Many inherited metabolic diseases may lead to varying degrees of brain damage and thus also to intellectual disability. Bone marrow transplantation (BMT) has been used for over two decades as a form of secondary prevention to stop or reverse the progress of the disease process in some of these conditions. At the population level the impact of BMT on the prevalence of intellectual disability is minute, but at the individual level its impact on the prognosis of the disease (...) and the well-being of the patient can be substantial. The dark side of BMT use is the burden of side effects, complications and transplantation-related mortality in less successful cases. The ethical issues involved in this therapy are discussed in this review. (shrink)

Whipple disease is a rare, infectious, disease first described from a single case by Whipple in 1907. As well as characterising the clinical and pathological features of the condition, Whipple made two suggestions regarding its aetiology. These were either than the disease was caused by an infectious agent, or that it was of metabolic origin. As the disease is now thought to be caused by infection with the bacterium Tropheryma whipplei, historical reviews of the history of the disease typically (...) mention only the first of these suggestions. In this paper, we therefore revisit Whipple’s other theory. We argue that a diverse and often successful research programme was developed around this mechanism of disease causation which gave rise to many useful findings on the condition. In the later parts of this article, we then turn to discuss the surprising neglect of this period of Whipple disease research in the current literature, and conclude by offering a brief reconstruction of this early history suitable for use in a technical context. (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)

Medical practice is ideally based on robust, relevant research. However, the lack of disease-modifying treatments for Alzheimer’s disease has motivated “innovative practice” to improve patients’ well-being despite insufficient evidence for the regular use of such interventions in health systems treating millions of patients. Innovative or new non-validated practice poses at least three distinct ethical questions: first, about the responsible application of new non-validated practice to individual patients ; second, about the way in which data from new non-validated practice are communicated (...) via the scientific and lay press ; and third, about the prospect of making new non-validated interventions widely available before more definitive testing. We argue that the authors of metabolic enhancement protocols for Alzheimer’s disease have overstated the evidence in favor of these interventions within the scientific and lay press, failing to communicate weaknesses in their data and uncertainty about their conclusions. Such unmeasured language may create false hope, cause financial harm, undermine informed consent, and frustrate the production of generalizable knowledge necessary to face the societal problems posed by this devastating disease. We therefore offer more stringent guidelines for responsible innovation in the treatment of Alzheimer’s disease. (shrink)

The reprogramming of metabolism has been identified as one of the hallmarks of cancer. It is becoming more and more frequent to connect other diseases with metabolic reprogramming. This article aims to argue that metabolic reprogramming is not driven by disease but instead is the main hallmark of metabolism, based on its dynamic behavior that allows it to continuously adapt to changes in the internal and external conditions.

The definition of metabolic syndrome has been, and still is, extremely controversial. My purpose is not to give a solution to the associated debate but to argue that the controversy is at least partially due to the different ‘causal content’ of the various definitions: their theoretical validity and practical utility can be evaluated by reconstructing or making explicit the underlying causal structure. I will therefore propose to distinguish the alternative definitions according to the kinds of causal content they carry: (...) definitions grounded on associations, definitions presupposing a causal model built upon statistical associations, and definitions grounded on underlying mechanisms. I suggest that analysing definitions according to their causal content can be helpful in evaluating alternative definitions of some diseases. I want to show how the controversy over MetS suggests a distinction among three kinds of definitions based on how explicitly they characterise the syndrome in causal terms, and on the type of causality involved. I will call ‘type 1 definitions’ those definitions that are purely associative; ‘type 2 definitions’ the definitions based on statistical associations, plus generic medical and causal knowledge; and ‘type 3 definitions’ the definitions based on mechanisms. These kinds of definitions, although different, can be related to each other. A definition with more specific causal content may be useful in the evaluation of definitions characterised by a lower degree of causal specificity. Moreover, the identification of the type of causality involved is of help to constitute a good criterion for choosing among different definitions of a pathological entity. In section I introduce the controversy about MetS, in section I propose some remarks about medical definitions and their ‘causal import’, and in section I suggest that the different attitudes towards the definition of MetS are relevant to evaluate their explicative power. (shrink)

Lymphangiogenesis is an important developmental process that is critical to regulation of fluid homeostasis, immune surveillance and response as well as pathogenesis of a number of diseases, among them cancer, inflammation, and heart failure. Specification, formation, and maturation of lymphatic blood vessels involves an interplay between a series of events orchestrated by various transcription factors that determine expression of key genes involved in lymphangiogenesis. These are traditionally thought to be under control of several key growth factors including vascular growth (...) factor‐C (VEGF‐C) and fibroblast growth factors (FGFs). Recent insights into VEGF and FGF signaling point to their role in control of endothelial metabolic processes such as glycolysis and fatty acid oxidation that, in turn, play a major role in regulation of lymphangiogenesis. These advances have significantly increased our understanding of lymphatic biology and opened new therapeutic vistas. Here we review our current understanding of metabolic controls in the lymphatic vasculature. (shrink)

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a breast cancer (...) predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

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

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)

This perspective paper aims at discussing theoretical principles that could explain how emotion regulation and physical diseases mutually influence each other in the context of borderline personality disorder (BPD). Furthermore, this paper discusses the clinical implications of the functional relationships between emotion regulation, BPD and medical conditions considering dialectical behavior therapy (DBT) as a well-validated therapeutic intervention, which encompasses these issues. The inflexible use of maladaptive emotion regulation strategies (e.g., suppression, experiential avoidance, and rumination) might directly increase the probability (...) of developing physical diseases through a physiological pathway, or indirectly through a behavioral pathway. Some metabolic and chronic medical conditions could significantly impact emotional functioning through biological alterations involved in emotion regulation. Several empirical studies have shown high co-occurrence rates between BPD and several chronic physical diseases, especially ones linked to emotion-based maladaptive behaviors. DBT addresses physical diseases reported by individuals with BPD reducing problematic behaviors functionally associated to emotion dysregulation and identifying physical health as a goal forBuilding a Life Worth Living. (shrink)

The Liver kinase B1 with its downstream target AMP activated protein kinase (LKB1‐AMPK), and the key nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) form two signaling systems that coordinate metabolic and cellular activity with changes in the environment in order to preserve homeostasis. For example, nutritional fluctuations rapidly feed back on these signaling systems and thereby affect cell‐specific functions. Recent studies have started to reveal important roles of these strategic metabolic regulators in Schwann cells for the (...) trophic support and myelination of axons. Because aberrant intermediate metabolism along with mitochondrial dysfunction in Schwann cells is mechanistically linked to nerve abnormalities found in acquired and inherited peripheral neuropathies, manipulation of the LKB1‐AMPK, and mTORC1 signaling hubs may be a worthwhile therapeutic target to mitigate nerve damage in disease. Here, recent advances in our understanding of LKB1‐AMPK and mTORC1 functions in Schwann cells are covered, and future research areas for this key metabolic signaling network are proposed. (shrink)

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

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)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than (...) T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

The heart has a high‐metabolic rate, and its “around‐the‐clock” vital role to sustain life sets it apart in a regenerative setting from other organs and appendages. The landscape of vertebrate species known to perform intrinsic heart regeneration is strongly biased toward ectotherms—for example, fish, salamanders, and embryonic/neonatal ectothermic mammals. It is hypothesized that intrinsic heart regeneration is exclusively limited to the low‐metabolic hearts of ectotherms. The biomedical field of regenerative medicine seeks to devise biologically inspired regenerative therapies to (...) diseased human hearts. Falsification of the ectothermy dependency for heart regeneration hypothesis may be a crucial prerequisite to meaningfully seek inspiration in established ectothermic regenerative animal models. Otherwise, engineering approaches to construct artificial heart components may constitute a more viable path toward regenerative therapies. A more strict definition of regenerative phenomena is generated and several testable sub‐hypotheses and experimental avenues are put forward to elucidate the link between heart regeneration and metabolism. Also see the video abstract here https://youtu.be/fZcanaOT5z8. (shrink)

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

Inflammatory immune cells, when activated, display much the same metabolic profile as a glycolytic tumor cell. This involves a shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis, a phenomenon known as the Warburg effect. The result of this change in macrophages is to rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins. In addition, a rise in certain tricarboxylic acid cycle intermediates occurs notably in citrate for lipid biosynthesis, and succinate, which (...) activates the transcription factor Hypoxia‐inducible factor. In this review we take a look at the emerging evidence for a role for the Warburg effect in the immune and inflammatory responses. The reprogramming of metabolic pathways in macrophages, dendritic cells, and T cells could have relevance in the pathogenesis of inflammatory and metabolic diseases and might provide novel therapeutic strategies. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Obesity as Disease:Definition by DesperationJeremy ShermakI hated removing my shirt. Each visit to my doctor’s office, following a blood pressure and temperature check, the nurse would instruct me to take off my shirt so the doctor could examine me further. She would then leave the room. I remained perched atop the exam table, now half exposed, and a mirror on the wall would not leave me alone. In the (...) reflection, I saw my oversized breasts and “fat roll” oozing out from my pants, hiding my belt. I tried to straighten my back—breathe in, no wait, breathe out—to resculpt the appearance, but it did nothing. I hated myself. Soon, a gentle knock at the door would interrupt the loathing and I’d shake hands with my doctor.I have been obese for the majority of my life—from childhood until I turned 34, when shortly thereafter, I had gastric bypass surgery. Since that time, I have lost 155 pounds and now write this at a comfortable, healthy 180 pounds. That said, my mind remains “obese”. My thinking remains shrouded deep within the obese personality that I embodied for all of those years. I still automatically walk to the big–and–tall section of clothing stores; I don’t recognize the 34–waist pants when they come [End Page 114] out of the dryer; I’m not used to seeing my ribs; and I’m still terrified of that exam room mirror.Upon hearing the news that the American Medical Association (AMA) now classifies obesity as a disease, my initial reaction was that of relief. My recent success was due in large part to the discovery and treatment of hindering endocrinological issues. My history—like repeatedly slamming head–long into a brick wall—suggests that these medically verified roadblocks have existed for some time. Despite my efforts, I didn’t stand a chance.If anyone were a “poster child” for obesity as a disease, it would be me. The lifelong sparring with my weight had its ups and downs; I worked very hard to maintain or lose weight with mixed results. I lost 85 pounds my freshman year of college by running and fervently watching my portions. I kept that weight off for a good five years before the summer of 2003, when I started gaining weight very quickly. I gained 25 pounds in each month of June and July that year, despite maintaining my usual eating habits and running schedule. I soon lost faith. I felt as though I was up against forces that I could not control and I began to forget about losing weight. I didn’t binge, but I didn’t eat well. By 2008, my weight had reached 375 pounds—an all–time personal high.Following a bad relationship and seeking rejuvenation, I embarked on a diet that summer like I’ve never tried before. I cooked everything naturally—from regular dishes like stuffed peppers all the way to condiments like ketchup. It was a militant effort on my part. I lost 50 pounds that summer and felt that I was well on my way back to the body that once felt so comfortable. It was at that point where I hit a wall. I could not get past 321. I can still see that number staring back at me on the scale. It was frustrating. I felt I had done all I could. That’s when I visited a doctor who ran some tests that revealed problems with my hormones and metabolic systems.As it turned out, I had a tumor on my pituitary gland. This may have been the issue all along. That led to low testosterone, which had a really negative impact on my weight loss efforts. After thorough consideration, I decided to have gastric bypass surgery to “reset” my hormones and get a “boost” in my weight loss efforts. It worked.In my particular circumstance, I could view obesity as a disease because its causes, for the most part, were not a result of conscious lifestyle choices. I had no control over the pituitary tumor. However, I know that I could have done more to limit my... (shrink)

I discuss the two different responses from the angiosperms to the specific molecular mechanisms of the tumor-inducing agent contained in the bacteriumAgrobacterium tumefaciens. This is done in terms of the collective variables for expressing genetic response to a continuously varying supply of energy from metabolic pathways. We are led to the conjecture that the expression of the recessive oncogenes may not be restricted to humans (retinoblastoma and osteosarcoma), but may also occur in plants (crown gall), and be expressed through (...) a heat-shock. (shrink)

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (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)

IntroductionCognitive impairment is a highly prevalent non-motor feature of Parkinson’s disease. A better understanding of the underlying pathophysiology may help in identifying therapeutic targets to prevent or treat dementia. This study sought to identify metabolic alterations in the prefrontal cortex, a key region for cognitive functioning that has been implicated in cognitive dysfunction in PD.MethodsProton Magnetic Resonance Spectroscopy was used to investigate metabolic changes in the PFC of a cohort of cognitively normal individuals without PD, as well as (...) PD participants with either normal cognition, mild cognitive impairment, or dementia. Ratios to Creatine resonance were obtained for glutamate, glutamine and glutamate combined, N-acetylaspartate, myoinositol, and total choline, and correlated with cognitive scores across multiple domains administered to the PD participants only.ResultsWhen individuals retain cognitive capabilities, the presence of Parkinson’s disease does not create metabolic disturbances in the PFC. However, when cognitive symptoms are present, PFC Glu/Cre ratios decrease with significant differences between the PD-NC and PPD groups. In addition, Glu/Cre ratios and memory scores were marginally associated, but not after Bonferroni correction.ConclusionThese preliminary findings indicate that fluctuations in prefrontal glutamate may constitute a biomarker for the progression of cognitive impairments in PD. We caution for larger MRS investigations of carefully defined PD groups. (shrink)

A paradigm shift in the human chronotoxicity of xenobiotics would study two‐sided desynchronized phenomena of interfacial interactions between cyclic or periodic environmental insults and the endogenous response and recovery profile. These systems‐based networks are under the influence of well‐synchronized biological clocks and their metabolic regulators. This perspective argues in favor of addressing the concept of synchronization in studies involving critical life windows of susceptibility, or circadian rhythms, or 24‐hour (periodic) diurnal rhythms and answering whether these disruptions in synchronization would (...) affect response and recovery or disease phenotypes associated with environmental insults, e.g., xenobiotics. Synchronization or synchrony is defined as the totality of elements that appear during the same time period within a system, including the network of interactions between the system's elements. Desynchronized interfaces during critical life windows or in time‐repeated exposure events would likely lead to initiating a cascade of adverse health effects associated with differentiated disease phenotypes. (shrink)

This book provides a detailed account of intellectual, other neuropsychological and behavioral manifestations of general pediatric diseases. The conditions discussed include the whole range of pediatric diseases - genetic syndromes, other congenital conditions, metabolic, endocrine, gastrointestinal, infectious, immunologic, toxic, trauma, and neoplastic, as well as sensory disabilities including deafness and blindness. Although the book is not intended to discuss cognitive and behavioral manifestations of conditions usually considered to be primary neurological disease, some of those, including cerebral palsy, (...) muscular dystrophy, myotonic dystrophy and epilepsy, are included.Where possible, a. (shrink)

As crucial interface organs gut and skin have much in common. Therefore it is unsurprising that several gut pathologies have skin co‐morbidities. Nevertheless, the reason for this remains ill explored, and neither mainstream gastroenterology nor dermatology research have systematically investigated the ‘gut‐skin axis'. Here, in reviewing the field, we propose several mechanistic levels on which gut and skin may interact under physiological and pathological circumstances. We focus on the gut microbiota, with its huge metabolic capacity, and the role of (...) dietary components as potential principle actors along the gut‐skin axis. We suggest that metabolites from either the diet or the microbiota are skin accessible. After defining open key questions around the nature of these metabolites, how they are sensed, and which cutaneous changes they can induce, we propose that understanding of these pathways will lead to novel therapeutic strategies based on targeting one organ to improve the health of the other. (shrink)

The contribution of inherited non‐genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre‐ and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non‐genetic contribution of the parents to offspring health. Discovering new mechanisms of (...) disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high‐throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease. (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)

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

Alterations in the gut microbiome have increasingly been implicated in driving obesity and its associated diseases, but underlying mechanisms remain poorly defined. Herein, in addition to reviewing the field, we hypothesize that a highly significant causative factor of such inflammatory disease‐associated microbiome alterations is a more aggressive microbiota that encroaches upon its host, with components having high potential to activate host pro‐inflammatory gene expression in a manner that drives metabolic disease. We further hypothesize that a range of societal (...) changes, including use of antibiotics and increasing consumption of food additives, have provoked such microbiota aggression and, consequently, may be contributing factors to the increased incidence of obesity and its associated diseases. (shrink)

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

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)

Cancer is a paradigmatic case of a complex causal process; causes of cancer operate at a variety of temporal and spatial scales, and the respects in which these causes act and interact are diverse. There are, for instance, temporal order effects, organizational effects, structural effects, and dynamic relationships between causes operating at different temporal and spatial scales. Because of this complexity, models of cancer initiation and progression often involve deliberate choices to focus on one time scale, one causal pathway, or (...) one aspect of cancer’s dynamics. As in most of biology, modeling cancer involves simplification and idealization. At the same time, theoretical perspectives inform the construction of these models. Such perspectives might involve viewing cancer ‘as’ a genetic disease, metabolic disease, stem cell disease, an infectious disease, or a disease of tissue disorganization. This paper will argue that purportedly competing theoretical views of cancer are not at odds, but can be viewed as mutually informative. Models are most often developed in the service of asking very specific questions, and this requires limiting our view of the phenomena to a specific temporal or spatial scale, a particular cause, or a particular outcome, dynamic, or pattern. Thus, while some models may seem at odds, often they are simply concerned with different questions, or, they are complementary and mutually informative. I hope to bring this case to bear on debates among philosophers of science over perspectivism and realism, as well pluralism about the aims and scope of scientific theory. (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)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for (...) calcium dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

Newborn screening consists of taking a few drops of blood from a baby's heel in the first week of life and testing it for a list of disorders. In the United States and most countries in Europe, newborn screening programs began in the 1960s and 1970s with screening for phenylketonuria (PKU), a rare metabolic disease that causes severe and irreversible mental retardation unless treated before problems arise. As knowledge about rare diseases expanded and new screening technologies were introduced—such (...) as the tandem mass spectrometer and high‐performance liquid chromatography—the same blood sample could be used to test for a whole list of disorders. In general, screening programs in most countries have tended to expand, but in different countries they have expanded in different ways. Regulation also varies. In some states, screening is mandatory, whereas in others—Wyoming and Maryland—parents are asked for their informed consent. Germany and France have adopted an explicit informed consent procedure, whereas other European countries have a more informal “opt‐out” procedure that does not require signing an informed consent form. Whether newborn screening requires informed consent is an ongoing issue in bioethics. In this article, we will focus on the tension between informed consent and the problem of compliance in newborn screening. Asking for informed consent—allowing parents to opt out—is often thought to pose a threat to compliance. Building on the work of Onora O'Neill on informed consent and trust, however, as well as on work she coauthored with Neil Manson, we will argue that informed consent procedures may actually help maintain trust in newborn screening and may therefore support compliance. (shrink)

This article reformulates Stephan Helmreich´s the ¨microbiomisation of race¨ as the historiality of otherness in the foundations of human microbiome science. Through the lens of my ethnographic fieldwork of a transnational community of microbiome scientists that conducted a landmark human microbiome research on indigenous microbes and its affiliated and first personalised microbiome initiative, the American Gut Project, I follow and trace the key actors, experimental systems and onto-epistemic claims in the emergence of human microbiome science a decade ago. In doing (...) so, I show the links between the reinscription of race, comparative research on the microbial genetic variation of human populations and the remining of bioprospected data for personalised medicine. In these unpredictable research movements, the microbiome of non-Western peoples and territories is much more than a side project or a specific approach within the field: it constitutes the nucleus of its experimental system, opening towards subsequent and cumulative research processes and knowledge production in human microbiome science. The article demonstrates that while human microbiome science is articulated upon the microbial ‘makeup’ of non-wester(nised) communities, societies, and locales, its results and therapeutics are only applicable to medical conditions affecting rich nations (i.e., inflammatory, autoimmune, and metabolic diseases). My reformulation of ¨microbiomisation of race¨ as the condition of possibility of human microbiome science reveals that its individual dimension is sustained by microbial DNA data from human populations through bioprospecting practices and gains meaning through personalised medicine initiatives, informal online networks of pseudoscientific and commodified microbial-related evidence. (shrink)

The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on ‘what regulates cell size’, the question ‘why cell size needs to be maintained’ has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative cell surface area impose biophysical limitations on cells, which (...) can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity. Cell size is intimately connected to metabolism and growth rate, which are influenced by mitochondrial activity and biophysical constraints. We discuss that cellular fitness is often cell-size dependent. While the current evidence relies largely on proliferating cells, this connection from cell size to fitness may also help explain metabolic diseases. (shrink)

This article addresses the ethics of betel nut use in Taiwan. It first presents scientific facts about the betel quid and its consumption and the generally accepted negative health consequences associated with its use: oral and esophageal cancer, coronary artery disease, metabolic diseases, and adverse effects in pregnancy. It then analyzes the cultural background and economic factors contributing to its popularity in Asia. The governmental and institutional attempts to curb betel nut cultivation, distribution, and sales are also described. (...) Finally, the article analyzes the bioethical implications of this often-ignored subject from the perspectives of human dignity, the good of health, vulnerable groups, cultural diversity, informed consent, and ethical blind spots. (shrink)

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new (...) substrates that are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed. (shrink)

There is much discussion in the media and some of the scientific literature of how many of the conclusions from scientific research should be doubted. These critiques often focus on studies – typically in non‐experimental spheres of biomedical and social sciences – that search large datasets for novel correlations, with a risk that inappropriate statistical evaluations might yield dubious conclusions. By contrast, results from experimental biological research can often be interpreted largely without statistical analysis. Typically: novel observation(s) are reported, and (...) an explanatory hypothesis is offered; multiple labs undertake experiments to test the hypothesis; interpretation of the results may refute the hypothesis, support it or provoke its modification; the test/revise sequence is reiterated many times; and the field moves forward. I illustrate this experimental/non‐experimental dichotomy by examining the contrasting recent histories of: (a) our remarkable and growing understanding of how several inositol‐containing phospholipids contribute to the lives of eukaryote cells; and (b) the difficulty of achieving any agreed mechanistic understanding of why consuming dietary supplements of inositol is clinically beneficial in some metabolic diseases. (shrink)

Coordinated daily rhythms are evident in most aspects of our physiology, driven by internal timing systems known as circadian clocks. Our understanding of how biological clocks are built and function has grown exponentially over the past 20 years. With this has come an appreciation that disruption of the clock contributes to the pathophysiology of numerous diseases, from metabolic disease to neurological disorders to cancer. However, it remains to be determined whether it is the disruption of our rhythmic physiology (...) per se (loss of timing itself), or altered functioning of individual clock components that drive pathology. Here, we review the importance of circadian rhythms in terms of how we (and other organisms) relate to the external environment, but also in relation to how internal physiological processes are coordinated and synchronized. These issues are of increasing importance as many aspects of modern life put us in conflict with our internal clockwork. (shrink)

Diabetes is one of the most common metabolic diseases that cause high blood sugar. Early diagnosis of such a condition is challenging due to its complex interdependence on various factors. There is a need to develop critical decision support systems to assist medical practitioners in the diagnosis process. This research proposes developing a predictive model that can achieve a high classification accuracy of type 2 diabetes. The study consisted of two fundamental parts. Firstly, the study investigated handling missing (...) data adopting data imputation, namely, median value imputation, K-nearest neighbor imputation, and iterative imputation. Consequently, the study validated the implications of these imputations using various classification algorithms, i.e., linear, tree-based, and ensemble algorithms, to see how each method affected classification accuracy. Secondly, Artificial Neural Network was employed to model the best performing imputed data, balanced with SMOTETomek ensuring each class is represented fairly. This approach provided the best accuracy of 98% on the test data, outperforming accuracies achieved in prior studies using the same dataset. The dataset used in this study is concerned with gender and population. As a prospect, the study recommends adopting a larger population sample without geographic boundaries. Additionally, as the developed Artificial Neural Network model did not undergo any specific hyperparameter tuning, it would be interesting to explore tuning on top of normalized data to optimize accuracy further. (shrink)

Recent research shows that a faulty or sub‐optimally operating metabolic network can often be rescued by the targeted removal of enzyme‐coding genes – the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene‐deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I approach these questions from (...) the perspective of compensatory perturbations on networks. Relations are drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogs in physical and other biological networks. I specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases. Editor's suggested further reading in BioEssaysThe evolutionary context of robust and redundant cell biological mechanisms AbstractReprogramming cell fates: reconciling rarity with robustness Abstract. (shrink)

Metabolic Syndrome is a cluster of risk factors (including obesity, hypertension and insulin resistance), which is associated with late‐onset diabetes and coronary heart disease. Elevated levels of the protease inhibitor PAI‐1 are well‐known molecular markers of the Metabolic Syndrome. Here, however, we present a hypothesis that PAI‐1 acts as a causative factor in the development of Metabolic Syndrome and its clinical sequelae. We propose that PAI‐1 inhibits the activity of members of the proprotein convertase (PC) class of (...) serine proteases and that this underlies, at a molecular level, many of the other features of the Metabolic Syndrome cluster. BioEssays 28: 629–641, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The metabolic defect which results in the accumulation of cystine within tissues of children with the recessively inherited disease cystinosis has baffled investigators for almost half a century. Investigations by numerous laboratories have finally culminated in the delineation of the basic defect in this unusual disorder.

Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have (...) been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies. (shrink)

The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is not (...) clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The coronavirus disease-2019 pandemic impacted the lives of children and adolescents, leading to many changes in their routines, especially in education. Face-to-face physical education classes during COVID-19 were affected in organization, possibly conditioning students' participation, motivation, and learning. In the extreme conditions of the coronavirus, it may be assumed that daily physical activity became much less than before, partly because students are learning outside the school environment and PE lessons taught using remote forms do not fulfill their purpose. The aim (...) of the study was to assess the pupil's perception of inclusion in school education during the remote learning caused by the COVID-19 pandemic and to compare the results with the control group. Moreover, the physical activity of respondents during social isolation due to the coronavirus was examined. The sample consisted of 111 pupils of both genders, aged 14–21 years. The Perceptions of Inclusion Questionnaire was used to measure the perception of inclusion in school education. The structure of the participants' physical activity was examined using the International Physical Activity Questionnaire-Long Form for adolescents. It was observed that the pupils' gender did not differentiate their perception of inclusion in school education. It was proved that respondents participating in research during the COVID-19 pandemic obtained statistically significantly lower results in the case of “emotional wellbeing in school” but a higher mean was observed in relation to “social relationships with other pupils” than the control group. Girls achieved a higher mean in the case of walk Metabolic Equivalent of Task than boys. In addition, it was observed that the recommendation of vigorous physical activities was achieved by 37.78% of boys and 34.85% of girls. In turn, 69.70% of female pupils and 77.78% of male respondents met the recommendations for medium physical activities. It was also noted that 87.88% of girls and 86.67% of boys participating in the research achieved the recommendation for total physical activities. The analysis showed negligible and low positive correlations between examined variables. (shrink)