Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre‐clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress‐induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation of oxygen (...) and nutrients. The resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors. (shrink)

Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune‐obesogenic memory that hinders long‐term weight loss management. Lipid‐associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT. Our previous study found that LAM abundance increases with weight loss (...) via intermittent fasting (IF) in obese mice, which is driven by adipocyte p53 signalling. However, the specific signals causing LAM accumulation in AT under IF remain unknown. In this piece, we hypothesise on a range of adipocyte‐secreted signals that can harbor immune‐attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including cell death signalling, matrikines, and other damage‐associated molecular patterns (DAMPs), as well as adipo(‐cyto)kines, lipid mediators, metabolites, extracellular vesicles, and epigenetic rewiring. Finally, we consider how advances in mechanisms of AT LAM recruitment gleaned from preclinical models might be translatable to long‐term weight management in humans. Thus, we provide vantage points to study signals driving monocyte recruitment, polarisation towards LAMs, and LAM retention, to harness the therapeutic potential of modulating AT LAM levels by impacting the immune‐obesogenic memory in metabolic disease. (shrink)

The co-occurrence of stress-induced posttraumatic stress disorder (PTSD) and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage (...) prior knowledge to systematically highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing (NLP) to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin (OXT), Neuropeptide-Y (NPY), and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated (...) for lung adenocarcinomas (LUAD) with KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

Beyond protein synthesis and autophagy, emerging evidence has implicated mTORC1 in regulating protein folding and proteasomal degradation as well, highlighting its prominent role in cellular proteome homeostasis or proteostasis. In addition to growth signals, mTORC1 senses and responds to a wide array of stresses, including energetic/metabolic stress, genotoxic stress, oxidative stress, osmotic stress, ER stress, proteotoxic stress, and psychological stress. Whereas growth signals unanimously stimulate mTORC1, stresses exert complex impacts on mTORC1, most (...) of which are repressive. mTORC1 suppression, as a generic adaptive strategy, empowers cell survival under various stressful conditions. In this essay, we provide an overview of the emerging role of mTORC1 in proteostasis, the distinct molecular mechanisms through which mTORC1 reacts to diverse stresses, and the schemes exploited by cancer cells to circumvent stress‐induced mTORC1 suppression. Hence, acting as a stress sensor, mTORC1 intimately couples stresses to cellular proteostasis. (shrink)

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

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy (...) – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging. (shrink)

Western Kenya has been a labour-exporting region for over a century, with many households straddling both rural and urban contexts. While the spatial separation of migrants from their rural places of origin represented the first tangible metabolic rift within Kenyan agricultural production systems, that rift is being reshaped as rural families engage in new forms of interconnection with migrant members (“multilocationality”). These changes appear to be driven by the ongoing crisis of agrarian livelihoods and are supported by the advent (...) of cellphone communication and mobile money transfer technologies. Interviews and ethnographic data collected in a western Kenyan community and amongst its out-migrants reveal the role of cellphones in mediating social, financial, and knowledge flows within multilocational households. The increased ease of communicating and sending money is associated with less frequent physical movements between rural and urban settings, with commensurate disruptions in the acquisition and development of agro-ecological knowledge, and a shifting burden of agricultural labour. Gender relations are also put under further stress: migrant men remain (or believe they have remained) involved in rural affairs but appear to be using cellphone technologies to reinvent their household roles, replacing previously social or labour contributions with financial ones and by asserting claims over the on-farm decision-making of rural households previously considered female-headed. (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)

BackgroundPositive psychosocial factors can play an important role in the development of cardiovascular disease. Among them, psychological resilience is defined as the capacity of responding positively to stressful events. Our aim was to assess whether PR is associated with CVD or metabolic disturbances through a systematic review.MethodsWe gathered articles from PubMed, Web of Science, PsycInfo, and Google Scholar up to October 28, 2021. We included articles that were in English, were observational, and had PR examined as exposure. The CVD (...) outcomes were either clinical or metabolic outcomes.ResultsOur literature search identified 3,800 studies, of which 17 met the inclusion criteria. Of them, seven were longitudinal and 10 cross-sectional, and 13 were on adults and four on children. The exposure assessment was heterogeneous, i.e., 12 studies used different kinds of self-administered questionnaires and five used interviews with a psychologist. Regarding outcomes, five studies investigated CVD, seven obesity, one metabolic syndrome, two hypertension, four dyslipidemia, and four diabetes. In longitudinal studies, PR was found to have an inverse association with included outcomes in five studies from the Swedish military conscription cohort but had no association with CVD in a study on African-American women and was associated with slower progression of diabetes in a general population. The cross-sectional studies showed that the prevalence of disease was not associated with PR in many cases but the progression of disease was associated with PR.ConclusionPR seems to have a possibly favorable association with CVD and metabolic disturbances that differs according to the type of outcome and population. Our study limitations are given by the small number of studies available and the heterogeneity in PR measurement.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=237109], identifier [CRD42021237109]. (shrink)

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER (...) stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. (shrink)

Early life adversity, such as child maltreatment or child poverty, engenders problems with emotional and behavioral regulation. In the quest to understand the neurobiological sequelae and mechanisms of risk, the amygdala has been of major focus. While the basic functions of this region make it a strong candidate for understanding the multiple mental health issues common after ELA, extant literature is marked by profound inconsistencies, with reports of larger, smaller, and no differences in regional volumes of this area. We believe (...) integrative models of stress neurodevelopment, grounded in “allostatic load,” will help resolve inconsistencies in the impact of ELA on the amygdala. In this review, we attempt to connect past research studies to new findings with animal models of cellular and neurotransmitter mediators of stress buffering to extreme fear generalization onto testable research and clinical concepts. Drawing on the greater impact of inescapability over unpredictability in animal models, we propose a mechanism by which ELA aggravates an exhaustive cycle of amygdala expansion and subsequent toxic-metabolic damage. We connect this neurobiological sequela to psychosocial mal/adaptation after ELA, bridging to behavioral studies of attachment, emotion processing, and social functioning. Lastly, we conclude this review by proposing a multitude of future directions in preclinical work and studies of humans that suffered ELA. (shrink)

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive (...) responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. (shrink)

Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded (...) factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator. (shrink)

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. (...) class='Hi'>Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo‐SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies. (shrink)

Oncogene activation leads to cellular transformation by deregulation of biological processes such as proliferation and metabolism. Paradoxically, this can also sensitize cells to nutrient deprivation, potentially representing an Achilles' heel in early stage tumors. The mechanisms underlying this phenotype include loss of energetic and redox homeostasis as a result of metabolic reprogramming, favoring synthesis of macromolecules. Moreover, an emerging mechanism involving the deregulation of mRNA translation elongation through inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is presented. The potential (...) consequences of eEF2K deregulation leading to cell death under nutrient depletion are discussed. Finally, the relevance of eEF2K as a master regulator of the response to nutrient deprivation in vivo, and its potential exploitation for therapeutic targeting of cancers, are elaborated. Overall, a better understanding of the adaptive mechanisms allowing tumors to circumvent oncogene‐induced hypersensitivity to nutrient deprivation is a promising avenue for uncovering novel therapeutic targets in cancers. (shrink)

Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three‐decade‐old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now independently (...) reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR‐governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation. (shrink)

The main aim of our study was to determinate whether a repeated bout (RB) (vs. first bout [FB]) of sprint interval cycling exercise (SIE) is sufficient to mitigate SIE-induced psychological and physiological biomarker kinetics within 48 h after the exercise. Ten physically active men (age, 22.6 ± 5.2 years; VO2max, 44.3 ± 5.7 ml/kg/min) performed the FB of sprint interval cycling exercise (12 repeats of 5 s each) on one day and the RB 2 weeks later. The following parameters were (...) measured: motor performance (voluntary, electrically induced and isokinetic skeletal muscle contraction torque, and central activation ratio [CAR]); stress markers (BDNF, cortisol, norepinephrine, and epinephrine); inflammatory markers (IL-6, IL-10, and TNF-); metabolic markers (glucose and lactate); muscle and rectal temperature; cycling power output; and psychological perceptions. The average cycling power output and neuromuscular fatigue after exercise did not differ between the FB and RB. There were significant decreases in cortisol and BDNF concentration at 12 h (P < 0.05) and 24 h (P < 0.001) after the FB, respectively. The decrease in cortisol concentration observed 12 h after exercise was significantly greater after the RB (P < 0.05) than after the FB. The immune-metabolic response to the RB (vs. FB) SIE was suppressed and accompanied by lower psychological exertion. Most of the changes in psychological and physiological biomarkers in the FB and RB were closely related to the response kinetics of changes in BDNF concentration. (shrink)

B cell activation is accompanied by metabolic adaptations to meet the increased energetic demands of proliferation. The metabolic composition of the microenvironment is known to change during a germinal center response, in inflamed tissue and to vary significantly between different organs. To sustain cellular homeostasis B cells need to be able to dynamically adapt to changes in their environment. An inability to take up and process available nutrients can result in impaired B cell growth and a diminished humoral (...) immune response. Furthermore, the metabolic microenvironment can affect B cell signaling and provide a means to avoid aberrant proliferation or modulate B cell function. Thus, a better understanding of the intricate interplay between cell signaling and metabolism could provide novel insight into how B cell function is regulated and have implications for the development of vaccines or treatment of autoimmune disorders and B cell derived malignancies. Throughout their lifespan, B cells are exposed to different metabolic environments. Signaling pathways regulating cellular responses to metabolic stress not only help to maintain B cell viability and to facilitate cellular functions but may also play an important role in preventing excessive proliferation and malignant transformation. (shrink)

On ‘Mismatch’ and ‘Metabolic Ghettos:’ The Conceptualization of Global Health Differences in Research on the Developmental Origins of Health and Disease. Epigenetic approaches to human health have received growing attention in the past two decades. They allow to view the development of human organisms as plastic, i.e. as open to influences from the social and material environment such as nutrition, stress, and trauma. This has lent new credence to approaches in biomedicine that aim to draw attention to the (...) importance of development for later life health. Some scholars in the social sciences and humanities have welcomed such approaches as a departure from gene‐centric perspectives and as an opportunity for highlighting the social and political determinants of health and illness. Others have warned that they might lead to new forms of biological reductionisms and determinisms. In this article, we explore how research on developmental plasticity addresses and articulates global health disparities, specifically in the context of postcolonial India. We discuss two prominent approaches from the field of Developmental Origins of Health and Disease (DOHaD) that build on epigenetic perspectives on health and illness and view different global rates of disease susceptibility as the result of developmental processes: first, the ‘mismatch paradigm’ by Peter Gluckman and Mark Hanson and second, the ‘metabolic ghetto’ concept by Jonathan Wells. We highlight how both approaches render historical and social factors meaningful for the development of global health disparities, but emphasize how they at the same time remain prone to determinisms and reductionisms reminiscent of a gene‐centric perspective. DOHaD actors themselves are critical of these tendencies, and in conclusion we explore novel opportunities for interdisciplinary collaborations enabled by this critical potential. (shrink)

If we are to ensure the persistence of species in an increasingly warm world, of interest is the identification of drivers that affect the ability of an organism to resist thermal stress. Underpinning any organism's capacity for resistance is a complex interplay between biological and physical factors occurring over multiple scales. Tropical coral reefs are a unique system, in that their function is dependent upon the maintenance of a coral–algal symbiosis that is directly disrupted by increases in water temperature. (...) A number of physical factors have been identified as affecting the biological responses of the coral organism under broadscale thermal anomalies. One such factor is water flow, which is capable of modulating both organismal metabolic functioning and thermal environments. Understanding the physiological and hydrodynamic drivers of organism response to thermal stress improves predictive capabilities and informs targeted management responses, thereby increasing the resilience of reefs into the future. (shrink)

The emergence of organic, metabolic, cognitive and cultural codes points us to the need for a new kind of explanatory causality, and a different kind of bio-logic— one dependent on, but different from, the deterministic logic derived from mechanical causality, and one which can account for the increase in semiotic freedom which is evident in the biological hierarchy. Building upon previous work (Bruni 2003), in this article I provide a stipulative definition of semiotic freedom and its relation to causality (...) in biological and cognitive systems. To do so, I will first discuss the close relation that triadic causality and semiotic freedom have to the notions of teleology and emergence, and how the latter two are interrelated in living systems. I pinpoint some of the reservations that these notions have encountered in the history of science (including evolutionary biology and cognitive science), but stress also their necessity in the study of any given biological and cognitive system. I draw a distinction between horizontal and vertical emergence in order to arrive at a notion of ‘second order emergence’ that affords us a more viable definition of semiotic freedom. I will then attempt to show that all of these concepts are of paramount importance when we come to study processes of sensing, perception andcognition at any level of a living system. Accordingly, these ideas are part of a framework-in-development to research the scale of thresholds of semiotic freedom, by assuming a top-down approach i.e., by starting from the highest levels of semiotic freedom and cognitive processes, and exploring how those processes disaggregate into lesser degrees of freedom. I thus hope to bridge the gap between those levels from above. (shrink)

This book reveals a stunning thread of scientific data that points the way to the natural anabolic state a biochemical condition wherein body fat is metabolized, muscle tissue is built, strength and speed are increased, mental acuity is enhanced, and the mind and body perform at top efficiency. This inspirational book is a must-read for athletes and coaches in every sport, students and teachers at every level, people of faith, people seeking faith, and anyone competing for success. Readers will learn (...) how one simple thought altered the blood chemistry of students taking the GRE and raised test scores and how that same thought increased athletic performance in multiple sports. Readers will also come to understand why honesty, gratitude, humility, self-discipline, assertiveness, love, faith, and playing-to-win induce an empowering anabolic blood chemistry. If you read this book, you will meet Jenny (the girl who achieved a seemingly impossible goal), Susie (the most aggressive infielder I ve ever seen), Hank (the shortstop who experienced his worst nightmare), John Doe (the guy who experienced all five types of stress before leaving his driveway), Attila the Hun (an example of humility), and several more unforgettable characters. If you read this book, I promise you that, by the time you finish the third chapter, you will fervently wish you'd read it earlier in your life. (shrink)

A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which (...) links the Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C. (shrink)

The World Health Organisation recently listed air pollution as the most significant threat to human health. Air pollution comprises particulate matter (PM), metals, black carbon and gases such as ozone (O3), nitrogen dioxide (NO2) and carbon monoxide (CO). In addition to respiratory and cardiovascular disease, PM exposure is linked with increased risk of neurodegeneration as well as neurodevelopmental impairments. Critically, studies suggest that PM crosses the placenta, making direct in utero exposure a reality. Rodent models reveal that neuroinflammation, neurotransmitter imbalance (...) and oxidative stress are triggered following gestational/early life exposure to PM, and may be exacerbated by concomitant mitochondrial dysfunction. Gestational PM exposure (potentiated by mitochondrial impairment in the metabolically active neonatal brain) not only impacts neurodevelopment but may sensitise the brain to subsequent cognitive impairment. Having reviewed this field, we conclude that strategies are urgently required to reduce exposure to PM during this sensitive developmental period. (shrink)

Early theorists speculated that extremely shy children, or those with anxious temperament, were likely to have anxiety problems as adults. More recent studies demonstrate that these children have heightened responses to potentially threatening situations reacting with intense defensive responses that are characterized by behavioral inhibition and physiological arousal. Confirming the earlier impressions, data now demonstrate that children with this disposition are at increased risk to develop anxiety, depression, and comorbid substance abuse. Additional key features of anxious temperament are that it (...) appears at a young age, it is a stable characteristic of individuals, and even in non-threatening environments it is associated with increased psychic anxiety and somatic tension. To understand the neural underpinnings of anxious temperament, we performed imaging studies with 18- fluoro-deoxyglucose high-resolution Positron Emission Tomography in young rhesus monkeys. Rhesus monkeys were used because they provide a well validated model of anxious temperament for studies that cannot be performed in human children. Imaging the same animal in stressful and secure contexts, we examined the relation between regional metabolic brain activity and a trait-like measure of anxious temperament that encompasses measures of BI and pituitaryadrenal reactivity. Regardless of context, results demonstrated a trait-like pattern of brain activity that is predictive of individual phenotypic differences. Importantly, individuals with extreme anxious temperament also displayed increased activity of this circuit when assessed in the security of their home environment. These findings suggest that increased activity of this circuit early in life mediates the childhood temperamental risk to develop anxiety and depression. (shrink)

Eukaryotic origins are heavily debated. The author as well as others have proposed that they are inextricably linked with the arrival of a pre‐mitochondrion of alphaproteobacterial‐like ancestry, in a so‐called symbiogenic scenario. The ensuing mutual adaptation of archaeal host and endosymbiont seems to have been a defining influence during the processes leading to the last eukaryotic common ancestor. An unresolved question in this scenario deals with the means by which the bacterium ends up inside. Older hypotheses revolve around the application (...) of known antagonistic interactions, the bacterium being prey or parasite. Here, in reviewing the field, the author argues that such models share flaws, hence making them less likely, and that a “pre‐symbiotic stage” would have eased ongoing metabolic integration. Based on this the author will speculate about the nature of the (endo) symbiosis that started eukaryotic evolution–in the context of bacterial entry being a relatively “early” event–and stress the differences between this uptake and subsequent ones. He will also briefly discuss how the mutual adaptation following the merger progressed and how many eukaryotic hallmarks can be understood in light of coadaptation. Also see the video abstract here https://youtu.be/ekqtNleVJpU. (shrink)

Pulmonary ventilation and respiration are considered to be primarily involved in oxygenation of blood for oxygen delivery to cells throughout the body for metabolic purposes. Other pulmonary physiological observations, such as respiratory sinus arrhythmia, Hering Brewer reflex, cardiorespiratory synchronization, and the heart rate variability (HRV) relationship with breathing rhythm, lack complete explanations of physiological/functional significance. The spectrum of waveforms of breathing activity correlate to anxiety, depression, anger, stress, and other positive and negative emotions. Respiratory pattern has been thought (...) not only to be influenced by emotion but to itself influence emotion in a bi-directional relationship between the body and the mind. In order to show how filling in gaps in understanding could lead to certain future developments in mind–body medicine, biofeedback, and personal health monitoring, we review and discuss empirical work and tracings to express the vital role of bodily rhythms in influencing emotion, autonomic nervous system activity, and even general neural activity. Future developments in measurement and psychophysiological understanding of the pattern of breathing in combination with other parameters such as HRV, cardiorespiratory synchronization, and skin conductivity may allow for biometric monitoring systems to one day accurately predict affective state and even affective disorders such as anxiety. Better affective prediction based on recent research when incorporated into personal health monitoring devices could greatly improve public mental health by providing at-home biofeedback for greater understanding of one’s mental state and for mind–body affective treatments such as breathing exercises. (shrink)

Hannah Arendt, who was Hans Jonas’s lifelong friend, always stressed the importance and rarity of the independent thinker. The independent thinker is the thinker who has the imagination to break new ground, who does not follow current fashions, and has the courage to pursue thought trains wherever they may lead. Her model was Lessing, but she might have considered Hans Jonas to be an outstanding twentieth century exemplar of the independent thinker. Although Hans Jonas was a student of both Heidegger (...) and Bultmann in the 1920’s, he did not become a disciple of anyone. Both of these teachers encouraged him to pursue his research into the history of Gnosticism. Jonas’s path-breaking achievement can be compared with what Gershom Scholem did for the study of the Kabbalah. For Jonas literally created a new field of research in the history of religions. His study of Gnosticism became one of those rare twentieth century landmarks that opened up our understanding of Gnosticism and revealed its powerful subterranean influence throughout the history of the West. The first volume of Jonas’s study, Gnosis und spätantiker Geist was published in Germany in 1934 only after he fled from Nazi Germany and decided to emigrate to Palestine. If Jonas had never published anything else he would be known today as the major twentieth-century scholar of Gnosticism.. But Jonas was much more than an original scholar. He was a creative thinker—and he remained one until his death in 1993, shortly before his ninetieth birthday. During the Second World War, he fought in the famous Jewish Brigade of the British army. It was during this period, when he faced death all around him on the battlefield, that the phenomenon of life in all its ramifications became his central philosophical preoccupation. Jonas had been compelled to suspend his scholarly research during the war years, but he never suspended his independent thinking. He felt it was his obligation to fight the Nazis, but his dream was to return to his true vocation—philosophical speculation. After fighting in the Israeli War of Independence, he accepted a fellowship at McGill University in Canada in 1949, and eventually accepted a position at the Graduate Faculty of the New School for Social Research in 1955. The line of inquiry that he began when he was able to return to philosophical study resulted in the publication of The Phenomenon of Life. Jonas’s project was to understand what is distinctive about living organisms, and the emergence and consequences of life in the cosmos. But in order to do this, Jonas had to engage in a systematic radical critique of the dualisms of matter and mind, body and soul, which have dominated and shaped so much of modern thought. From Jonas’s perspective, even those philosophers who had rejected dualism were still tainted by the misguided ontology of dualism. The variety of monisms that arose in reaction to dualism tended to move to the extremes of materialism or idealism. Neither of these extremes is adequate for illuminating what is distinctive about bios. In German idealism there was a failure to do justice to the needs and character of the lived body. And in the varieties of “reductive materialism” that have been—and continue to be—so fashionable in twentieth century there is also a failure to appreciate what is distinctive about dynamic metabolic processes. To engage in a critique of dualism and its legacy, it was also necessary to rethink what can be learned from the biological sciences, and especially, the theory of evolution. Here we also witness the philosophical daring of Jonas. A dominant prejudice of the twentieth century has been that philosophy as a discipline has nothing significant to contribute to our understanding of biological processes. All that philosophy can do is to reflect on the methodological and epistemological status of the sciences because, presumably, the only legitimate source of knowledge about living organisms is what we learn from the natural sciences. Jonas argues that this prevailing prejudice has led to disastrous intellectual consequences. Of course, philosophers qua philosophers cannot and should not engage in “armchair” scientific speculation. Furthermore, they must be fully informed about the hypotheses and claims of the best biological research. But at the same time it is a philosophical endeavor to understand critically the meaning of what we learn from the sciences, and to develop an adequate philosophical account of the meaning of nature. Philosophers cannot and should not abandon this task. There is an important distinction to be drawn between the scientific achievements and the philosophical reflection on their meaning—a distinction that too frequently is forgotten or neglected. (shrink)

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptors hypersensitivity may result from the systemic state of inflammation characteristic of obesity as well (...) as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally-released neuropeptides sustain immunocytes’ function. Here, we posit that along with mechanical stressed stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping the harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity. (shrink)

The article focuses on the ability of some animals and plants to respond to changing environmental conditions by temporarily suspending metabolic processes. In contemporary biology, this state between life and death is commonly labelled ‘cryptobiosis’, combining the Greek kryptos (hidden, concealed, secret) with biōsis (mode of life). I argue that the notion of ‘cryptobiosis’ does not account sufficiently for the processual and relational dimensions of ametabolic life. The article advances a related but different concept, which better addresses this liminal (...) state of biological organisation: s uspended life. While cryptobiosis still nurtures the imaginary of some latent life, suspended life stresses the liminality of the neither-nor life and death. The notion also grasps the dynamic and ongoing transfer between the biological and the technological. While the debate on cryptobiosis has so far remained confined to the description of natural processes, suspended life (or limbiosis) promises to account for contemporary technological practices of cryopreservation. (shrink)

We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds (...) gut dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. (shrink)

Pregnancy is thought to be a metabolically very expensive endeavor, yet investigations have produced inconsistent results concerning the responsiveness of human birth weight to maternal nutritional stress or nutritional intervention. These findings have led some researchers to conclude that fetal growth is strongly buffered against fluctuations in maternal energy balance, making the fetus in effect a “nearly perfect parasite.” This buffering would appear to be a reasonable adaptive response given the high risk of morbidity and mortality associated with low (...) birth weight. However, a life-history approach leads to the prediction that maternal investment strategies in pregnancy should be geared toward maximizing lifetime reproductive success rather than simply the success of the current pregnancy, and by extension that maternal investment strategies should vary with reproductive value. The physiology of human pregnancy in fact appears to include a number of mechanisms that protect maternal energy resources from diversion to the fetus and preserve them for future reproductive events. These mechanisms include adjustment of blood flow to the uterus and perhaps minor adjustments in gestation length, although evidence for the latter is scant. Suggestions are made for ways of investigating these maternal options. (shrink)

The conditions animals experience during the early developmental stages of their lives can have critical ongoing effects on their future health, welfare, and proper development. In this paper we draw on evolutionary theory to improve our understanding of the processes of developmental programming, particularly Predictive Adaptive Responses (PAR) that serve to match offspring phenotype with predicted future environmental conditions. When these predictions fail, a mismatch occurs between offspring phenotype and the environment, which can have long-lasting health and welfare effects. Examples (...) include metabolic diseases resulting from maternal nutrition and behavioral changes from maternal stress. An understanding of these processes and their evolutionary origins will help in identifying and providing appropriate developmental conditions to optimize offspring welfare. This serves as an example of the benefits of using evolutionary thinking within veterinary science and we suggest that in the same way that evolutionary medicine has helped our understanding of human health, the implementation of evolutionary veterinary science (EvoVetSci) could be a useful way forward for research in animal health and welfare. (shrink)

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

Given an equal sex ratio at conception, the excess of human males at birth can only be explained by greater loss of females during pregnancy. It is proposed that the bias against females during human development is the result of a greater degree of genetic and metabolic “differentness” between female embryos and maternal tissues than for similarly aged males, and that successful implantation and placentation represents a threshold dichotomy, where the acceptance threshold shifts depending on maternal condition, especially (...) class='Hi'>stress. Right and left ovaries are not equal, and neither are the eggs and follicular fluid that they produce, and it is further hypothesized that during times of stress, the implantation threshold is shifted sufficiently to favor survival of females, most likely those originating from the right ovary, and that this, rather than simply a greater loss of males, explains at least some of the variability in the human sex ratio at birth. (shrink)

Dormancy or hibernation is a non‐proliferative state of cells with low metabolic activity and gene expression. Dormant cells sequester ribosomes in a translationally inactive state, called dormant/hibernating ribosomes. These dormant ribosomes are important for the preservation of ribosomes and translation shut‐off. While recent studies attempted to elucidate their modes of formation, the regulation and roles of the diverse dormant ribosomal populations are still largely understudied. The mechanistic details of the formation of dormant ribosomes in stress and especially their (...) disassembly during recovery remain elusive. In this review, we discuss the roles of dormant ribosomes and their potential regulatory mechanisms. Furthermore, we highlight the paradigms that need to be answered in the field of ribosomal dormancy. (shrink)

Adversities in pregnancy, including poor diet and stress, are associated with increased risk of developing both metabolic and mental health disorders later in life, a phenomenon described as fetal programming or developmental origins of disease. Predominant hypotheses proposed to explain this relationship suggest that the adversity imposes direct changes to the developing fetus which are maintained after birth resulting in an increased susceptibility to ill health. However, during pregnancy the mother, the developing fetus, and the placenta are all (...) exposed to the adversity. The same adversities linked to altered offspring outcome can also result in suboptimal maternal care, which is considered an independent adverse exposure for the offspring. Recent key experiments in mice reveal the potential of prenatal adversity to drive alterations in maternal care through abnormal maternal–pup interactions and via alterations in placental signaling. Together, these data highlight the critical importance of viewing fetal programming holistically paying attention to the intimate, bidirectional, and reiterative relationship between mothers and their offspring. (shrink)

This article argues for a shift in evolutionary metaphor-from fitness and the elimination of the less fit to fragility and passage through fragile periods of change. Childhood, for example, can be viewed as state of protected weakness, allowing time for more neural development, learning, and play. Similarly, evolutionary change can be released precisely when competitive pressure is relaxed. The fragility of evolution in time extends to several biological domains. The genetic system exhibits a surprising fluidity, whether from mobile genetic elements (...) or hypermutation due to stress. Through gene duplication, organisms build up redundancy, which can more readily diverge into novelty. With endo-symbiosis one organism becomes incorporated into another, merging genomes, membranes, and metabolisms. As a result novel structures and genetic restructuring occur, making for profound evolutionary change. In a sexual life cycle, gametes within a species group fuse and amplify subtle variation. Hybridization, or unions between atypical sexual partners, can cause instant speciation and an instability that leads to more evolution. With development organisms go through rapid morphological change and sensitive transition phases. Importantly, dissociation of developmental modules in both temporal and spatial ways allow for evolutionary novelty to emerge. Several lines of evidence lead to the hypothesis that the organism's inner matrix can respond to stresses and help shape a fluid genome. In a second article, three more biological domains will be examined, in which organisms and environment more obviously interpenetrate: the remarkably plastic neural/behavioral system, novel synergisms between organisms, and the multiple, complex dynamics of ecosystems-all of which help to generate life's outstanding diversity. Last, the protection of fragile human populations will be discussed. (shrink)

Genetic analysis of Drosophil has provided evidence in support of two proposed evolutionary genetic mechanisms of aging: mutation accumulation and antagonistic pleiotropy. Both mechanisms result from the lack of natural selection acting on old organisms. Analyses of large numbers of flies have revealed that mortality rates do not continue to rise with age as previously thought, but plateau at advanced ages. This phenomenon has implications both for models and for definitions of aging, and may be explained by the evolutionary theories. (...) The physiological processes and genes most relevant to aging are being identified using Drosophila lines selected in the laboratory for postponed senescence. Oxidative stress and insufficient metabolic reserves/capacity may be particularly important factors in limiting the fruitfly lifespan. Genes which exhibit aging‐related changes in expression are now being identified. Transgenic flies are being used to analyze the mechanisms of such aging‐related gene expression, and to test the effects of specific genes on aging and aging‐related deterioration. (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)

Variations in life history define key comparative and evolutionary biological questions, important for understanding the mechanisms of mammalian evolutionary divergence, developmental adaptability and plasticity. In this regard, the differences among predominantly altricial and precocial species represent a particularly significant, if still poorly understood and contested case. Here, it will be shown how the classical analysis of such ontogenetic variations, going back to the semantic biology of A. Portmann, can be expanded and synthesized with comparative physiological approaches, based on the negentropic (...) theory of ontogeny by I. A. Arshavsky and his school. In this little received but pioneering tradition, extensive comparative and experimental investigations were carried out on the role of musculoskeletal systems and stressors in driving life history variations, particularly in the altricial-precocial spectrum. As shown by Arshavsky and co-workers, by focusing on general allometric regularities, the approximations based on the classical energy rules of surface and mass offer valuable benchmarks, but also predictions that are frequently violated by the variability of physiological and metabolic scaling relationships among altricials and precocials, and thus, a complex and historical approach is needed to describe their local physiological mechanisms and systemic regularities. This paper shows how Arshavsky’s findings and framework can play an integrative role in this context, potentially helping to bridge the mainly descriptive approach of semantic morphology, as developed by Portmann’s school, with the more functional explanations predominating current ecology and life history theory. These problems can be important for biosemiotics by highlighting the contingent, activity-dependent, and surplus anabolic stress mechanisms underlying diversification in eutherian developmental systems and possibly, the epigenetic evolution of pace-of-life syndromes. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy, Psychiatry, & Psychology 10.1 (2003) 53-55 [Access article in PDF] A Pragmatic Consideration of the Relation between Depression and Melancholia David H. Brendel THE MELANCHOLIA OF THE PAST and the major depression of the present are extraordinarily complex notions that represent different things to different people. With her compelling article "Is This Dame Melancholy? Equating Today's Depression and Past Melancholia," Jennifer Radden makes an important contribution to the (...) debate on whether these concepts are identical, overlapping, or distinct. Exploring both conditions from descriptive and causal points of view, Radden appropriately concludes that fully equating the two of them would constitute a "troubling oversimplification." Her line of reasoning runs as follows. Because past descriptions of melancholia and current descriptions of major depression are marked by dissimilarities (such as the genius and creativity associated with the former and the self-loathing and emphasis on loss associated with the latter), only an underlying causal base common to both conditions would justify our equating them. But the cause (or causes) of melancholia and depression remain mysterious. Thus, although Radden acknowledges that a causal explanation might yield substantial benefits ("research possibilities, further hypotheses, and even hope of prevention, or cure"), she suggests that we remain in a descriptive mode when comparing the two conditions and conclude that they are not one and the same.Radden's argument that past melancholia and contemporary depression are descriptively distinct is convincing and, I think, indisputable. But I would like to challenge and expand upon some of her ideas about considerations of causality and about the role of pragmatic reasoning in working out the relation between melancholia and depression. First of all, although Radden is correct that the cause of many (or perhaps most) depressive states is unknown, she underrates the extent of the empirical knowledge that we have acquired about the causation of depression and, in so doing, undervalues the relevance of causal reasoning to making the melancholia/depression distinction. Recent empirical research has revealed that major depressive episodes can result from brain lesions such as left-sided strokes or metabolic disorders such as hypothyroidism (Yudofsky and Hales 2002). Psychosocial research, moreover, has suggested that stressful life events also can be understood as causes of depression (Kendler, [End Page 53] Karkowski, and Prescott 1999). These findings provide some hope that the identification of causes of various clinical states is a real possibility. Identification of such causes, I believe, could empower us to make some plausible claims about the similarities or differences between past melancholia and current depression. A melancholic individual like van Gogh, for example, had a different illness than a contemporary stroke patient with major depression in a present-day hospital, not only on the basis of descriptive distinctions between their conditions, but also on the basis of the causes of their respective states. Although of course we cannot know the cause of van Gogh's melancholia, we can reasonably assume that it was not the result of a left-sided stroke due to the absence in his case of other clinical deficits that usually result from such a stroke (such as language and motor deficits). Plausible assertions about the causes of melancholic and depressive states would add to the robustness of any claims regarding the distinctness of the conditions.Conversely, careful consideration of the etiology of various clinical presentations might prompt us to hypothesize a shared pathophysiology and thereby lead us to believe that they are essentially identical conditions. It is difficult or impossible to discover a cause of melancholia in individuals who lived in past eras. But we might achieve our goal by comparing well-defined major depression to various forms of what Radden calls "masked depression," such as those seen in cross-cultural settings, where the subjective symptoms of sad mood are absent but numerous somatic signs of depression are observed. If it turned out that major depression and masked depression had the same cause, then differences in their clinical phenomenology would become merely surface differences that belie a shared etiological process. How might one discover the existence of such a process... (shrink)

Alzheimer’s disease is an example of age-related dementia, and there are still no known preventive or curative measures for this disease. Obesity and associated metabolic changes are widely accepted as risk factors of age-related cognitive decline. Insulin is the prime mediator of metabolic homeostasis, which is impaired in obesity, and this impairment potentiates amyloid-β accumulation and the formation of neurofibrillary tangles. Obesity is also linked with functional and morphological alterations in brain mitochondria leading to brain insulin resistance and (...) memory deficits associated with AD. Also, increased peripheral inflammation and oxidative stress due to obesity are the main drivers that increase an individual’s susceptibility to cognitive deficits, thus doubling the risk of AD. This enhanced risk of AD is alarming in the context of a rapidly increasing global incidence of obesity and overweight in the general population. In this review, we summarize the risk factors that link obesity with AD and emphasize the point that the treatment and management of obesity may also provide a way to prevent AD. (shrink)

Cranial electrotherapy stimulation is a neuromodulation tool used for treating several clinical disorders, including insomnia, anxiety, and depression. More recently, a limited number of studies have examined CES for altering affect, physiology, and behavior in healthy, non-clinical samples. The physiological, neurochemical, and metabolic mechanisms underlying CES effects are currently unknown. Computational modeling suggests that electrical current administered with CES at the earlobes can reach cortical and subcortical regions at very low intensities associated with subthreshold neuromodulatory effects, and studies using (...) electroencephalography and functional magnetic resonance imaging show some effects on alpha band EEG activity, and modulation of the default mode network during CES administration. One theory suggests that CES modulates brain stem, limbic, and cortical regions and increases relative parasympathetic to sympathetic drive in the autonomic nervous system. There is no direct evidence supporting this theory, but one of its assumptions is that CES may induce its effects by stimulating afferent projections of the vagus nerve, which provides parasympathetic signals to the cardiorespiratory and digestive systems. In our critical review of studies using CES in clinical and non-clinical populations, we found severe methodological concerns, including potential conflicts of interest, risk of methodological and analytic biases, issues with sham credibility, lack of blinding, and a severe heterogeneity of CES parameters selected and employed across scientists, laboratories, institutions, and studies. These limitations make it difficult to derive consistent or compelling insights from the extant literature, tempering enthusiasm for CES and its potential to alter nervous system activity or behavior in meaningful or reliable ways. The lack of compelling evidence also motivates well-designed and relatively high-powered experiments to assess how CES might modulate the physiological, affective, and cognitive responses to stress. Establishing reliable empirical links between CES administration and human performance is critical for supporting its prospective use during occupational training, operations, or recovery, ensuring reliability and robustness of effects, characterizing if, when, and in whom such effects might arise, and ensuring that any benefits of CES outweigh the risks of adverse events. (shrink)

Cognition in living entities—and their social groupings or institutional artifacts—is necessarily as complicated as their embedding environments, which, for humans, includes a particularly rich cultural milieu. The asymptotic limit theorems of information and control theories permit construction of a new class of empirical ‘regression-like’ statistical models for cognitive developmental processes, their dynamics, and modes of dysfunction. Such models may, as have their simpler analogs, prove useful in the study and re-mediation of cognitive failure at and across the scales and levels (...) of organization that constitute and drive the phenomena of life. These new models particularly focus on the roles of sociocultural environment and stress, in a large sense, as both trigger for the failure of the regulation of bio-cognition and as ‘riverbanks’ determining the channels of pathology, with implications across life-course developmental trajectories. We examine the effects of an embedding cultural milieu and its socioeconomic implementations using the ‘lenses’ of metabolic optimization, control system theory, and an extension of symmetry-breaking appropriate to information systems. A central implication is that most, if not all, human developmental disorders are fundamentally culture-bound syndromes. This has deep implications for both individual treatment and public health policy. (shrink)

Microbial systems biology has made enormous advances in relating microbial physiology to the underlying biochemistry and molecular biology. By meticulously studying model microorganisms, in particular Escherichia coli and Saccharomyces cerevisiae, increasingly comprehensive computational models predict metabolic fluxes, protein expression, and growth. The modeling rationale is that cells are constrained by a limited pool of resources that they allocate optimally to maximize fitness. As a consequence, the expression of particular proteins is at the expense of others, causing trade‐offs between cellular (...) objectives such as instantaneous growth, stress tolerance, and capacity to adapt to new environments. While current computational models are remarkably predictive for E. coli and S. cerevisiae when grown in laboratory environments, this may not hold for other growth conditions and other microorganisms. In this contribution, we therefore discuss the relationship between the instantaneous growth rate, limited resources, and long‐term fitness. We discuss uses and limitations of current computational models, in particular for rapidly changing and adverse environments, and propose to classify microbial growth strategies based on Grimes's CSR framework. (shrink)

Flavin‐containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo‐2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo‐2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S‐adenosyl‐methionine (SAM) to S‐adenosyl‐homocysteine (SAH), consequently diminishing methylation capacity. Here we (...) discuss how FMO‐2‐mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo‐2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan. (shrink)

To enable microbial colonisation of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Safety recognition, paradoxically, is mediated by the same environmental sensors that are involved in signalling danger. Indeed, in addition to their well established role in inducing inflammation in response to stress signals, pattern recognition receptors (PRRs) and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated (...) molecular patterns", markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical role of immune receptors and other environmental sensors define the microbiota signature of the individual. (shrink)