ions, small metabolites, and growth factors in normal plant tissue, the plasmodesmata presumably serve as routes for cell‐to‐cell movement of plant viruses in infected tissue. Virus cell‐to‐cell spread through plasmodesmata is an active process mediated by specialized virus encoded movement proteins; however, the mechanism by which these proteins operate is not clear. We incorporate recent information on the biochemical properties of plant virus movement proteins and their interaction with plasmodesmata in a (...) model for transport of nucleic acids through plasmodesmatal channels. We propose that only single stranded (ss) nucleic acids can be transported efficiently through plasmodesmata, and that movement proteins function as molecular chaperones for ss nucleic acids to form unfolded movement protein‐ss nucleic acid complexes. These complexes are targeted to plasmodesmata. Plasmodesmatal permeability is then increased following interaction with movement protein and the entire movement complex or its nucleic acid component is translocated across the plasmodesmatal channel. (shrink)

The blood oxygen level dependent effect that provides the contrast in functional magnetic resonance imaging has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed (...) water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods. (shrink)

Emerging evidence supports the role for the intracellular domains of amyloid precursor protein (APP) in the physiology and function of APP. In this short report, I discuss the hypothesis that mutation of Tyr682 on the Y682ENPTY687 C‐terminal motif of APP may be directly or indirectly associated with alterations in APP functioning and activity, leading to neuronal defects and deficits. Mutation of Tyr682 induces an early and progressive age‐dependent cognitive and locomotor decline that is associated with a loss of synaptic (...) connections, a decrease in cholinergic tone, and defects in NGF signaling. These findings support a model in which APP‐C‐terminal domain exerts a pathogenic function in neuronal development and decline, and suggest that Tyr682 potentially could modulate the properties of APP metabolites in humans. (shrink)

The mechanisms of Darwinian theory applied at the cellular level can explain the embryogenesis of an organism. On the one hand, DNA is not the bearer or carrier of a program composed of rigid instructions, in which the adult organism is « written », in advance. It is a generator of diversity that functions in a probabilistic fashion and thus enables cells to change states without being guided by signals. On the other hand, the environment is not only that which (...) is external to the organism. It exists within the embryo inasmuch as it constitutes the micro-environment of the cell. It determines the concentration of metabolites to which the cell has access and which enable it to multiply. In a colony of cells there are numerous variations in the composition of this microenvironment. Cells exchange the products of their metabolism. They use what their neighbours provide them. By means of their probabilistic functioning, they adapt to changing life conditions by activating the necessary proteins, whence the cellular differentiation generating the tissue of which an adult being is composed. In this theory, the embryo is not the passive object subject to the cumulative determinisms of the genome and the environment. These are integrated into a single mechanism. The cell is the fundamental level which constructs the living being by an active process of Darwinian selection. By bringing together phylogeness and ontogenesis in one explanatory model, cellular Darwinism allows us to get rid of the old concepts of purposiveness and formal cause which genetics has rehabilitated in the new clothing of the « generic program ». (shrink)

The amdS gene of A. nidulans has proved extremely favourable for the isolation of mutations affecting gene regulation. Trans‐acting regulatory genes involved in amdS induction by small molecular weight effectors have been identified – amdR (ω‐amino acids) facB (acetate) and amdA (acetate). Another gene, the areA gene, has properties expected of a major activator gene involved in nitrogen metabolite repression of amdS. All of these regulatory genes are also involved in the control of various other functions encoded by structural (...) genes unlinked to amdS. Mutations in the 5′‐region adjacent to amdS have been isolated and allow the identification of independent cis‐acting sequences which are the target sites for the regulatory genes. The involvement of these sequences in regulatory product binding has been deduced from titration studies using transformants containing multiple copies of the 5′ sequences. A combination of genetics and molecular analysis is allowing a detailed characterization of this system. (shrink)

Reversible acetylation at the ϵ‐amino group of lysines located at the conserved domain of core histones is supposed to play an important role in the regulation of chromatin structure and its transcriptional activity. One promising strategy for analyzing the precise function of histone acetylation is to block the activities of acetylating or deacetylating enzymes by specific inhibitors. Recently, two microbial metabolites, trichostatin A and trapoxin, were found to be potent inhibitors of histone deacetylases. Trichostatin A reversibly inhibits the mammalian (...) histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme. The histone deacetylase from a trichostatin A‐resistant cell line is resistant to trichostatin A, indicating that the enzyme is the primary target. Both of the agents induce a variety of biological responses of cells such as induction of differentiation and cell cycle arrest. Trichostatin A and trapoxin are useful in analyzing the role of histone acetylation in chromatin structure and function as well as in determining the genes whose activities are regulated by histone acetylation. (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)

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy in the prefrontal white matter at the beginning and end of season in contact and non-contact varsity athletes. Sedentary women were scanned once, at a time (...) equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline. (shrink)

Watching, looking at, and listening to, are all things that perceiving agents actively do. Though the occurrence of these activities appears to entail perception of elements of the agent's environment, perception is not something that can be actively done by agents. This raises the question how perceptual activity and perception are related to one another. This chapter, through reflecting on a discussion of listening offered by Brian O'Shaughnessy, argues that listening to material particulars ought to be understood as the (...) agential maintenance of aural awareness of those particulars, with the aim of knowing what sounds they are making. He goes on to explore some of the consequences of these claims about listening for exercises of perceptual agency involving the other sensory modalities. (shrink)

In the United States, a longstanding legal rule exists against patenting natural phenomena. The Supreme Court recently had an opportunity to help define the boundaries and clarify the implications of this “natural phenomenon doctrine” in Laboratory Corporation of America v. Metabolite Labs., dismissed as improvidently granted. This article argues that the natural phenomenon doctrine renders both the patent claim at issue in LabCorp, and the patents that directly or indirectly claim biological correlations between genotypes and medical phenotypes, invalid or (...) unenforceable under U.S. patent law. (shrink)

This paper propounds a new reading of Berkeley's account of the activity of finite spirits. Against existing interpretations, the paper argues that Berkeley does not hold that we causally contribute to the movement of our bodies. In contrast, our volitions to move our bodies are but occasions for God to cause their movement. In answer to the question of wherein then consists our activity, the paper proposes that our activity consists in the dual powers to produce (1) (...) our volitions ? the acts of willing ? and (2) our ideas of imagination. (shrink)

How chromatin bridges are detected by the abscission checkpoint during mammalian cell division is unknown. Here, we discuss recent findings from our lab showing that the DNA topoisomerase IIα (Top2α) enzyme binds to catenated (“knotted”) DNA next to the midbody and forms abortive Top2‐DNA cleavage complexes (Top2ccs) on chromatin bridges. Top2ccs are then processed by the proteasome to promote localization of the DNA damage sensor protein Rad17 to Top2‐generated double‐strand DNA ends on DNA knots. In turn, Rad17 promotes local recruitment (...) of the MRN protein complex and downstream ATM‐Chk2‐INCENP signaling to delay abscission and prevent chromatin bridge breakage in cytokinesis. (shrink)

Molecular genetic testing has increasingly been incorporated into clinical medicine, and this trend is likely to accelerate in the future. The introduction of genetic testing into medical practice is beginning to collide head on with patents that claim ownership of correlations between human genetic variants and predisposition to disease, response to therapeutic drugs, and susceptibility to pharmacologic side effects. Patent holders or licensees of genes, genetic variants, and their genotype-phenotype correlations are already using the threat of litigation to monopolize genetic (...) tests for important well-known syndromes like Duchenne Muscular Dystrophy and inherited breast and ovarian cancer, in addition to a host of less commonly discussed conditions. (shrink)

Recently research on imitation and its role in social cognition has been flourishing across various disciplines. After briefly reviewing these developments under the headings of behavior, subpersonal mechanisms, and functions of imitation, I advance the _shared circuits_.

People display recognizably characteristic behavioral patterns across time and situations, with a given degree of regularity. These patterns may justify the attribution of personality traits. It is arguably the commonsense view that the proper explanation of these behavioral regularities is given by intrinsic properties of the agent’s psychology. In this paper, I argue for an externalistic view of the causal basis of personality-characteristic behaviors. According to the externalistic view, the relevant behavioral regularities are better understood as the result of a (...) systematic interaction between features internal to the agent and environmental-situational factors. Moreover, if the premise is granted that people are typically able to exercise a certain degree of control over the environmental-situational conditions they find themselves in, the resulting picture is of active sort of externalism, as people may at times engage in selection and manipulation of environmental-situational conditions as a way of managing their own behavioral tendencies. (shrink)

Internalist approaches to epistemic justification are, though controversial, considered a live option in contemporary epistemology. Accordingly, if ‘active’ externalist approaches in the philosophy of mind—e.g. the extended cognition and extended mind theses—are _in principle_ incompatible with internalist approaches to justification in epistemology, then this will be an epistemological strike against, at least the _prima facie_ appeal of, active externalism. It is shown here however that, contrary to pretheoretical intuitions, neither the extended cognition _nor_ the extended mind theses are in principle (...) incompatible with two prominent versions of epistemic internalism—viz., accessibilism and mentalism. In fact, one possible diagnosis is that pretheoretical intuitions regarding the incompatibility of active externalism with epistemic internalism are symptomatic of a tacit yet incorrect identification of epistemic internalism with epistemic individualism. Thus, active externalism is not in principle incompatible with epistemic internalism per se and does not significantly restrict one’s options in epistemology. (shrink)

Cognitive niche construction is the process whereby organisms create and maintain cause–effect models of their niche as guides for fitness influencing behavior. Extended mind theory claims that cognitive processes extend beyond the brain to include predictable states of the world. Active inference and predictive processing in cognitive science assume that organisms embody predictive (i.e., generative) models of the world optimized by standard cognitive functions (e.g., perception, action, learning). This paper presents an active inference formulation that views cognitive niche construction as (...) a cognitive function aimed at optimizing organisms' generative models. We call that process of optimization extended active inference. (shrink)

Unless one embraces activities as foundational, understanding activities in mechanisms requires an account of the means by which entities in biological mechanisms engage in their activities—an account that does not merely explain activities in terms of more basic entities and activities. Recent biological research on molecular motors exemplifies such an account, one that explains activities in terms of free energy and constraints. After describing the characteristic “stepping” activities of these molecules and mapping the stages of those steps onto the stages (...) of the motors’ hydrolytic cycles, researchers pieced together from images of the molecules in different hydrolyzation states accounts of how the chemical energy in ATP is transformed in the constrained environments of the motors into the characteristic activities of the motors. We argue that New Mechanism’s standard set of analytic categories—entities, activities, and organization—should be expanded to include constraints and energetics. Not only is such an expansion required descriptively to capture research on molecular motors but, more importantly from a philosophical point of view, it enables a non-regressive account of activities in mechanisms. In other words, this expansion enables a philosophical account of mechanistic explanation that avoids a regress of entities and activities “all the way down.” Rather, mechanistic explanation bottoms out in constraints and energetics. (shrink)

In this commentary, we point to guidelines for performing human neuroimaging studies and their reporting in microbiota-gut-brain articles. Moreover, we provide a view on interpretational issues in MGB studies, with a specific focus on gut microbiota–derived metabolites. Thus, extending the target article, we provide recommendations to the field to increase reproducibility and relevance of this type of MGB study.

Aujourd’hui, la notion de geste semble saturée. Elle se trouve épuisée par certaines déterminations de l’art du XX e siècle, comme l’expressivité de la main, la distanciation théâtrale brechtienne, la performance et ses déclinaisons subséquentes en attitude et posture. Pourtant, l’épuisement, voire la disparition de son évidence peut aussi être l’occasion d’en ressaisir d’en réactualiser les enjeux. Nous nous proposons de nous emparer du geste à l’endroit où il se construit aujourd’hui, entre répétition et différence, à la croisée des disciplines (...) et des pratiques. Comment la peinture ou la littérature peuvent-elles procéder du geste et conserver un ancrage intense dans la pratique d’un medium? Comment la performance, à l’ère de son re-enactment, et à l’époque de la prolifération des images, redéfinit-elle un espace-temps spécifique? Comment le cinéma contemporain, entre le geste filmé et le geste de filmer, nous renseigne-t-il sur notre réel? Réinterroger le geste sans le restreindre à une notion, mais l’envisager comme une force active, une dynamique à même d’ouvrir des espaces : un colloque, un livre, un site internet, autant d’espaces-temps proposés pour donner lieu à des rencontres inédites et à l’exercice en commun de la pensée. (shrink)

This paper deals with the question of agency and intentionality in the context of the free-energy principle. The free-energy principle is a system-theoretic framework for understanding living self-organizing systems and how they relate to their environments. I will first sketch the main philosophical positions in the literature: a rationalist Helmholtzian interpretation (Hohwy 2013; Clark 2013), a cybernetic interpretation (Seth 2015b) and the enactive affordance-based interpretation (Bruineberg and Rietveld 2014; Bruineberg et al. 2016) and will then show how agency and intentionality (...) are construed differently on these different philosophical interpretations. I will then argue that a purely Helmholtzian is limited, in that it can account only account for agency in the context of perceptual inference. The cybernetic account cannot give a full account of action, since purposiveness is accounted for only to the extent that it pertains to the control of homeostatic essential variables. I will then argue that the enactive affordance-based account attempts to provide broader account of purposive action without presupposing goals and intentions coming from outside of the theory. In the second part of the paper, I will discuss how each of these three interpretations conceives of the sense agency and intentionality in different ways. (shrink)

This essay traces the development of the philosophical debates concerning active powers and human agency in eighteenth-century Scotland. I examine how and why Scottish philosophers such as Francis Hutcheson, George Turnbull, David Hume, and Henry Home, Lord Kames, depart from John Locke’s and other traditional conceptions of the will and how Thomas Reid and Dugald Stewart reinstate Locke’s distinction between volition and desire. Moreover, I examine what role desires, passions, and motives play in the writings of these and other Scottish (...) Enlightenment philosophers on human agency and draw attention to their underlying disputes concerning liberty and necessity. I end by reflecting on how classifications of principles of actions changed in eighteenth and early nineteenth-century Scottish philosophy. (shrink)

Contemporary literature in philosophy of action seems to be divided overthe place of action in the natural causal world. I think that a disagreementabout ontology underlies the division. I argue here that human action isproperly understood only by reference to a category of process or activity,where this is not a category of particulars.