Showing papers in "Frontiers in Physiology in 2012"
TL;DR: The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia.
Abstract: Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the aetiology of sarcopenia. Cross-sectional studies comparing young (18-45yrs) and old (>65yrs) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75yrs, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-0.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75yrs, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2 – 5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.
926 citations
TL;DR: It is concluded that SSNA, comprising cutaneous vasoconstrictor and sudomotor activity, increases with both positively charged and negatively charged emotional images.
Abstract: The sympathetic innervation of the skin primarily subserves thermoregulation, but the system has also been commandeered as a means of expressing emotion. While it is known that the level of skin sympathetic nerve activity (SSNA) is affected by anxiety, the majority of emotional studies have utilized the galvanic skin response as a means of inferring increases in SSNA. The purpose of the present study was to characterize the changes in SSNA when showing subjects neutral or emotionally-charged images from the International Affective Picture System. Skin sympathetic nerve activity was recorded via tungsten microelectrodes inserted into cutaneous fascicles of the common peroneal nerve in ten subjects. Neutral images, positively-charged images (erotica) or negatively-charged images (mutilation) were presented in blocks of fifteen images of a specific type, each block lasting two minutes. Images of erotica or mutilation were presented in a quasi-random fashion, each block following a block of neutral images. Both images of erotica or images of mutilation caused significant increases in SSNA, but the increases in SSNA were greater for mutilation. The increases in SSNA were often coupled with sweat release and cutaneous vasoconstriction, however, these markers were not always consistent with the SSNA increases. We conclude that SSNA, comprising cutaneous vasoconstrictor and sudomotor activity, increases with both positively-charged and negatively-charged emotional images. Measurement of SSNA provides a more comprehensive assessment of sympathetic outflow to the skin than does the use of sweat release alone as a marker of emotional processing.
744 citations
TL;DR: The main aim of the tutorial is to give the reader a simple self-sustained guide to the implementation of MFDFA and interpretation of the resulting multifractal spectra.
Abstract: Physiological and behavioural phenomena are often complex, characterized by variations in time series. Variations in time series reflect how these phenomena organize into coherent structures by interactions that span multiple scales in both time and space. The present tutorial is an introduction to multifractal analyses that can identify these scale invariant interactions within time series by its multifractal spectrum. The multifractal spectrum can be estimated directly from scale-dependent measurements or from its q-order statistics. The tutorial emphasizes the most common scale-dependent measurements defined by the wavelet transforms and the detrended fluctuation analyses. The tutorial also emphasizes common features of all multifractal analyses, like the choice of linear regression method, scaling range and elimination of spurious singularities, which are important for a robust estimation of the multifractal spectrum. The tutorial ends with two brief examples where multifractal analyses are employed to time series from multifractal models and the complex phenomena of cognitive performance. References to available software for multifractal analyses are included at the end of the tutorial. The main aim of the tutorial is to give the reader an introduction to multifractal analyses without the extensive technicalities typically provided in mathematical journals.
693 citations
TL;DR: The method allows, for the first time, to define a theoretical framework in terms of an order and control parameter derived from fMRI data, where the dynamical regime can be interpreted as one corresponding to a system close to the critical point of a second order phase transition.
Abstract: Functional magnetic resonance imaging (fMRI) techniques have contributed significantly to our understanding of brain function. Current methods are based on the analysis of gradual and continuous changes in the brain blood oxygenated level dependent (BOLD) signal. Departing from that approach, recent work has shown that equivalent results can be obtained by inspecting only the relatively large amplitude BOLD signal peaks, suggesting that relevant information can be condensed in discrete events. This idea is further explored here to demonstrate how brain dynamics at resting state can be captured just by the timing and location of such events, i.e., in terms of a spatiotemporal point process. The method allows, for the first time, to define a theoretical framework in terms of an order and control parameter derived from fMRI data, where the dynamical regime can be interpreted as one corresponding to a system close to the critical point of a second order phase transition. The analysis demonstrates that the resting brain spends most of the time near the critical point of such transition and exhibits avalanches of activity ruled by the same dynamical and statistical properties described previously for neuronal events at smaller scales. Given the demonstrated functional relevance of the resting state brain dynamics, its representation as a discrete process might facilitate large-scale analysis of brain function both in health and disease.
671 citations
TL;DR: The two forms of inorganic arsenic, arsenate (AsV) and arsenite (AsIII), are easily taken up by the cells of the plant root Once in the cell, AsV can be readily converted to AsIII, the more toxic of the two forms AsV and AsIII both disrupt plant metabolism, but through distinct mechanisms as mentioned in this paper.
Abstract: The two forms of inorganic arsenic, arsenate (AsV) and arsenite (AsIII), are easily taken up by the cells of the plant root Once in the cell, AsV can be readily converted to AsIII, the more toxic of the two forms AsV and AsIII both disrupt plant metabolism, but through distinct mechanisms AsV is a chemical analog of phosphate that can disrupt at least some phosphate-dependent aspects of metabolism AsV can be translocated across cellular membranes by phosphate transport proteins, leading to imbalances in phosphate supply It can compete with phosphate during phosphorylation reactions, leading to the formation of AsV adducts that are often unstable and short-lived As an example, the formation and rapid autohydrolysis of AsV-ADP sets in place a futile cycle that uncouples photophosphorylation and oxidative phosphorylation, decreasing the ability of cells to produce ATP and carry out normal metabolism AsIII is a dithiol reactive compound that binds to and potentially inactivates enzymes containing closely spaced cysteine residues or dithiol co-factors Arsenic exposure generally induces the production of reactive oxygen species that can lead to the production of antioxidant metabolites and numerous enzymes involved in antioxidant defense Oxidative carbon metabolism, amino acid and protein relationships, and nitrogen and sulfur assimilation pathways are also impacted by As exposure Readjustment of several metabolic pathways, such as glutathione production, has been shown to lead to increased arsenic tolerance in plants Species- and cultivar-dependent variation in arsenic sensitivity and the remodeling of metabolite pools that occurs in response to As exposure gives hope that additional metabolic pathways associated with As tolerance will be identified
645 citations
TL;DR: The concept of criticality is explained and substantial objections to the criticality hypothesis raised by skeptics are reviewed, and counter points are presented in dialog form.
Abstract: Relatively recent work has reported that networks of neurons can produce avalanches of activity whose sizes follow a power law distribution. This suggests that these networks may be operating near a critical point, poised between a phase where activity rapidly dies out and a phase where activity is amplified over time. The hypothesis that the electrical activity of neural networks in the brain is critical is potentially important, as many simulations suggest that information processing functions would be optimized at the critical point. This hypothesis, however, is still controversial. Here we will explain the concept of criticality and review the substantial objections to the criticality hypothesis raised by skeptics. Points and counter points are presented in dialog form.
463 citations
TL;DR: This review provides basic principles and a broad set of references useful for the management of phenotyping practices for the study and genetic dissection of drought tolerance and, ultimately, for the release of drought-tolerant cultivars.
Abstract: Improving crops yield under water-limited conditions is the most daunting challenge faced by breeders. To this end, accurate, relevant phenotyping plays an increasingly pivotal role for the selection of drought-resilient genotypes and, more in general, for a meaningful dissection of the quantitative genetic landscape that underscores the adaptive response of crops to drought. A major and universally recognized obstacle to a more effective translation of the results produced by drought-related studies into improved cultivars is the difficulty in properly phenotyping in a high-throughput fashion in order to identify the quantitative trait loci that govern yield and related traits across different water regimes. This review provides basic principles and a broad set of references useful for the management of phenotyping practices for the study and genetic dissection of drought tolerance and, ultimately, for the release of drought-tolerant cultivars.
448 citations
TL;DR: Encouraging results indicate that MSC-MVs have similar protective and reparative properties as their cellular counterparts in tissue repair and possibly anti-cancer therapy, and represent a promising opportunity to develop novel cell-free therapy approaches that might overcome the obstacles and risks associated with the use of native or engineered stem cells.
Abstract: Mesenchymal stem cells (MSCs) are adult multipotent cells that give rise to various cell types of the mesodermal germ layer. MSCs are of great interest in the field of regenerative medicine and cancer therapy because of their unique ability to home to damaged and cancerous tissue. These cells also regulate the immune response and contribute to reparative processes in different pathological conditions, including musculoskeletal and cardiovascular diseases. The use of MSCs for tissue repair was initially based on the hypothesis that these cells home to and differentiate within the injured tissue into specialized cells. However, it now appears that only a small proportion of transplanted MSCs actually integrate and survive in host tissues. Thus, the predominant mechanism by which MSCs participate in tissue repair seems to be related to their paracrine activity. Indeed, MSCs provide the microenvironment with a multitude of trophic and survival signals including growth factors and cytokines. Recent discoveries suggest that lipid microvesicles released by MSCs may also be important in the physiological function of these cells. Over the past few years the biological relevance of micro- and nano-vesicles released by cells in intercellular communication has been established. Alongside the conventional mediators of cell secretome, these sophisticated nanovesicles transfer proteins, lipids and, most importantly, various forms of RNAs to neighboring cells, thereby mediating a variety of biological responses. The physiological role of MSC-derived vesicles (MSC-MVs) is currently not well understood. Nevertheless, encouraging results indicate that MSC-MVs have similar protective and reparative properties as their cellular counterparts in tissue repair and possibly anti-cancer therapy. Thus, MSC-MVs represent a promising opportunity to develop novel cell-free therapy approaches that might overcome the obstacles and risks associated with the use of native or engineered stem cells.
441 citations
TL;DR: The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body’s known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers are the ultimate determinants of both fatigue and athletic performance.
Abstract: An influential book written by A. Mosso in the late 19th century proposed that fatigue that “at first sight might appear an imperfection of our body, is on the contrary one of its most marvellous perfections. The fatigue increasing more rapidly than the amount of work done saves us from the injury which lesser sensibility would involve for the organism” so that “muscular fatigue also is at bottom an exhaustion of the nervous system”. It has taken more than a century to confirm Mosso’s idea that both the brain and the muscles alter their function during exercise and that fatigue is predominantly an emotion, part of a complex regulation, the goal of which is to protect the body from harm. Mosso’s ideas were supplanted in the English literature by those of A.V. Hill who believed that fatigue was the result of biochemical changes in the exercising limb muscles - “peripheral fatigue” - to which the central nervous system makes no contribution. The past decade has witnessed the growing realization that this brainless model cannot explain exercise performance. This article traces the evolution of our modern understanding of how the CNS regulates exercise specifically to insure that each exercise bout terminates whilst homeostasis is retained in all bodily systems. The brain uses the symptoms of fatigue as key regulators to insure that the exercise is completed before harm develops. These sensations of fatigue are unique to each individual and are illusionary since their generation is largely independent of the real biological state of the athlete at the time they develop. The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body’s known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers, in both training and competition, are the ultimate determinants of both fatigue and athletic performance.
388 citations
TL;DR: It is suggested here that a novel axis of research is to assess the effects of hydrogen sulfide in shaping colonic microbiome structure, and Generation of hydrogen sulphide via pathways other than dissimilatory sulfate reduction may be as, or more, important than those involving the SRB.
Abstract: Sulfur is both crucial to life and a potential threat to health. While colonic sulfur metabolism mediated by eukaryotic cells is relatively well studied, much less is known about sulfur metabolism within gastrointestinal microbes. Sulfated compounds in the colon are either of inorganic (e.g., sulfates, sulfites) or organic (e.g., dietary amino acids and host mucins) origin. The most extensively studied of the microbes involved in colonic sulfur metabolism are the sulfate-reducing bacteria (SRB), which are common colonic inhabitants. Many other microbial pathways are likely to shape colonic sulfur metabolism as well as the composition and availability of sulfated compounds, and these interactions need to be examined in more detail. Hydrogen sulfide is the sulfur derivative that has attracted the most attention in the context of colonic health, and the extent to which it is detrimental or beneficial remains in debate. Several lines of evidence point to SRB or exogenous hydrogen sulfide as potential players in the etiology of intestinal disorders, inflammatory bowel diseases (IBDs) and colorectal cancer in particular. Generation of hydrogen sulfide via pathways other than dissimilatory sulfate reduction may be as, or more, important than those involving the SRB. We suggest here that a novel axis of research is to assess the effects of hydrogen sulfide in shaping colonic microbiome structure. Clearly, in-depth characterization of the microbial pathways involved in colonic sulfur metabolism is necessary for a better understanding of its contribution to colonic disorders and development of therapeutic strategies.
381 citations
TL;DR: The role of exosomes in neurodegenerative disorders is focused on and the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases are discussed.
Abstract: Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.
TL;DR: A pedagogical explanation of the DFA algorithm and its underlying theory is provided, and the putative relevance of criticality for understanding the mechanism underlying scale-free modulation of oscillations is discussed.
Abstract: Recent years of research have shown that the complex temporal structure of ongoing oscillations is scale-free and characterized by long-range temporal correlations. Detrended fluctuation analysis (DFA) has proven particularly useful, revealing that genetic variation, normal development, or disease can lead to differences in the scale-free amplitude modulation of oscillations. Furthermore, amplitude dynamics is remarkably independent of the time-averaged oscillation power, indicating that the DFA provides unique insights into the functional organization of neuronal systems. To facilitate understanding and encourage wider use of scaling analysis of neuronal oscillations, we provide a pedagogical explanation of the DFA algorithm and its underlying theory. Practical advice on applying DFA to oscillations is supported by MATLAB scripts from the Neurophysiological Biomarker Toolbox (NBT) and links to the NBT tutorial website http://www.nbtwiki.net/. Finally, we provide a brief overview of insights derived from the application of DFA to ongoing oscillations in health and disease, and discuss the putative relevance of criticality for understanding the mechanism underlying scale-free modulation of oscillations.
TL;DR: CXCL4 may represent an important orchestrator of macrophage heterogeneity within atherosclerotic lesions within atherogenesis and is suggested to call these macrophages “M4.”
Abstract: During atherogenesis, blood monocytes transmigrate into the subendothelial space and differentiate towards macrophages and foam cells. The major driver of this differentiation process is macrophage colony-stimulation factor (M-CSF). M-CSF-induced macrophages are important promoters of atherogenesis as demonstrated in M-CSF and M-CSF receptor knock out mice. However, M-CSF is not the only relevant promoter of macrophage differentiation. The platelet chemokine CXCL4 prevents monocyte apoptosis and promotes macrophage differentiation in vitro. It is secreted from activated platelets and has effects on various cell types relevant in atherogenesis. Knocking out the Pf4 gene coding for CXCL4 in Apoe-/- mice leads to reduced atherogenesis. Thus, it seems likely that CXC4-induced macrophages may have specific pro-atherogenic capacities. We have studied CXC4-induced differentiation of human macrophages using gene chips, systems biology and functional in vitro and ex vivo experiments. Our data indicate that CXCL4-induced macrophages are distinct from both their M-CSF-induced counterparts and other known macrophage polarizations like M1 macrophages (induced by LPS and interferon-gamma) or M2 macrophages (induced by interleukin-4). CXCL4-induced macrophages have distinct phenotypic and functional characteristics, e.g. the complete loss of the hemoglobin-haptoglobin (Hb-Hp) scavenger receptor CD163 which is necessary for effective hemoglobin clearance after plaque hemorrhage. Lack of CD163 is accompanied by the inability to upregulate the atheroprotective enzyme heme oxygenase-1 in response to Hb-Hp complexes. This review covers the current knowledge about CXCL4-induced macrophages, which based on their unique properties we have suggested to call these macrophages “M4”. CXCL4 may represent an important driver of macrophage heterogeneity within atherosclerotic lesions. Further dissecting its effects on macrophage differentiation may help to identify novel therapeutic targets.
TL;DR: This review provides a comprehensive overview of the ecology, physiology, biochemistry, and molecular biology of the mechanisms of osmotic and ionic regulation performed by the gill.
Abstract: The crustacean gill is a multi-functional organ,and it is the site of a number of physiological processes, including ion transport, which is the basis for hemolymph osmoregulation; acid-base balance; and ammonia excretion. The gill is also the site by which many toxic metals are taken up by aquatic crustaceans, and thus it plays an important role in the toxicology of these species. This review provides a comprehensive overview of the ecology, physiology, biochemistry, and molecular biology of the mechanisms of osmotic and ionic regulation performed by the gill. The current concepts of the mechanisms of ion transport, the structural, biochemical, and molecular bases of systemic physiology, and the history of their development are discussed. The relationship between branchial ion transport and hemolymph acid-base regulation is also treated. In addition, the mechanisms of ammonia transport and excretion across the gill are discussed. And finally, the toxicology of heavy metal accumulation via the gill is reviewd in detail.
TL;DR: Age-related changes in the ER stress response and the role of the UPR in age-related diseases are discussed.
Abstract: The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases.
TL;DR: The review focuses on in vitro solubility, dialyzability, the dynamic gastrointestinal model (TIM)™, and Caco-2 cell models, and a discussion of how these methods have been applied to generate data for a range of nutrients, carotenoids, and polyphenols.
Abstract: A review of in vitro bioaccessibility and bioavailability methods for polyphenols and selected nutrients is presented. The review focuses on in vitro solubility, dialyzability, the dynamic gastrointestinal model (TIM)™, and Caco-2 cell models, the latter primarily for uptake and transport, and a discussion of how these methods have been applied to generate data for a range of nutrients, carotenoids, and polyphenols. Recommendations are given regarding which methods are most justified for answering bioaccessibility or bioavailability related questions for specific nutrients. The need for more validation studies in which in vivo results are compared to in vitro results is also discussed.
TL;DR: It is now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression and several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as Pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate Chronic pancreatitis or reduce tumor growth in pancreaticcancer.
Abstract: While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as twenty years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas - chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other additional functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumour growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.
TL;DR: The aim of this review was to examine the mechanisms by which physical activity and inactivity modify muscle fatigue and the beneficial effects of intermittent high-intensity exercise training in patients with different health conditions to demonstrate the powerful effect of exercise on health and well being.
Abstract: The aim of this review was to examine the mechanisms by which physical activity and inactivity modify muscle fatigue It is well known that acute or chronic increases in physical activity result in structural, metabolic, hormonal, neural and molecular adaptations that increase the level of force or power that can be sustained by a muscle These adaptations depend on the type, intensity and volume of the exercise stimulus, but recent studies have highlighted the role of high intensity, short duration exercise as a time-efficient method to achieve both anaerobic and aerobic/endurance type adaptations The factors that determine the fatigue profile of a muscle during intense exercise include muscle fibre composition, neuromuscular characteristics high energy metabolite stores, buffering capacity, ionic regulation, capillarization and mitochondrial density Muscle fiber type transformation during exercise training is usually towards the intermediate type IIA at the expense of both type I and type IIx myosin heavy chain isoforms High intensity training results in increases of both glycolyic and oxidative enzymes, muscle capilarization, improved phosphocreatine resynthesis and regulation of K+, H+ and lactate ions Decreases of the habitual activity level due to injury or sedentary lifestyle result in partial or even compete reversal of the adaptations due to previous training, manifested by reductions in fibre cross-sectional area, decreased oxidative capacity and capillarization Complete immobilization due to injury results in markedly decreased force output and fatigue resistance Muscle unloading reduces electromyographic activity and causes muscle atrophy and significant decreases in capillarization and oxidative enzymes activity The last part of the review discusses the beneficial effects of intermittent high intensity exercise training in patients with different health conditions to demonstrate the powerful effect exercise on health and well being
TL;DR: Current knowledge about EMV functions in the nervous system under both physiological and pathological conditions, as well as emerging EMV-based therapies that could be applied to the nervousSystem in the foreseeable future are summarized.
Abstract: Extracellular membrane vesicles (EMVs) are nanometer sized vesicles, including exosomes and microvesicles capable of transferring DNAs, mRNAs, microRNAs, non-coding RNAs, proteins, and lipids among cells without direct cell-to-cell contact, thereby representing a novel form of intercellular communication. Many cells in the nervous system have been shown to release EMVs, implicating their active roles in development, function, and pathologies of this system. While substantial progress has been made in understanding the biogenesis, biophysical properties, and involvement of EMVs in diseases, relatively less information is known about their biological function in the normal nervous system. In addition, since EMVs are endogenous vehicles with low immunogenicity, they have also been actively investigated for the delivery of therapeutic genes/molecules in treatment of cancer and neurological diseases. The present review summarizes current knowledge about EMV functions in the nervous system under both physiological and pathological conditions, as well as emerging EMV-based therapies that could be applied to the nervous system in the foreseeable future.
TL;DR: This review summarizes such FBA-based methods for integrating expression data into genome-scale metabolic network reconstructions, highlighting their advantages as well as their limitations.
Abstract: With the advent of high-throughput technologies, the field of systems biology has amassed an abundance of “omics” data, quantifying thousands of cellular components across a variety of scales, ranging from mRNA transcript levels to metabolite quantities. Methods are needed to not only integrate this omics data but to also use this data to heighten the predictive capabilities of computational models. Several recent studies have successfully demonstrated how flux balance analysis (FBA), a constraint-based modeling approach, can be used to integrate transcriptomic data into genome-scale metabolic network reconstructions to generate predictive computational models. In this review, we summarize such FBA-based methods for integrating expression data into genome-scale metabolic network reconstructions, highlighting their advantages as well as their limitations.
TL;DR: The role of exosomes in nervous system cell communication is highlighted with particular focus on exosome released by oligodendrocytes and their potential implications in axon–glia interaction and myelin disease, such as multiple sclerosis.
Abstract: Brain function depends on coordinated interactions between neurons and glial cells. Recent evidence indicates that these cells release endosome-derived microvesicles termed exosomes, which are 50-100 nm in size and carry specific protein and RNA cargo. Exosomes can interact with neighboring cells raising the concept that exosomes may mediate signaling between brain cells and facilitate the delivery of bioactive molecules. Oligodendrocytes myelinate axons and furthermore maintain axonal integrity by an yet uncharacterized pathway of trophic support. Here, we highlight the role of exosomes in nervous system cell communication with particular focus on exosomes released by oligodendrocytes and their potential implications in axon-glia interaction and myelin disease, such as multiple sclerosis. These secreted vesicles may contribute to eliminate overproduced myelin membrane or to transfer antigens facilitating immune surveillance of the brain. Furthermore, there is emerging evidence that exosomes participate in axon-glia communication.
TL;DR: The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may represent interesting novel targets for future therapeutic approaches in ALF.
Abstract: Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.
TL;DR: This paper reviews the methods used for editing of the R–R interval time series and how this editing can influence the results of heart rate (HR) variability analyses, and summarizes the pre-processing methods for HR variability signal.
Abstract: Measurement of the heart rate (HR) variability from short and long-term electrocardiographic (ECG) recordings is a non-invasive method, which can used be as a tool to evaluate cardiac autonomic regulation. HR variability can give information about the sympathetic-parasympathetic autonomic balance. One important clinical application is to measure HR variability from patients suffering acute myocardial infarction (AMI). However, HR variability signals, R-R interval time series obtained from ambulatory ECG recordings contain in most of the cases different amount of artefacts. Artefacts appear due to disturbances of either physiological or technical origin. For instance, technical artefacts may result from poorly fastened electrodes or be due to motion artefacts. Ectopic beats and atrial fibrillation are examples of biological artefacts. Since the ectopic beats and other artifacts are common phenomena in the R-R interval time series, they make a reliable analysis of the HR variability difficult or even impossible. In conjunction with the increased usage of HR variability analyses, various studies have confirmed the need of different approaches to handle artefacts in the R-R interval time series. The editing process of the R-R interval time series has become an important part of the HR variability analysis. Several different editing and HR variability signal preprocessing methods have been introduced and tested for the artefact correction. Artifact correction can be performed with different methods such as deletion, various interpolation methods and different filtering systems. However, different editing methods can have different effects on the HR variability measures. The effects of editing is depended on the study setting including the editing method, HR variability measure, type of study population, length of the R-R interval time series.
TL;DR: It is demonstrated that MVs recovery inversely correlates with viscosity and as a result, sample dilutions should be considered prior to ultracentrifugation when processing any biofluids.
Abstract: Microvesicles are nano-sized lipid vesicles released by all cells in vivo and in vitro. They are released physiologically under normal conditions but their rate of release is higher under pathological conditions such as tumors. Once released they end up in the systemic circulation and have been found and characterized in all biofluids such as plasma, serum, cerebrospinal fluid (CSF), breast milk, ascites, and urine. Microvesicles represent the status of the donor cell they are released from and they are currently under intense investigation as a potential source for disease biomarkers. Currently, the “gold standard” for isolating microvesicles is ultracentrifugation, although alternative techniques such as affinity purification have been explored. Viscosity is the resistance of a fluid to a deforming force by either shear or tensile stress. The different chemical and molecular compositions of biofluids have an effect on its viscosity and this could affect movements of the particles inside the fluid. In this manuscript we addressed the issue of whether viscosity has an effect on sedimentation efficiency of microvesicles using ultracentrifugation. We used different biofluids and spiked them with polystyrene beads and assessed their recovery using the Nanoparticle Tracking Analysis. We demonstrate that MVs recovery inversely correlates with viscosity and as a result, sample dilutions should be considered prior to ultracentifugation when processing any biofluids.
TL;DR: In vitro evidence now demonstrates that exosomes are released by neurons in a way depending on synaptic activity; these exosome can be retaken by other neurons suggesting a novel way for inter-neuronal communication.
Abstract: Exosomes are small extracellular vesicles, which stem from endosomes fusing with the plasma membrane, and can be recaptured by receiving cells. They contain lipids, proteins and RNAs able to modify the physiology of receiving cells. Functioning of the brain relies on intercellular communication between neural cells. These communications can modulate the strength of responses at sparse groups of specific synapses, to modulate circuits underlying associations and memory. Expression of new genes must then follow to stabilize the long-term modifications of the synaptic response. Local changes of the physiology of synapses from one neuron driven by another, have so far been explained by classical signal transduction to modulate transcription, translation and post-translational modifications. In vitro evidence now demonstrate that exosomes are released by neurons in a way depending on synaptic activity; these exosomes can be retaken by other neurons suggesting a novel way for interneuronal communication. The efficacy of inter-neuronal transfer of biochemical information allowed by exosomes would be far superior to that of direct cell to-cell contacts or secreted soluble factors. Indeed, lipids, proteins and RNAs contained in exosomes secreted by emitting neurons could directly modify signal transduction and protein expression in receiving cells. Exosomes could thus represent an ideal mechanism for inter-neuronal transfer of information allowing anterograde and retrograde signalling across synapses necessary for plasticity. They might also allow pathological proteins to spread across the nervous system.
TL;DR: How vector tick species occupy the habitat as a function of different climatic factors, and how these factors impact on tick survival and seasonality is discussed.
Abstract: Recent advances in climate research together with a better understanding of tick-pathogen interactions, the distribution of ticks and the diagnosis of tick-borne pathogens raise questions about the impact of environmental factors on tick abundance and spread and the prevalence and transmission of tick-borne pathogens. While undoubtedly climate plays a role in the changes in distribution and seasonal abundance of ticks, it is always difficult to disentangle factors impacting on the abundance of tick hosts from those exerted by human habits. All together, climate, host abundance and social factors may explain the upsurge of epidemics transmitted by ticks to humans. Herein we focused on tick-borne pathogens that affect humans with pandemic potential. Borrelia burgdorferi s.l. (Lyme disease), Anaplasma phagocytophilum (human granulocytic anaplasmosis) and tick-borne encephalitis virus (tick-borne encephalitis) are transmitted by Ixodes spp. Crimean-Congo hemorrhagic fever virus (Crimean-Congo hemorrhagic fever) is transmitted by Hyalomma spp. In this review, we discussed how vector tick species occupy the habitat as a function of different climatic factors, and how these factors impact on tick survival and seasonality. How molecular events at the tick-pathogen interface impact on pathogen transmission is also discussed. Results from statistically and biologically derived models are compared to show that while statistical models are able to outline basic information about tick distributions, biologically derived models are necessary to evaluate pathogen transmission rates and understand the effect of climatic variables and host abundance patterns on pathogen transmission. The results of these studies could be used to build early alert systems able to identify the main factors driving the subtle changes in tick distribution and seasonality and the prevalence of tick-borne pathogens.
TL;DR: The present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized is reviewed.
Abstract: Cardiac arrhythmias are a major cause of morbidity and mortality. In younger patients, the majority of sudden cardiac deaths have an underlying Mendelian genetic cause. Over the last 15 years, enormous progress has been made in identifying the distinct clinical phenotypes and in studying the basic cellular and genetic mechanisms associated with the primary Mendelian (monogenic) arrhythmia syndromes. Investigation of the electrophysiological consequences of an ion channel mutation is ideally done in the native cardiomyocyte environment. However, the majority of such studies so far have relied on heterologous expression systems in which single ion channel genes are expressed in non-cardiac cells. In some cases, transgenic mouse models haven been generated, but these also have significant shortcomings, primarily related to species differences. The discovery that somatic cells can be reprogrammed to pluripotency as induced pluripotent stem cells (iPSC) has generated much interest since it presents an opportunity to generate patient- and disease-specific cell lines from which normal and diseased human cardiomyocytes can be obtained These genetically diverse human model systems can be studied in vitro and used to decipher mechanisms of disease and identify strategies and reagents for new therapies. Here we review the present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized. Human iPSC (hiPSC) models have been described for the cardiac arrhythmia syndromes, including LQT1, LQT2, LQT3-Brugada Syndrome, LQT8/Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia. In most cases, the hiPSC-derived cardiomyoctes recapitulate the disease phenotype and have already provided opportunities for novel insight into cardiac pathophysiology. It is expected that the lines will be useful in the development of pharmacological agents for the management of these disorders.
TL;DR: In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients, and peripheral sympathetic discharge is also able to modulate wave reflection, which can interfere with autonomic regulation by impairing carotid baroreflex sensitivity.
Abstract: The sympathetic nervous system (SNS) is known to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular system. In the past decades increasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels. Evidence from experimental studies indicates that the SNS is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, such as nitric oxide (NO), reactive oxygen species (ROS), endothelin (ET), the renin-angiotensin system. Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SNS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute increase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects. However, direct evidence of a cause-effect relationship from human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. On the other hand, large artery stiffness can interfere with autonomic regulation by impairing carotid baroreflex sensitivity.
TL;DR: Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people.
Abstract: Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO-); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of cyclooxygenase-derived vasoconstrictor compounds; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people.
TL;DR: The current prevalence of canine and feline cardiopulmonary dirofilariasis in the European continent, the transmission vectors, the current changes in the distribution and the possible causes are reviewed, though the analysis of the epidemiological studies carried out until 2001 and between 2002 and 2011 are reviewed.
Abstract: Cardiopulmonary dirofilariasis is a cosmopolitan disease caused by Dirofilaria immitis, which affects mainly canids and felids. Moreover, it causes zoonotic infections, producing pulmonary dirofilariasis in humans. Heartworm disease is a vector-borne transmitted disease, thus transmission depends on the presence of competent mosquito species, which is directly related to favorable climate conditions for its development and survival. Cardiopulmonary dirofilariasis is mainly located in countries with temperate and tropical climates. Europe is one of the continents where animal dirofilariasis has been studied more extensively. In this article we review the current prevalence of canine and feline cardiopulmonary dirofilariasis in the European continent, the transmission vectors, the current changes in the distribution and the possible causes, though the analysis of the epidemiological studies carried out until 2001 and between 2002-2011. The highest prevalences have been observed in the southern European countries, which are considered historically endemic/hyperendemic countries. Studies carried out in the last 10 years suggest an expansion of cardiopulmonary dirofilariasis in dogs towards central and northern Europe. Several factors can exert an influence on the spreading of the disease, such as movement of infected animals, the introduction of new species of mosquitoes able to act as vectors, the climate change caused by the global warming, and development of human activity in new areas. Veterinary controls to prevent the spreading of this disease, programs of control of vectors, and adequate protocols of prevention of dirofilariasis in the susceptible species should be carried out.